Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:13])[CH:3]=1.CN(C(ON1N=[N:29][C:24]2[CH:25]=[CH:26][CH:27]=[N:28][C:23]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.CN1CC[C@@H](N)C1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([NH:29][C@@H:24]2[CH2:25][CH2:26][N:28]([CH3:27])[CH2:23]2)=[O:8])=[C:4]([F:13])[CH:3]=1
Reactant: COc1cc(C(=O)O)c(F)cc1N
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN1CC[C@@H](N)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N[C@@H]2CCN(C)C2)c(F)cc1N
Reaction time: 2 h

Procedure:
4-amino-2-fluoro-5-methoxybenzoic acid (Intermediate 183; 500 mg, 2.70 mmol), HATU (1.55 g, 4.05 mmol) and (3R)-1-methylpyrrolidin-3-amine di Hydrochloride (Intermediate 184; 631 mg, 3.31 mmol) were stirred in DMF (7.5 mL) and diisopropylethylamine (2.36 ml, 13.50 mmol) added. The reaction mixture was stirred for 2 hours and then absorbed on to an SCX column, which was then washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by column chromatography (2.5% ammonia in methanol/DCM) to yield the title compound as a viscous brown oil. (662 mg, 92%).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:22].[K+]>O>[I:22][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Nc1cc(O)cc(C(F)(F)F)c1
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Oc1cc(I)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
To a stirred solution of 3-amino-5-(trifluoromethyl)phenol (42 g, 237.12 mmol, 1.00 equiv) in water (80 mL) at 0° C. was added 50% sulfuric acid (240 mL) dropwise. The resulting solution was stirred at 0° C. for 30 min. A solution of sodium nitrite (24.5 g, 355.07 mmol, 1.50 equiv) in water (90 mL) followed by a solution of potassium iodide (78.7 g) in water (80 mL) was added dropwise at 0° C. The resulting solution was stirred at 25° C. for 8 h. The reaction mixture was extracted with 2×100 mL of ethyl acetate. The combined organic layers were washed with 2×150 mL of saturated Na2SO3 solution and 2×200 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrate under reduced pressure. The residue was purified on a silica gel column eluted with 0-7% of ethyl acetate in petroleum ether to give 54 g (79%) of 3-iodo-5-(trifluoromethyl)phenol as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:26])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.Br[CH2:28][CH2:29][CH2:30][C:31](OCC)=[O:32]>>[F:1][C:2]1[CH:3]=[C:4]([N:26]2[CH2:28][CH2:29][CH2:30][C:31]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: CCOC(=O)CCCBr
Reactant: Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Product: O=C1CCCN1c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reaction time: 1 h

Procedure:
3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzenamine (110 mg, 0.304 mmol) was dissolved in ethyl 4-bromobutanoate (59 mg, 0.304 mmol) before it was placed in the microwave for 60 min at 140° C. The title compound was obtained after flash chromatography. MS (ESI) m/z: Calculated: 429.1; Observed: 430.1 (M++1).
Reaction SMILES: [CH2:1]([N:8]1[C:13]([C:14]2[C:18]([Cl:19])=[C:17]([O:20][CH:21]([F:23])[F:22])[N:16]([CH3:24])[N:15]=2)=[C:12]([F:25])[CH:11]=[C:10]([Cl:26])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>C(Cl)Cl>[CH2:1]([N:8]1[C:13]([C:14]2[C:18]([Cl:19])=[C:17]([O:20][CH:21]([F:23])[F:22])[N:16]([CH3:24])[N:15]=2)=[C:12]([F:25])[CH:11]=[C:10]([Cl:26])[C:9]1=[S:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1nc(-c2c(F)cc(Cl)c(=O)n2Cc2ccccc2)c(Cl)c1OC(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cn1nc(-c2c(F)cc(Cl)c(=S)n2Cc2ccccc2)c(Cl)c1OC(F)F
Temperature: 120 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
0.50 g of 1-benzyl-3-chloro-6-(4-chloro-5-difluoromethoxy-1-methyl-[1H]-pyrazol-3-yl)-5-fluoro-[1H]-pyridin-2-one is introduced into 5 ml of toluene, 0.63 g of Lawesson's reagent is added and the resulting yellow suspension is stirred overnight at 120° C. The next day, the mixture is cooled to 22° C., diluted with methylene chloride and, after the addition of 3 g of silica gel, concentrated to dryness in vacuo. The silica gel is applied to a flash chromatography column and eluted first with toluene/ethyl acetate 30/1 (v/v) and then with n-hexane/ethyl acetate 2/1 (v/v). 0.32 g of the desired title compound is obtained in the form of a yellow solid having a melting point of 135-138° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9]2[N:23]=[CH:22][CH:21]=[CH:20][C:10]=2[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:12][N:13]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:1][C@H:2]1[N:3]([C:8]2[N:13]=[N:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10]3[CH:20]=[CH:21][CH:22]=[N:23][C:9]=23)[CH2:4][CH2:5][N:6]([C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:38])[CH2:7]1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@@H]1CNCCN1c1nnc(-c2ccccc2)c2cccnc12
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(-c2ccccc2)c2cccnc12

