Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[N:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([NH:23][C:35]([C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[NH:26][N:27]=2)=[O:36])=[CH:24][CH:25]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OCc2ccccc2)cc1)c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
DIEA (9.3 mL, 53.4 mmol) was added to a solution of 4-benzyloxyaniline hydrochloride (4.0 g, 17.0 mmol), indazole-3-carboxylic acid (2.89 g, 17.8 mmol) and HBTU (7.1 g, 18.7 mmol) in DMF (60 mL), and the resulting solution was stirred at ambient temperature for 24 hours. The solution was heated to 70° C. for 4 hours, and then poured into a mixture of saturated aqueous sodium bicarbonate on ice. The product, an off white solid, 6.0 g, was collected by filtration, washed with water and used without further purification in the subsequent reaction. MS m/z 344 (MH+). 1H NMR (DMSO-d6) δ 5.11 (s, 2H), 7.02 (d, 2H), 7.26-7.48 (m, 7H), 7.67 (d, 1H), 7.75 (d, 2H), 7.81 (d, 1H), 8.24 (d, 1H) and 10.24 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:23])=[C:6]([CH:22]=1)[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[Cl:23][C:5]1[CH:4]=[CH:3][C:2]([C:29]2[CH:30]=[CH:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=2)=[CH:22][C:6]=1[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:29]2[CH:30]=[CH:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=2)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(N[C@@H](Cc1ccc(Br)cc1)C(=O)O)c1cc(Br)ccc1Cl
Product: O=C(N[C@@H](Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1Cl
Yield: 91.7 %

Procedure:
(2S)-(5-Bromo-2-chloro-benzoyl-amino)-3-(4-bromo-phenyl)-propionic acid (100 mg, 0.21 mmol) was reacted with 4-trifluoromethyl-phenyl-boronic acid (243 mg, 1.2 mmol) by following general procedure D yielding the title compound (114 mg, 75%) as a light yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[N:22][N:23]([CH3:25])[N:24]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[CH3:25][N:23]1[N:22]=[N:21][C:20]([C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:19][CH:18]=2)=[N:24]1
Reactant: Cn1nnc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1nnc(-c2ccc(N3CCNCC3)cc2)n1

Procedure:
Prepared in analogy to example 4.4 (b) from 4-[4-(2-Methyl-2H-tetrazol-5-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester and hydrochloric acid in dioxane. MS (m/e): 245.1 (MH+, 100%)
Reaction SMILES: [CH3:1][Si:2]([CH:5]=[N+:6]=[N-:7])([CH3:4])[CH3:3].C([Li])CCC.C1(S([CH:22]=[CH:23][C:24]2[CH:25]=[CH:26][C:27]3[S:32][C:31]4[N:33]=[CH:34][CH:35]=[N:36][C:30]=4[N:29]([CH2:37][O:38][CH3:39])[C:28]=3[CH:40]=2)(=O)=O)C=CC=CC=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]1[C:23]([C:24]2[CH:25]=[CH:26][C:27]3[S:32][C:31]4[N:33]=[CH:34][CH:35]=[N:36][C:30]=4[N:29]([CH2:37][O:38][CH3:39])[C:28]=3[CH:40]=2)=[CH:22][NH:7][N:6]=1
Reactant: COCN1c2cc(C=CS(=O)(=O)c3ccccc3)ccc2Sc2nccnc21
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCN1c2cc(-c3c[nH]nc3[Si](C)(C)C)ccc2Sc2nccnc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1.5 ml of a 2.0 M solution of (trimethylsilyl)-diazomethane in hexane was added to dry tetrahydrofuran (7 ml) in a nitrogen atmosphere and cooled to −78° C. After dropping 1.0 ml of a 1.6 M n-butyllithium solution in n-hexane thereinto, the resulting mixture was stirred for 30 minutes. Into the reaction mixture was dropped a solution of 410 mg of 8-(2-benzenesulfonylvinyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine obtained in Example 1080-1 in dry tetrahydrofuran (5 ml). Then the reaction mixture was gradually heated to room temperature and an aqueous solution of ammonium chloride was added thereto followed by extraction with ethyl acetate. Then the mixture was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluted with ethyl acetate/n-hexane) to thereby give 130 mg of the title compound as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:4]2[CH2:5][C:6]3[C:10]([CH:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12]([NH:14][NH2:15])=[O:13].[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([CH3:27])[N:26]=1)[C:21](O)=O>>[Cl:17][C:18]1[CH:19]=[C:20]([C:21]2[O:13][C:12]([C:7]3[S:8][C:9]([CH3:11])=[C:10]4[C:6]=3[CH2:5][C@H:4]3[C:2]([CH3:16])([CH3:1])[C@H:3]34)=[N:14][N:15]=2)[CH:24]=[C:25]([CH3:27])[N:26]=1
Reactant: Cc1sc(C(=O)NN)c2c1C1C(C2)C1(C)C
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Product: Cc1cc(-c2nnc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)o2)cc(Cl)n1

