Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:4]2[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[C:5]2=[N:6][N:7]=1)C.[Li+].[OH-]>C1COCC1.O.CO>[CH3:1][C:3]1[N:4]2[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[C:5]2=[N:6][N:7]=1
Reactant: CCc1nnc2n1CCC2C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1nnc2n1CCC2C(=O)O
Temperature: 60 °C

Procedure:
To a solution of ethyl 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]-triazole-7-carboxylic acid (400 mg, 2.05 mmol) in THF/water/MeOH was added LiOH (250 mg, 10.25 mmol) and the resulting solution was heated via oil bath to 60° C. for 16 h. (Round bottom was equipped with a condenser.) The solution was cooled to room temperature and concentrated to remove organic solvents. The aqueous layer was then acidified to pH of ˜5 using 2N HCl. The mixture was concentrated to dryness under vacuum, azeotroping with toluene (2×20 mL) to make sure all water was removed. The material was used without further purification with lithium chloride as a by-product. LC-MS: m/z (ES)=168 (MH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH:22]1([NH:25][C:26]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][CH:32]=[CH:31]3)=[O:27])[CH2:24][CH2:23]1>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:33]3[C:34]4[C:30](=[CH:29][C:28]([C:26](=[O:27])[NH:25][CH:22]5[CH2:24][CH2:23]5)=[CH:36][CH:35]=4)[CH:31]=[CH:32]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(NC1CC1)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(C(=O)NC5CC5)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and N-cyclopropyl-1H-indole-5-carboxamide (intermediate-11).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=1>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)=[C:6]([CH:10]=1)[C:7]([O:9][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=1)=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Fc1ccc(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccc(F)c(F)c1)c1cc(Br)ccc1OCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-bromo-2-hydroxybenzoic acid (1.8 g, 8.29 mmol) in acetone (50 ml) at room temperature was added potassium carbonate (2.87 g, 20.74 mmol) followed by 4-(bromomethyl)-1,2-difluorobenzene (2.34 ml, 18.25 mmol). The mixture was stirred at room temperature for 30 min and then heated to reflux for 15 hr. The solid was filtered off and washed with acetone (3×50 ml). The organic layer was evaporated under reduced pressure and the oil was purified by chromatography using a silica cartridge, eluting with 0-15% ethyl acetate/isohexane to give a clear oil, which solidified on standing to yield the title compound. 3.9 g.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[C:21]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].[OH-].[Na+]>>[C:21]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[CH:33][C:34]([O:37][CH2:16][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)=[CH:35][CH:36]=2)=[CH:27][CH:26]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 4′-tert-Butyl-biphenyl-4-ol from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C29H34O5 [M+NH4]+: 480, [M+Na]+: 485.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([Cl:18])[CH:20]=3)([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Cn1cc(C2C(=O)Nc3cc(Cl)ccc32)cn1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Cn1cc(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)cn1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydro-indol-2-one (0.1 g, 0.4 mmol) (from Example 14b supra), 3-chlorobenzyl bromide (0.098 g, 0.48 mmol) (Aldrich), potassium iodide (0.08 g, 0.481 mmol) and potassium carbonate (0.12 g, 0.87 mmol) in acetone (4 mL) was heated at 60° C. for 4 hours in a capped pressure tube. After cooling, the mixture was diluted with ethyl acetate and extracted with water and brine. Aqueous layers were back washed with ethyl acetate. Organic layers were combined, dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography (ethyl acetate: dichloromethane, 1:1 V/V) to give rac-6-chloro-3-(3-chloro-benzyl)-3-[1-methyl-1H-pyrazol-4-yl]-1,3-dihydro-indol-2-one as a white solid. (Yield, 0.05 g, 33%).
Reaction SMILES: [Na].[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][OH:6].F[C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[C:16]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1>CCOCC>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][O:6][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[C:16]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:17]([F:18])([F:19])[F:20])=[CH:11][CH:10]=1
Reactant: COc1ccc(C(=C(c2ccc(OC)cc2)C(F)(F)F)c2ccc(F)cc2)cc1
Reactant: CN(C)CCO
Agent: [Na]
Solvent: CCOCC
Product: COc1ccc(C(=C(c2ccc(OC)cc2)C(F)(F)F)c2ccc(OCCN(C)C)cc2)cc1
Temperature: 170 °C
Yield: 72.7 %