Procedure:
Using methods described in Example 10 and starting with (R)-8-(2-methylpiperazin-1-yl)-5-phenylpyrido[3,2-d]pyridazine 75 (245 mg, 802 μmol), triethylamine (224 μl, 1.60 mmol), and benzoyl chloride (116 μl, 1.00 mmol) afforded (R)-(3-methyl-4-(5-phenylpyrido[2,3-d]pyridazin-8-yl)piperazin-1-yl)(phenyl)methanone 76. MS 409.2 (calc'd) 410.2 (M+H, found).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH:9]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][NH2:22])[CH2:17][CH2:16]1)=[O:14])([CH3:11])[CH3:10].[Cl:23][C:24]1[C:29]([C:30](=O)[CH3:31])=[C:28](Cl)[N:27]=[CH:26][N:25]=1>C1(C)C=CC=CC=1>[CH:9]([O:12][C:13]([N:15]1[CH2:16][CH2:17][CH:18]([N:21]2[C:28]3=[N:27][CH:26]=[N:25][C:24]([Cl:23])=[C:29]3[C:30]([CH3:31])=[N:22]2)[CH2:19][CH2:20]1)=[O:14])([CH3:11])[CH3:10]
Reactant: CC(=O)c1c(Cl)ncnc1Cl
Reactant: CC(C)OC(=O)N1CCC(NN)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1nn(C2CCN(C(=O)OC(C)C)CC2)c2ncnc(Cl)c12
Yield: 33.3 %