Procedure:
2-Chloro-6-methyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine is synthesized from 1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid hydrazide and 2-chloro-6-methyl-isonicotinic acid in analogy to Example 5; LC-MS: tR=1.17 min, [M+1]=374.22.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][C:12]3[N:15]=[C:16]([NH2:18])[S:17][C:11]=3[CH2:10]2)=[N:7][CH:8]=1.[CH:21]([C:32](OCC)=[O:33])([C:27](OCC)=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1(C)C(C)=CC=CC=1>[CH2:25]([O:24][C:22]([C:21]1[C:27](=[O:28])[N:15]2[C:16]([S:17][C:11]3[CH2:10][N:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:8][N:7]=4)[CH2:14][CH2:13][C:12]=32)=[N:18][C:32]=1[OH:33])=[O:23])[CH3:26]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: Nc1nc2c(s1)CN(c1ccc(C(F)(F)F)cn1)CC2
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1c(O)nc2sc3c(n2c1=O)CCN(c1ccc(C(F)(F)F)cn1)C3
Temperature: 145 °C
Reaction time: 0.25 h
Yield: 15.5 %

Procedure:
The mixture of 5-(5-trifluoromethyl-pyridin-2-yl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylamine (5.7 gm, 0.019 mol) and triethyl methantricarboxylate (16.1 ml, 0.076 mol) in xylene (100 ml) was heated at 140-150° C. for 6 hours. Xylene was evaporated and diethyl ether was then added and the suspension was stirred for 15 minutes. It was filtered and washed with ether. The crude solid was digested with dichloromethane (200 ml) and filtered to remove insoluble residue. Dichloromethane layer was distilled off under vacuum to give 1.3 gm of title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)[N:5]=[C:4]([NH:14][C@H:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH3:16])[N:3]=1.[NH2:24][C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C@@H:15]([NH:14][C:4]2[N:3]=[C:2]([NH:24][C:25]3[CH:30]=[N:29][CH:28]=[CH:27][N:26]=3)[CH:7]=[C:6]([N:8]3[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]3)[N:5]=2)[CH3:16])=[CH:18][CH:19]=1
Reactant: Nc1cnccn1
Reactant: Cc1cn(-c2cc(Cl)nc(N[C@@H](C)c3ccc(F)cc3)n2)cn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cn(-c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)n2)cn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
60 mg of (S)-4-chloro-N-[1-(4-fluorophenyl)ethyl]-6-(4-methyl-1H-imidazol-1-yl)pyrimidine-2-amine, 19 mg of 2-aminopyrazine, 17 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 35 mg of sodium t-butoxide and 9 mg of tris(dibenzylideneacetone)dipalladium were added in turn to 2 ml of degassed toluene, and the mixture was stirred at 100° C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 69 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-6-(4-methyl-1H-imidazol-1-yl)-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain 48 mg of the objective compound as pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[CH:4][C:3]=1[CH:16]([CH3:35])[C:17]([OH:34])([C:22]1[CH:23]=[CH:24][C:25]2[O:30][CH2:29][C:28](=[O:31])[N:27]([CH3:32])[C:26]=2[CH:33]=1)[C:18]([F:21])([F:20])[F:19].[C:36]([C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1)([OH:38])=[O:37]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:43]2[CH:42]=[CH:41][CH:40]=[C:39]([C:36]([OH:38])=[O:37])[CH:44]=2)=[CH:4][C:3]=1[CH:16]([CH3:35])[C:17]([OH:34])([C:22]1[CH:23]=[CH:24][C:25]2[O:30][CH2:29][C:28](=[O:31])[N:27]([CH3:32])[C:26]=2[CH:33]=1)[C:18]([F:21])([F:20])[F:19]
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: CC(c1cc(OS(=O)(=O)C(F)(F)F)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Product: CC(c1cc(-c2cccc(C(=O)O)c2)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 17, step 2, trifluoromethanesulfonic acid 4-chloro-3-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-propyl]-phenyl ester (Example 17, step 1) was reacted with 3-carboxyphenylboronic acid to give the title compound as a light brown solid. MS (m/e, ISP neg. ion)=518.2 [M−H+].
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[Cl:16][C:17]1[N:18]=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=1.[CH3:24][Si:25](Cl)([CH3:27])[CH3:26]>C1COCC1>[Cl:16][C:17]1[N:18]=[N:19][C:20]([Cl:23])=[CH:21][C:22]=1[Si:25]([CH3:27])([CH3:26])[CH3:24]
Reactant: Clc1ccc(Cl)nn1
Reactant: C[Si](C)(C)Cl
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(Cl)nnc1Cl
Temperature: -78 °C
Reaction time: 0.29 h
Yield: 91.6 %