Procedure:
0.46 g (0.02 g.-atoms) of sodium are dissolved in 3.56 g (40 mmoles) of 2-dimethylamino-ethanol, 4.02 g (10 mmoles) of 1-(4-fluorophenyl)-3,3,3-trifluoro-1,2-bis-(4-methoxyphenyl)-propene are added, and the mixture is heated at 170° C. for one hour. The reaction mixture is cooled, diluted with 200 ml of ether, washed with water until neutral, dried and then evaporated. The residue is recrystallized from 45 ml of hexane. 3.43 g (73%) of the aimed compound are obtained; m.p.: 77°-79° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[N:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl-].C(C1C=CC=C(C(C)C)C=1[N+:62]1[CH:66]=[CH:65][N:64]([C:67]2[C:72](C(C)C)=CC=CC=2C(C)C)C=1)(C)C.O1CCOCC1>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].O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[N:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:28]2[CH:33]=[CH:32][C:31]([C:66]3[CH:65]=[N:64][CH:67]=[CH:72][N:62]=3)=[CH:30][CH:29]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1cccc(C(C)C)c1-n1cc[n+](-c2c(C(C)C)cccc2C(C)C)c1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(nnn4-c4cccc(S(C)(=O)=O)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)c1cccc(-n2nnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5cnccn5)cc4)nc32)c1
Temperature: 90 °C

Procedure:
A reaction tube is charged with 6-(4-chloro-phenyl)-3-(3-methanesulfonyl-phenyl)-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one (32 mg, 0.053 mmol), 2-chloropyrizine (12.1 mg, 0.106 mmol), Cs2CO3 (34.5 mg, 0.106 mmol), Pd2(dba)3 (5.5 mg, 0.005 mmol), 1,3-bis-(2,6-diisopropyl-phenyl)-3H-imidazol-1-ium chloride (4.7 mg, 0.011 mmol) and anhydrous 1,4-dioxane (0.5 mL). The mixture is thoroughly degassed by alternately connecting the flask to vacuum and N2 for three times. The dark red reaction mixture is then heated at 90° C. for 16 h. The reaction mixture is then cooled down to room temperature and treated with H2O (10 mL). EtOAc is used for the extraction (3×3 mL). The combined extracts are concentrated under vacuum and purified by preparative LC/MS to provide the title compound. 1H NMR (CDCl3) δ (ppm) 9.03 (s, 1H), 8.93 (s, 1H), 8.66 (s, 1H), 8.55-8.60 (m, 2H), 8.07 (d, 1H), 7.99 (d, 2H), 7.83 (t, 1H), 7.52 (d, 2H), 7.37 (d, 2H), 7.16 (d, 2H), 3.14 (s, 1H). HPLC-MS calculated C27H17ClN6O (M+H+): 477.1, found: 477.1. HPLC-MS calculated C27H18ClN7O3S (M+H+): 556.1, found: 556.1
Reaction SMILES: [CH3:1][C@:2]12[CH2:10][CH2:9][C:8]3[C:11]4[CH:12]=[CH:13][C:14]([OH:19])=[CH:15][C:16]=4[CH2:17][CH2:18][C:7]=3[C:6]1=[CH:5][CH2:4][C:3]2=[O:20]>C1C=CC=CC=1.[H][H].C>[CH3:1][C@:2]12[CH2:10][CH2:9][C:8]3[C:11]4[CH:12]=[CH:13][C:14]([OH:19])=[CH:15][C:16]=4[CH2:17][CH2:18][C:7]=3[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:20]
Reactant: [H][H]
Reactant: C[C@]12CCC3=C(CCc4cc(O)ccc43)C1=CCC2=O
Solvent: c1ccccc1
Product: C[C@]12CCC3=C(CCc4cc(O)ccc43)[C@@H]1CCC2=O
Yield: 69.5 %