Procedure:
Triethylamine (0.33 mL, 2.4 mmol) was added to a stirred mixture of 4-hydrazino-piperidine-1-carboxylic acid isopropyl ester hydrochloride (Intermediate 10; 188 mg, 0.8 mmol) and 1-(4,6-dichloro-pyrimidin-5-yl)-ethanone (Intermediate 17; 150 mg, 0.8 mmol) in toluene (5 mL) at room temperature under nitrogen and the resulting mixture was heated to reflux for 8 hours. The solvent was removed in vacuo and the crude reaction mixture was purified on a flash silica column (30 mm×4″) eluting with 10-33% ethyl acetate/hexanes to give 4-(4-chloro-3-methyl-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid isopropyl ester (90 mg, 33%). 1H NMR (300 MHz, DMSO-d6) δ 1.19 (d, 6H, J=6.3 Hz), 1.86-1.99 (m, 4H), 2.63 (s, 3H), 2.94-3.10 (m, 2H), 4.04-4.15 (m, 1H), 4.74-4.82 (m, 1H), 4.91-4.98 (m, 1H), 8.77 (s, 1H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[C:18]([CH2:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22].CN([CH:26]=[O:27])C>C1COCC1>[Br:13][C:14]1[C:15]([F:22])=[C:16]([CH:17]=[C:18]([CH2:20][CH3:21])[CH:19]=1)[CH:26]=[O:27]
Reactant: CCc1ccc(F)c(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCc1cc(Br)c(F)c(C=O)c1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine (0.449 mL, 3.20 mmol) in 10 mL THF at −15° C., was added BuLi (1.6M, 1.85 mL, 2.95 mmol). The mixture was stirred 10 min at −10° C., then was cooled to −78° C. A solution of 2-bromo-4-ethyl-1-fluorobenzene (228.1) in 2 mL THF was added, then the mixture was stirred at −70° C. for 25 min. DMF (0.381 mL, 4.92 mmol) was added, then the reaction was removed from the cooling bath and stirred 30 min. The reaction was quenched with sat. NH4Cl, then was diluted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0-20% EtOAc/hexanes gradient) to afford 429 mg of Intermediate 398.1 at a colorless solid. LCMS (2 min gradient) RT=1.70 min, 231.0 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 1.25 (t, J=7.69 Hz, 3H) 2.67 (q, J=7.47 Hz, 2H) 7.61-7.66 (m, 2H) 10.33 (s, 1H).
Reaction SMILES: [OH:1][C:2]1([C:14]([F:17])([F:16])[F:15])[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[C:18]([C:22](O)=[O:23])([F:21])([F:20])[F:19]>C(Cl)Cl>[F:19][C:18]([F:21])([F:20])[C:22]([O:1][C:2]1([C:14]([F:15])([F:16])[F:17])[CH2:6][CH2:5][NH:4][CH2:3]1)=[O:23]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C(F)(F)F)C1
Solvent: ClCCl
Product: O=C(OC1(C(F)(F)F)CCNC1)C(F)(F)F

Procedure:
tert-Butyl 3-hydroxy-3-(trifluoromethyl)pyrrolidine-1-carboxylate (310 mg, 1.21 mmol) was treated with 20% CF3CO2H in CH2Cl2 for 4 h at room temperature. The volatiles were removed in vacuo to give the subtitled compound (330 mg).
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]([O:6][CH3:7])=[O:5])=O.[C:9]([NH2:12])(=[S:11])[CH3:10]>O>[CH3:10][C:9]1[S:11][C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:1][N:12]=1
Reactant: CC(N)=S
Reactant: COC(=O)C(Cl)C=O
Solvent: O
Product: COC(=O)c1cnc(C)s1
Yield: 43.6 %