Procedure:
A four-neck flask equipped with a mechanical stirrer, thermowell, and addition funnel was charged with 2,2,6,6-tetramethylpiperidine (25.1 mL, 147.7 mmol) and anhydrous THF (200 mL). The solution was cooled to −10° C.-0° C. and n-BuLi (2.5 M in hexanes, 59 mL, 147.7 mmol) was added over 10 min. The solution was stirred for 15-20 min then further cooled to −78° C. A mixture of freshly purified 3,6-dichloro-pyridazine (10 g, 67.1 mmol) and trimethylsilyl chloride (9.3 mL, 73.8 mmol) in THF (100 mL) was added dropwise via an addition funnel. The dark red solution was stirred at −78° C. for 1 hr, at which point the reaction was complete. The reaction was quenched cold with saturated ammonium chloride solution (100 mL) and immediately diluted with MTBE (200 mL). The layers were separated while still cold (additional water was added if necessary until all solids dissolved) and the aqueous phase was washed with MTBE (100 mL). The combined organic solution was washed with dilute citric acid solution (30 mL portions) until the aqueous washes were pH 6-7. The organic solution was then washed with brine, dried over Na2SO4, and concentrated to a residue. The crude material was purified by column chromatography on silica gel (100 g, 2:1 heptane:EtOAc) to provide 13.6 g of 20 as a reddish oil.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(=O)([O-])[O-].[K+].[K+].Br[CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]1>CC(C)=O>[CH:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH:22]1[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]1)=[O:9]
Reactant: O=Cc1ccccc1O
Reactant: BrC1C=CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccccc1OC1C=CCCC1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
In a 10-liter reactor there were introduced 633.4 g (5.19 moles) of salicylaldehyde, 5 liters of acetone and 717.3 g of potassium carbonate, and the mixture was left with stirring at room temperature. After precipitation of the phenate, 836 g (5.19 moles) of 3-bromocyclohexene were rapidly added dropwise, and the mixture was brought to reflux for 21/2 hours. After removal of the inorganic salts by filtration, and evaporation of the solvent, the residue was taken up in ethyl ether, washed with 10% caustic soda and then water, and the ether phase was then dried over Na2SO4. After filtration and elimination of the ether, there were obtained 975 g of 3-(2-formylphenoxy)cyclohexene, which was used directly in the following stage.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=[C:5]([CH3:11])[N:4]=1)[CH3:2]>C(Cl)Cl.O=[Mn]=O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH:9]=[O:10])[CH:6]=[C:5]([CH3:11])[N:4]=1)[CH3:2]
Reactant: CCc1cc(CO)cc(C)n1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCc1cc(C=O)cc(C)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 107.2 %

Procedure:
A solution of crude (2-ethyl-6-methyl-pyridin-4-yl)-methanol (453.6 mg, 3 mmol) in DCM (30 mL) and MnO2 (2.6 g, 30 mmol) is added. The mixture is stirred at rt for 15 h, filtered and evaporated (130 mbar, 45° C.) to give crude 2-ethyl-6-methyl-pyridine-4-carbaldehyde (0.48 g); 1H NMR (CDCl3): δ 10.02 (s, 1H), 7.37 (s, 2H), 2.89 (q, J=7.6 Hz, 2H), 2.64 (s, 3H), 1.33 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[C:9]([F:16])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29]CC)=[O:28].[OH-].[Na+].Cl>O.CN(C=O)C>[Br:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[C:9]([F:16])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[C:4]([O:18][CH2:26][C:27]([OH:29])=[O:28])[CH:3]=1
Reactant: O=c1c2cc(O)cc(Br)c2oc2cccc(F)c12
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)COc1cc(Br)c2oc3cccc(F)c3c(=O)c2c1
Reaction time: 4 h
Yield: 67.4 %