Procedure:
Shake 13β-methyl-3-hydroxygona-1,3,5(10), 8,14-pentaen-17-one (0.05 g) in benzene (25 cc) in hydrogen at atmospheric pressure using a 10% palladized charcoal catalyst (0.025 g). Hydrogenation becomes very slow when 1.1 moles hydrogen has been absorbed. Filter and evaporate to obtain the title product (0.035 g), recrystallize from methanol to get pale blue crystals, m.p. 225°-228°, melting to a red liquid; ultraviolet absorption peak at 280 mμ (ε12,000).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[NH:11][C:12]1[C:13]2[N:14]([C:21]([CH3:25])=[C:22]([CH3:24])[N:23]=2)[CH:15]=[C:16]([C:18]([OH:20])=O)[CH:17]=1.F[B-](F)(F)F.[N:31]1(OC(N(C)C)=[N+](C)C)[C:35]2C=CC=CC=2N=N1.CN.C(=O)([O-])O.[Na+]>ClCCl>[OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[NH:11][C:12]1[C:13]2[N:14]([C:21]([CH3:25])=[C:22]([CH3:24])[N:23]=2)[CH:15]=[C:16]([C:18]([NH:31][CH3:35])=[O:20])[CH:17]=1
Reactant: Cc1nc2c(N[C@@H]3c4ccccc4C[C@H]3O)cc(C(=O)O)cn2c1C
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Product: CNC(=O)c1cc(N[C@@H]2c3ccccc3C[C@H]2O)c2nc(C)c(C)n2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 19 %

Procedure:
1.0 g (3.0 mmol) 8-(trans-2,3-dihydro-2-hydroxy-1-indenylamino)-2,3-dimethyl-imidazo[1,2-a]pyridine-6-carboxylic acid and 1.2 g (3.9 mmol) O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) are suspended in 50 ml dichloromethane and 0.74 ml (6.0 mmol) methylamine (8 M in ethanol) are added to the reaction mixture. After stirring for 3 d at room temperature, the reaction mixture is hydrolyzed with saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The combined organic phases are dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (20:1) and crystallization from diethyl ether/light petroleum ether yields 0.2 g (20%) of the title compound as a colourless solid (m.p. 143-144° C.).
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>>[CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)[S:46]([CH3:45])(=[O:48])=[O:47]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)S(C)(=O)=O)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 29, Step H in Step A and methylsulfonyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][CH:16]=[C:17]([C:19](OCC)=[O:20])[N:18]=2)=[CH:10][C:9]=1[CH3:24].O.[OH-].[Na+]>C1COCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][CH:16]=[C:17]([CH2:19][OH:20])[N:18]=2)=[CH:10][C:9]=1[CH3:24]
Reactant: CCOC(=O)c1coc(-c2ccc(Cl)c(C)c2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2nc(CO)co2)ccc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
46 mg (1.22 mmol) of lithium aluminum hydride are initially charged in 8.0 ml of THF and cooled to 0° C. A solution of 161 mg (0.61 mmol) of the compound from Example 26A in 2.5 ml of THF is then added dropwise. The mixture is stirred at RT for 2 h. The reaction solution is then once more cooled to 0° C., and 0.2 ml of water and 0.4 ml of 1 N aqueous sodium hydroxide solution are added. The mixture is stirred at RT overnight. The precipitate formed is filtered off, and the filtrate is freed from the solvent using a rotary evaporator. The residue is used without further purification in the subsequent reaction.
Reaction SMILES: OC[C:3]([NH:6][C:7](=[O:9])[CH3:8])([CH3:5])C.N1CC[CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1.CC#N.O.CC#N>O>[OH:17][CH2:16][CH:13]1[CH2:5][CH2:3][N:6]([C:7](=[O:9])[CH3:8])[CH2:11][CH2:12]1
Reactant: OCC1CCNCC1
Reactant: CC(=O)NC(C)(C)CO
Solvent: CC#N
Solvent: O
Product: CC(=O)N1CCC(CO)CC1