Procedure:
2.0 g (14.6 mmol) methyl formylchloroacetate (A. Gangjee, A. Vidwans, E. Elzein, et. Al. J. Med. Chem. 2001, 44, 1993-2003), and 1.6 g (21.3 mmol) thioacetamide were dissolved in 10 ml water, heated, and reacted at 95° C. for 5 hr. The reaction product was extracted with ethyl acetate for 3 times, the ethyl acetate phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by a column chromatography to obtain 1.0 g methyl 2-methylthiazol-5-carboxylate (yield 43%), 1H NMR (CDCl3) 2.76 (3H, s), 3.89 (3H, s), 8.25 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17].C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[C:40]([F:43])([F:42])[F:41])[CH2:35]Br>CN(C=O)C>[Cl:1][C:2]1[N:6]2[CH:7]=[C:8]([C:11]([F:12])([F:14])[F:13])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[N:15]([CH2:35][C:34]1[CH:37]=[CH:38][C:39]([C:40]([F:41])([F:42])[F:43])=[C:32]([F:31])[CH:33]=1)[S:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(Nc1nc2ccc(C(F)(F)F)cn2c1Cl)c1ccccc1
Reactant: Fc1cc(CBr)ccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)N(Cc1ccc(C(F)(F)F)c(F)c1)c1nc2ccc(C(F)(F)F)cn2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of compound 9-E (0.015 g, 0.025 mmol) in DMF (2.0 mL) was added Na2CO3 (0.011 g, 0.099 mmol) and 3-fluoro-4-trifluoromethylbenzyl bromide (0.006 g, 0.025 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2) eluting with a gradient of 0-100% ethyl acetate in hexane to afford Compound 60 (0.008 g, 58%); MS m/z (M+H+) 552.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([OH:18])[CH2:10][CH:11]=[CH:12][CH2:13][Si](C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].[B-](F)(F)(F)[F:25].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.CCCCCC>C(#N)C.CCOCC>[F:25][CH:11]([CH:12]=[CH2:13])[CH2:10][CH:9]([OH:18])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CC=CCC(O)CCc1ccccc1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Solvent: CCCCCC
Product: C=CC(F)CC(O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
A solution of 1-phenyl-7-trimethylsilanyl-hept-5-en-3-ol (776 mg, 2.96 mmol, 1 eq) in acetonitrile (30 mL), with sodium bicarbonate (497 mg, 5.92 mmol, 2 eq), was treated with Selectflour™ (2.097 g, 5.92 mmol, 2 eq) and stirred at room temperature under an atmosphere of argon for 18 h. The reaction was then concentrated under reduced pressure and water (10 mL) was added and then extracted with ether (3×15 mL). The combined organic phases were dried over MgSO4, filtered and the solvent removed under reduced pressure. Column chromatography (hexane:ether, 95:5, 9:1, 85:15) gave 5-fluoro-1-phenylhept-6-en-3-ol as a colourless oil (397 mg, 64% yield). For major diastereomer: 1H NMR (400 MHz, CDCl3) δ 1.63-2.04 (m, 4H, CH2CHF, CH2CHOH), 2.67-2.74 (m, 1H, PhCH2), 2.78-2.86 (m, 1H, PhCH2), 3.92-3.98 major (m, 1H, CHOH), 5.05-5.20 (m, 1H, CHF), 5.22-5.27 (m, 2H, CHCH2), 5.86-5.99 (m, 1H, CHCH2), 7.19-7.33 (m, 5H, Ph); 13C NMR (100 MHz, CDCl3) δ 31.8 (PhCH2), 39.1 (PhCH2CH2), 42.4 (CHOHCH2), 67.2 (CHOH), 90.0-91.7 (d, CHF, J=165 Hz), 116.7 (CHCH2), 125.9 (Ph), 128.4 (Ph), 136.0 (CHCH2), 141.7 (Ph); 19F NMR (376.5 MHz , CDCl3) δ −177. For minor diastereomer: 1H NMR (400 MHz, CDCl3) δ 1.63-2.04 (m, 4H, CH2CHF, CH2CHOH), 2.67-2.74 (m, 1H, PhCH2), 2.78-2.86 (m, 1H, PhCH2), 3.85-3.91 (m, 1H, CHOH), 5.05-5.20 (m, 1H, CHF), 5.22-5.27 (m, 2H, CHCH2), 5.33-5.39 (m, 1H, CHCH2), 7.19-7.33 (m, 5H, Ph); 13C NMR (100 MHz, CDCl3) δ 31.8 (PhCH2), 39.1 (PhCH2CH2), 42.4 (CHOHCH2), 68.9 (CHOH), 92.3-93.9 (d, CHF, J=164 Hz), 116.7(CHCH2), 125.9 (Ph), 128.4 (Ph), 136.0 (CHCH2), 141.7 (Ph); 19F NMR (376.5 MHz, CDCl3) δ −180. IR (v, cm−1) 3418 (OH), 1651 (C═C), 1496 (Ar), 1455 (Ar); MS (GCT, CI+) m/z 226.2 [M+NH4]+ HRMS required for C13H21FON: 226.1607, found 226.1611.
Reaction SMILES: C(OC=[C:6](C)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)(=O)C.CC(CC1C=CC2OCOC=2C=1)C=[O:21]>>[C:7]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)(=[O:21])[CH3:6]
Reactant: CC(=O)OC=C(C)Cc1ccc2c(c1)OCO2
Reactant: CC(C=O)Cc1ccc2c(c1)OCO2
Product: CC(=O)c1ccc2c(c1)OCO2