Procedure:
A mixture of 4-bromo-8-fluoro-2-hydroxy-9-oxo-9H-xanthene (1.5 g), potassium carbonate (3.4 g), ethyl bromoacetate (4.2 g) and DMF (60 ml) was stirred at 60°-65° C. for 4 hours. After cooling the mixture, sodium hydroxide (2 g) and water (100 ml) were added and the resulting mixture was stirred at 90°-100° C. for 30 minutes. After cooling, the mixture was rendered acidic with hydrochloric acid and the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 1.2 g of 4-bromo-8-fluoro-9-oxo-9H-xanthene-2-yloxyacetic acid. m.p. 220°-223° C. This compound gave a mass spectrum having a molecular ion peak at m/e 366.
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1)[C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]=[O:22])=[CH:19][CH:20]=1)[C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: CN(Cc1ccc(CO)cc1)c1nc(-c2ccccc2)cs1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: CN(Cc1ccc(C=O)cc1)c1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.1 %

Procedure:
To a solution of 4-[[methyl(4-phenyl-2-thiazolyl)amino]methyl]benzenemethanol (1.0 g, 3.2 mmol) in ethyl acetate (40 mL) was added manganese dioxide (4.0 g), and the mixture was stirred at room temperature for 3 hrs. Insoluble material was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5:1) to give the title compound (0.80 g, yield 81%). oil.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[NH:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][CH:11]=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:11]1[CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:14][C:10]=1[CH3:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1ccc(C)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(Cl)c(C)[nH]1
Temperature: 40 °C
Reaction time: 4 h
Yield: 37.8 %

Procedure:
N-Chlorosuccinimide (0.67 g, 5.08 mmol) was added to a solution of ethyl 5-methyl-1H-pyrrole-2-carboxylate (Intermediate 29, 0.65 g, 4.23 mmol) in chloroform (20 ml). The reaction was warmed to 40° C. and stirred for 4 h, then poured to a beaker containing 2 N NaOH (20 ml) at 0° C. The layers were separated and the aqueous layer was extracted with chloroform 3 times. The combined organic extracts were dried over magnesium sulfate and concentrated. The resultant off-white solid was purified by flash chromatography (hexanes/EtOAc, 16:1) to give the title product as a white solid (0.3 g, 38%). MS (ES): 188 (M+1) for C8H10ClNO2; NMR (CDCl3): 1.34 (t, 3H), 2.27 (s, 3H), 4.30 (q, 2H), 6.76 (s, 1H), 9.07 (brs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:60])[C@@H:4]([CH3:59])[NH:5][C:6](=[O:58])[C@H:7]([CH2:49][O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[NH:8][C:9](=[O:48])[C@@H:10]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:36][CH:35]=1)[NH:11][C:12](=[O:32])[C@H:13]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[NH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16].[CH2:61](OC(N[C@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1)=O)[C:62]1C=CC=C[CH:63]=1.C1(N=C=NC2CCCCC2)CCCCC1.C(ON[C@H](C(N[C@@H](C(N[C@H](C(N[C@@H](C(O)=O)C)=O)COCC1C=CC=CC=1)=O)CC1C=CC(OCC2C=CC=CC=2)=CC=1)=O)C(=C=O)C1C2C(=CC=CC=2)NC=1)C1C=CC=CC=1>CN(C)C=O.CO.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:60])[C@@H:4]([CH3:59])[NH:5][C:6](=[O:58])[C@H:7]([CH2:49][O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[NH:8][C:9](=[O:48])[C@@H:10]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:38][CH:39]=1)[NH:11][C:12](=[O:32])[C@H:13]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[NH:14][C:15]([O:17][CH2:18][C:19]1[CH:63]=[CH:62][CH:61]=[CH:21][CH:20]=1)=[O:16]
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Reactant: CCCCOC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@H](C)C(=O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[C@@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@@H](NOCc1ccccc1)C(=C=O)c1c[nH]c2ccccc12)C(=O)O
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1