Procedure:
The title compound is prepared analogously as described for N-(2-hydroxy-1,1-dimethyl-ethyl)-acetamide from piperidin-4-yl-methanol. MS (LC-MS): [M+H]+=158.3. tR (HPLC, Waters Symmetry C18 column, 5-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 0.39 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:3]=1.[Mg].BrCCBr.[CH2:17]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[O:25])[CH:18]([CH3:20])[CH3:19].Cl>O1CCCC1.II.C(OCC)(=O)C>[CH2:17]([C:21]1[CH:22]=[C:23]([CH:24]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:3]=2)[OH:25])[CH:26]=[CH:27][CH:28]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)Cc1cccc(C=O)c1
Reactant: CC(C)Cc1cccc(Br)c1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: BrCCBr
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Cc1cccc(C(O)c2cccc(CC(C)C)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
A mixture of 1-bromo-3-isobutylbenzene (3.16 g), magnesium (1.08 g), 1,2-dibromoethane (2.78 g) and iodine (10 mg) in tetrahydrofuran (10 ml) was refluxed for 1.5 hours. The mixture was cooled to 25° C., and a solution of 3-isobutylbenzaldehyde (2.40 g) in tetrahydrofuran (10 ml) was added at 25° C. After stirred for 1 hour at the same temperature, the mixture was poured into a mixture of ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (200 g) eluting with 5% ethyl acetate in hexane to give bis(3-isobutylphenyl)methanol (2.90 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][SH:6].S(Cl)[Cl:12].SC1C=CC=C[N+]=1[O-]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][S:6][Cl:12])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: SCc1ccc(Cl)c(Cl)c1
Reactant: ClSCl
Agent: [O-][n+]1ccccc1S
Product: ClSCc1ccc(Cl)c(Cl)c1

Procedure:
3,4-Dichlorophenylmethanesulfenyl chloride is prepared from the corresponding 3,4-dichlorobenzyl mercaptan in accordance with the procedure of Example I for the preparation of the sulfenyl chloride, except that this reaction is conducted under cooling conditions. The sulfenyl chloride is reacted with the mercaptopyridine-1-oxide as described in Example I, giving an 84% yield of 3,4-dichlorobenzyl 1-oxo-2-pyridyl disulfide having a melting point of 133.0°-134.0° C. and
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:15])[N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)=[O:5])[CH3:2].[B-](F)(F)(F)[F:17].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:15])[N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:10]=1[F:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1C
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1c(F)c(C(C)(C)C)nn1C
Temperature: 80 °C
Reaction time: 12 h

Procedure:
5-tert-Butyl-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (210 mg, 1.00 mmol) was added dropwise to a stirred solution of SELECTFLUOR® (531 mg, 1.50 mmol) in anhydrous acetonitrile (4 mL) under an Ar atmosphere. The resulting mixture was then stirred at 80° C. for 12 h, then cooled to room temperature, diluted with EtOAc (2 mL), and filtered. The solvent was removed under reduced pressure and the resulting residue was chromatographed on a 24-g SiO2 pre-packed column eluting with 0:1-1:4 EtOAc/hexanes to yield 5-tert-Butyl-4-fluoro-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester. 1H-NMRH-NMR (400 MHz, CDCl3) δ: 4.37 (q, J=7.2 Hz, 2H), 4.03 (d, J=1.0 Hz, 3H), 1.39 (t, J=7.1 Hz, 3H), 1.34 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:6][NH:7][C:8](=[O:26])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][C@H:19]1[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21][CH2:20]1.C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40]>ClCCl.CN(C)C1C=CN=CC=1>[C:39]([O:25][C@@H:22]1[CH2:21][CH2:20][C@H:19]([NH:18][C:10]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:9]=2[C:8]([NH:7][CH2:6][C:5]2[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:26])[CH2:24][CH2:23]1)(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2CC[C@@H](O)CC2)cc1OC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2CC[C@@H](OC(C)=O)CC2)cc1OC
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a suspension of N-(3,4-dimethoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzamide (1.0 g) in dichloromethane (20 mL) were added triethylamine (0.49 mL) and 4-dimethylaminopyridine (284 mg), and then acetyl chloride (0.20 mL) at 20° C. The reaction mixture was stirred for 2 hours at 20° C. and then, acetyl chloride (0.05 mL) was added. After stirring for an hour at 20° C., the reaction mixture was partitioned between chloroform and 1N-hydrochloric acid. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of ethyl acetate and hexane (1:2). The residual solid was recrystallized from ethyl acetate to give 2-[cis-4-(acetoxy)cyclohexylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (429 mg) as yellow crystals.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:19](=O)([O:28][CH2:29][CH:30]1[C:43]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:37][C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:20]N1C(=O)CCC1=O>O.O1CCOCC1>[CH:42]1[C:43]2[CH:30]([CH2:29][O:28][C:19]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[O:20])[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:37][C:38]=2[CH:39]=[CH:40][CH:41]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(OCC1c2ccccc2Oc2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.4 %