Procedure:
In the step (2), 1-acetoxy-2-methyl-3-(3,4-methylenedioxyphenyl)-1-propene represented by the following formula (3) which has been obtained in the step (1) is subjected to hydrolysis reaction or to transesterification reaction with an alcohol to obtain a crude product of 1-acetyl-3,4-methylenedioxybenzene represented by the following formula (4) and 2-methyl-3-(3,4-methylenedioxyphenyl)propanal represented by the following formula (5), and then the resulting reaction mixture is further subjected to distillative purification, to thereby obtain 2-methyl-3-(3,4-methylenedioxyphenyl)propanal having a content of 1-acetyl-3,4-methylenedioxybenzene of from 50 to 3000 ppm.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([OH:49])=O)[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].O.O[N:52]1[C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=2N=N1.C1(N)CCCCC1>C1COCC1>[CH:56]1([NH:52][C:47]([C:3]2[C:4]([CH3:46])=[CH:5][C:6]3[CH2:23][C@@H:22]([OH:24])[C@:21]4([O:25][CH3:26])[C@@:8]([OH:45])([C:9](=[O:44])[C:10]5[C:19]([C:20]4=[O:27])=[C:18]([OH:28])[C:17]4[C:16](=[O:29])[CH:15]=[C:14]([NH:30][CH:31]6[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]6)[C:13](=[O:43])[C:12]=4[CH:11]=5)[C:7]=3[C:2]=2[OH:1])=[O:49])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:55]1
Reactant: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)O)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Reactant: On1nnc2ccccc21
Solvent: NC1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)NC6CCCCC6)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (60 mg, 0.09 mmol) in THF (2 mL) was added polystyrene-carbodiimide (156 mg, 0.18 mmol), 1-hydroxybenzotriazole hydrate (24 mg, 0.18 mmol) and cyclohexylamine (10 mg, 0.13 mmol). The reaction mixture was stirred at room temperature under nitrogen for 4 h. The reaction was filtered through a micro filter and concentrated. The crude material was purified by preparative HPLC (10:90 acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10 min, then isocratic) to afford (6R,6aS,14aR)—N-cyclohexyl-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide as a mixture of diastereomers (14 mg, 20%) and as a dark red solid: 1H NMR (500 MHz, CD3OD) δ 8.10 (s, 1H), 6.59 (s, 1H), 6.15 (s, 0.3H), 6.00 (s, 0.7H), 5.19 (s, 0.3H), 4.95 (s, 0.7H), 4.89 (br s, 1H), 3.95-3.90 (m, 1H), 3.75 (s, 3H), 3.74-3.71 (m, 0.7H), 3.70-3.68 (m, 0.3H), 3.67-3.64 (m, 1H), 3.58 (s, 3H), 3.53 (s, 1H), 3.50 (s, 2H), 3.48-3.35 (m, 5H), 3.27-3.20 (m, 1H), 3.09-3.02 (m, 1H), 2.22 (s, 3H), 1.93-1.81 (m, 2H), 1.80-1.69 (m, 2H), 1.66-1.57 (m, 1H), 1.40-1.33 (m, 2H), 1.27 (d, J=6.5 Hz, 2H), 1.22 (d, J=6.5 Hz, 1H), 1.19-1.15 (m, 2H); MS (ESI+) m/z 765 (M+H); HPLC 95.4% (AUC), tR 13.79 min.
Reaction SMILES: [CH2:1]([C:13]1[CH:17]=[C:16]([CH2:18][C:19]([OH:21])=O)[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[CH3:23][O:24][C:25]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[C:26]=1[NH2:27].C(N(CC)CC)C>O1CCCC1.ClCCl>[CH2:1]([C:13]1[CH:17]=[C:16]([CH2:18][C:19]([NH:27][C:26]2[C:28]([O:34][CH3:35])=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:25]=2[O:24][CH3:23])=[O:21])[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1cc(CC(=O)O)on1
Reactant: COc1cc(OC)c(N)c(OC)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCc1cc(CC(=O)Nc2c(OC)cc(OC)cc2OC)on1
Reaction time: 2 h