Procedure:
Nα-t-Butoxycarbonyl-O-benzyl-O-tyrosyl-O-benzyl-L-seryl-D-alanine resin (Example 11), 6.4 g., 5.1 mmol, is coupled with 2.23 g., 6.3 mmol, of Nα-benzyloxycarbonyl-L-tryptophan and 1.3 g., 6.3 mmol, of dicyclohexylcarbodiimide according to the general procedure of Example 1. The resulting Nα-benzyloxy-carbonyl-L-tryptophyl-O-benzyl-D-tyrosyl-O-benzyl-L-seryl-D-alanine resin is mixed with 20 ml. of triethylamine, 150 ml. of methanol and 50 ml. of dimethylformamide and let stand overnight. After filtration and evaporation, the crude product is triturated with either-petroleum ether and crystallized from isopropanol; 1.75 g.; [α]D 23 -5° (c. 1.01, DMF).
Reaction SMILES: [Li+].[OH-].[CH3:3][N:4]([CH3:25])[C:5]([C:7]1[CH:8]=[CH:9][C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH:16]=1)[C:12]([O:14]C)=[O:13])=[O:6].Cl>O.O1CCCC1>[CH3:3][N:4]([CH3:25])[C:5]([C:7]1[CH:8]=[CH:9][C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH:16]=1)[C:12]([OH:14])=[O:13])=[O:6]
Reactant: COC(=O)c1cc(C(=O)N(C)C)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of LiOH (585 mg, 13.95 mmol) in water (8 ml) was added to a stirred solution of methyl 5-[(dimethylamino)carbonyl]-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 58; 437 mg, 1.40 mmol) in tetrahydrofuran (2 ml) at room temperature. The mixture was stirred at room temperature for 3 h. The mixture was acidified with HCl (6 mol/l) and extracted with ethyl acetate (3×40 ml). The organic phase was washed with saturated brine (25 ml), dried over sodium sulfate, and evaporated in vacuo to give the crude product as a white solid. 350 mg.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([C:14]1[S:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:17][CH:18]=1)=[O:13].Br[C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[F:8][C:7]1[C:2]([F:1])=[C:3]([CH2:10][CH2:11][C:12](=[O:13])[C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)[CH:4]=[CH:5][C:6]=1[O:9][C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: O=C(CCc1ccc(O)c(F)c1F)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(F)c1F

Procedure:
Tert-butyl 2-(2,3-difluoro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoate is prepared from 3-(2,3-difluoro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and tert-butyl bromoisobutyrate according to general procedure D.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]([CH:5]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH2:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20](O)=[O:21])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1)=[O:4].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.Cl.[CH2:66]([O:73][NH2:74])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>CN(C=O)C>[CH2:66]([O:73][NH:74][C:20]([CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH:5]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:27])=[O:28])[C:3]([N:2]([CH3:36])[CH3:1])=[O:4])=[CH:24][CH:23]=2)=[CH:13][CH:14]=1)=[O:21])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: Cc1ccc(S(=O)(=O)NC(Cc2ccc(Oc3ccc(CCC(=O)O)cc3)cc2)C(=O)N(C)C)cc1
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NC(Cc2ccc(Oc3ccc(CCC(=O)NOCc4ccccc4)cc3)cc2)C(=O)N(C)C)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 78.3 %

Procedure:
The acid compound 25 (0.85 g, 1.66 mmol) was dissolved in dry DMF (20 mL) and cooled to 0-5° C. 1-Hydroxybenzotriazole (0.25 g, 1.82 mmol), EDCI (0.32 g, 1.66 mmol), and triethylamine (0.7 mL, 5.0 mmol) were added to the above mixture followed by stirring for 15 min. O-Benzylhydroxylamine hydrochloride (0.3 g, 1.83 mmol) was added and the mixture was allowed to come to room temperature and stirred for 18 h. The solvent was evaporated under reduced pressure and the residual oil was taken up in EtOAc (50 mL). The organic layer was extracted with 2.0 M HCl (1×10 mL), saturated NaHCO3 (1×10 mL), and brine (1×25 mL). The resulting EtOAc layer was dried and concentrated to yield the crude product. Flash chromatography on silica gel (hexanes:ethyl acetate—1:1 containing 1% acetic acid) yielded the desired benzyl hydroxamate 26 (0.8 g, 78%). 1H NMR (400 MHz, DMSO-d6): 8.06 (d, J=9.6 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.30-7.36 (m, 5H), 7.29 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.09 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 6.81 (d, J=8.8 Hz, 2H), 4.72 (s, 2H), 4.26-4.32 (m, 1H), 2.75-2.82 (m, 3H), 2.68 (s, 3H), 2.57-2.63 (dd, J=13.6 and 7.6 Hz, 1H), 2.35 (s, 3H), 2.25 (t, J=7.2 Hz, 2H).