Procedure:
To a suspension of 0.467 g of L-phenylalanine and 0.6 g of sodium carbonate in 6 mL of water and 6 mL of dioxane was added dropwise at 0° C. a solution of 1.0 g of succinimidyl 9-xanthenylmethyl carbonate in 10 mL of dioxane over a period of 10 minutes. The mixture was stirred at room temperature for four hours, washed with ether (2×15 mL), and the ether layer was discarded. The aqueous layer was acidified with 10% HCl (Congo Red) and extracted with EtOAc (3×15 ml). The combined organic extracts were dried over MgSO4 and the solvent was evaporated in vacuo to give 1.02 g (89.43%) of the crude Xmoc-Phe-OH as a colorless oil. Crystallization from Skelly B -EtOAc (3:1) gave 0.77 g (67.51%) of the pure Xmoc-Phe-OH as white crystals, m.p. 143°-145° C.; IR KBr: 3420 (NH and OH), 1720 (C=O)cm-1 ; 1H NMR (CDCl3): δ 2.90-3.30 (m, 2H, CH2Ar), 4.40-4.45 (m, 3H, CH--CH2O), 4.65 (m, 1H, NCH), 5.18 (b, 1H, NH), 6.85-7.60 (m, 13H, aryl); [α]23D -3.1 (c=1, EtOAc), [α]23 546 -3.4 (c=1, EtOAc).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2].C([Li:22])CCC>C1(C)C=CC=CC=1>[C:13]([C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[O:17][Li:22])([CH3:16])([CH3:15])[CH3:14]
Reactant: [Li]CCCC
Reactant: COc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Product: [Li]Oc1c(C(C)(C)C)cc(OC)cc1C(C)(C)C
Yield: 95 %

Procedure:
Both 10 mmol (2.2 g) of monocyclopentadienyl titanium chloride(CpTiCl3) and 100 ml of toluene were added to a 200 ml Schlenk reactor in the atmosphere of inert gas. Then, 10 mmol of 2,6-di-t-butyl 4-methoxy phenoxy lithium, so obtained from the reaction between 2,6-di-t-butyl 4-methoxy phenol and n-butyl lithium, was slowly added to the mixture. The reactional solution was stirred at room temperature and stood for 1 hour. After 1 hour, some mixture was collected and was analyzed by 1H-NMR spectroscopy to ascertain the reaction results.
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[OH:30][C:31]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][C:32]=1[C:33](O)=[O:34]>>[OH:30][C:31]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][C:32]=1[C:33]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:3])=[O:29])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:34]
Reactant: O=C(O)c1cc(O)ccc1O
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Product: CN(C(=O)c1cc(O)ccc1O)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 2,5-dihydroxybenzoic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(2,5-dihydroxybenzoyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 502 (M+H)+.