Procedure:
To a stirred, room temperature solution of 3-dodecyl-5-isoxazole acetic acid (0.64 g, 0.0022 mol) in dry tetrahydrofuran (20 mL) under nitrogen was added in one portion, 1,1-carbonyldiimidazole (0.38 g, 0.0024 mol), and the mixture was stirred for 2 hours. To this solution was added 2,4,6-trimethoxyaniline hydrochloride (0.48 g, 0.0022 mol) and triethylamine (0.33 mL, 0.0024 mol) in THF (30 mL). The mixture was stirred for 2 days and allowed to cool. The solution was rotoevaporated and the residue dissolved in dichloromethane. The solid was filtered through silica gel (77 g, 70-230 mesh) using petroleum ether-acetone (4:1, 35×75 mL) and the filtrate rotoevaporated to an oil. The oil was dried in vacuo. The oil crystallized to give a pale yellow waxy solid; yield 0.96 g (96%); mp 107°-109° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:52])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:49][CH3:50])([C:27]3[CH:32]=[CH:31][C:30]([C:33]#[C:34][C:35]([O:44]COC)([C:40]([F:43])([F:42])[F:41])[C:36]([F:39])([F:38])[F:37])=[C:29]([CH3:48])[CH:28]=3)[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])[CH:17]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:8][O:9][C:10](=[O:52])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:25][CH3:26])([C:27]3[CH:32]=[CH:31][C:30]([C:33]#[C:34][C:35]([OH:44])([C:36]([F:37])([F:39])[F:38])[C:40]([F:42])([F:43])[F:41])=[C:29]([CH3:48])[CH:28]=3)[CH2:49][CH3:50])=[CH:20][C:19]=2[CH3:51])[CH:17]=1
Reactant: CCC(CC)(c1ccc(C#CC(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(C#CC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.4 %

Procedure:
Trifluoroacetic acid (0.20 mL) was added to a solution of [5-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 80-(1); 36.0 mg, 0.0566 mmol) in dichloromethane (1.0 mL) at 0° C., and the mixture was stirred at room temperature for three hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (34.3 mg, 99%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:11])=[CH:5][C:6]=1[S:7]([NH2:10])(=[O:9])=[O:8].[OH-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1.Cl>CC(C)=O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:10][S:7]([C:6]2[CH:5]=[C:4]([CH3:11])[S:3][C:2]=2[CH3:1])(=[O:9])=[O:8])=[O:23])=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cc1cc(S(N)(=O)=O)c(C)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1cc(S(=O)(=O)NC(=O)Nc2ccc(Cl)cc2)c(C)s1

Procedure:
The procedure of Example 4B was followed with 2,5-dimethyl-3-thiophenesulfonamide (1.73 g, 9.06 mmole), acetone (10 ml), 1N NaOH (9.1 ml), 4-chlorophenyl isocyanate (1.39 g, 9.0 mmole), 1N HCl (9.1 ml). The aqueous layer was extracted with two 100 ml aliquots of ethyl acetate, which were combined and washed with 50 ml of water. The organic layer was then dried over Na2SO4. The solvent was removed and the residue chromatographed using a mixture of 4% methanol/methylene chloride as the eluent over a 50 mm silica gel column. The solvent was removed to provide the named product.
Reaction SMILES: Br[CH:2]([C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:18](=[S:21])([S-:20])[NH2:19].[NH4+]>C(O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[N:19]=[C:18]([SH:21])[S:20][C:2]=2[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:11][CH:12]=1
Reactant: NC(=S)[S-]
Reactant: CCOC(=O)CC(Br)C(=O)c1ccc(Cl)cc1
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)Cc1sc(S)nc1-c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 80 %

Procedure:
50.0 g. (0.157 m.) 3-bromo-3-p-chlorobenzoylpropionic acid, ethyl ester and 17.5 g. (0.157 m.) ammonium dithiocarbamate in 500 ml. absolute ethanol are heated at gentle reflux for 5 hours. The reaction mixture is allowed to stand at room temperature overnight. The solid which results is dissolved in 800 ml. of methylene chloride and the solution is washed with 500 ml. of water. The methylene chloride layer is dried over anhydrous magnesium sulfate, and after removal of the methylene chloride the residual solid is recrystallized from ethanol. 39.2 g. (80% yield) of title product is obtained, m.p. 176°-178° C.