Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH:16]=[O:17])[CH2:12][CH2:11]1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:11][CH2:12][N:13]([CH:16]=[O:17])[CH2:14][CH2:15]1
Reactant: O=CN1CCN(c2ccccc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1N1CCN(C=O)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.8 %

Procedure:
A mixture of the 4-(2-nitrophenyl)piperazine-1-carbaldehyde (3.57 g, 15.2 mmol), obtained as in the proceeding paragraph, 10% palladium on carbon and ethanol (50 mL) was stirred approximately 12 hours at 25° C. under a hydrogen atmosphere (15 psi). The reaction mixture then was filtered and concentrated to give 4-(2-aminophenyl)piperazine-1-carbaldehyde (2.91 g, 14.1 mmol), m.p. 129°-133° C.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]1[C:12](OCC)=[O:13].[NH3:18]>C(O)C>[CH3:2][C:3]1([CH3:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]1[C:12]([NH2:18])=[O:13]
Reactant: CCOC(=O)C1Nc2ccccc2C1(C)C
Reactant: N
Agent: Cl
Solvent: CCO
Product: CC1(C)c2ccccc2NC1C(N)=O

Procedure:
The solution of 1 g of ethyl 3,3-dimethylindoline-2-carboxylate hydrochloride in 25 ml of ethanol is saturated with anhydrous ammonia and heated in a closed vessel to 50° for 4 days. It is evaporated, the residue crystallized from diethyl ether, suspended in water and 3N aqueous sodium hydroxide is added to render the mixture basic. It is extracted with methylene chloride, the extract dried and evaporated, to yield the 3,3-dimethylindoline-2-carboxamide melting at 156°-158°.
Reaction SMILES: C1[C:10]2[C:5](=C[C:7]([C:11]([O:13]C)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:15]([O:17]C)=[O:16].C(OC)(=O)CCCCCCCCC(OC)=O.[OH:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([C:45]2[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=2)([CH3:44])[CH3:43])=[CH:38][CH:37]=1.O=[Sb]O[Sb]=O.P(OC)(OC)(OC)=O>C(O)CO.O.O.O.O.C([O-])(=O)C.[Mn+2].C([O-])(=O)C.CO>[C:15]([OH:17])(=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:10][CH2:9][CH2:8][CH2:7][C:11]([OH:13])=[O:12].[OH:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]([C:45]2[CH:46]=[CH:47][C:48]([OH:51])=[CH:49][CH:50]=2)([CH3:44])[CH3:43])=[CH:40][CH:41]=1
Reactant: COC(=O)c1ccc2cc(C(=O)OC)ccc2c1
Agent: [Mn+2]
Agent: CC(=O)[O-]
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: COP(=O)(OC)OC
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCCCC(=O)O

Procedure:
Dimethyl 2,6-naphthalenedicarboxylate and dimethyl sebacate were dispersed in ethylene glycol and an addition product of two ethylene oxides tobisphenol A (BPA•2EO). Then, 0.029 part of manganese acetate tetrahydrate, 0.028 parts of antimony trioxide and 0.1% of spherical silica particles having a mean particle size of 0.3 μm were added to 100 parts of the total of dimethyl 2,6-naphthalenedicarboxylate and dimethyl sebacate, and heated with stirring to conduct the reaction. The temperature was elevated to 235° C. while removing methanol produced as a by-product. After the by-production of methanol was completed, 0.03 part of trimethyl phosphate was added thereto. Then, the pressure was reduced to 0.3 Torr while elevating the temperature to 285° C. to conduct the polymerization by changing the reaction time. Dyes described in JP-A-7-168309, compounds I-6 and I-24, were each further added to the solid matter in an amount of 54 ppm. The copolymerization composition ratios of sebacic acid (SA) and BPA•2EO and the intrinsic viscosities of polyesters thus obtained are shown in Table II-1.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[C:19]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17]([CH3:32])[C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:13][CH2:14][O:15][CH3:16])=[C:9]([CH:12]=1)C=O.C1C=C(Cl)C=C(C(OO)=[O:41])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:32][C:17]1[CH:18]=[C:19]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:23]([CH3:25])[CH3:24])[CH:26]([CH3:27])[CH3:28])[CH:20]=[C:2]([CH3:1])[C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:13][CH2:14][O:15][CH3:16])=[C:9]([OH:41])[CH:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCOc1ccc(Cc2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc1C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCOc1ccc(Cc2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
To 5-(2,6-dimethyl-4-triisopropylsilanyloxybenzyl)-2-methoxymethoxy-benzaldehyde (compound 15, step e; 0.460 g, 1.01 mmol) in dichloromethane 30 mL was add mCPBA (0.870 g, 2.52 mmol) and saturated sodium bicarbonate solution (2 mL). After stirring at rt overnight, the reaction mixture was poured into dichloromethane 50 mL and washed 3× with 10 mL of saturated aqueous sodium bicarbonate. The dichloromethane was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was combined with methanol (10 mL) and 2 mL of 1 N NaOH and stirred for 1.5 hours at room temperature. The reaction was acidified with 12 N HCl (pH<3) and poured into 50 mL ethyl acetate. The layers were separated and the organics were dried over sodium sulfate, filtered and concentrated. Flash column chromatography using silica and a step gradient of hexane/ethyl acetate [20:1], hexane/ethyl acetate [9:1] provided 5-(2,6-dimethyl-4-triisopropylsilanyloxybenzyl)-2-methoxymethoxy-phenol (0.189 g, 42%): 1H NMR (300 MHz, DMSO-d6): δ 8.95 (s, 1H), 6.86 (d, 1H, J=8.1 Hz), 6.56 (s, 2H), 6.41 (d, 1H, J=2.1 Hz), 6.34 (dd, 1H, J=2.1 Hz and J=8.7 Hz), 5.05 (s, 2H), 3.78 (s, 2H), 3.38 (s, 3H), 2.13 (s, 6H), 1.11 (m, 3H), 1.00 (m, 18H); Uniplate silica gel, 250 microns; Mobile phase=10% ethyl acetate in hexane: Rf=0.15
Reaction SMILES: C([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([CH2:13][CH3:14])[C:7]1=[O:15])(OCC)=O.Cl>>[CH2:13]([N:8]1[CH2:9][CH2:10][C:11](=[O:12])[CH2:6][C:7]1=[O:15])[CH3:14]
Reactant: CCOC(=O)C1C(=O)CCN(CC)C1=O
Agent: Cl
Product: CCN1CCC(=O)CC1=O
Yield: 69.6 %

Procedure:
Added to 36.0 g of 3-carboethoxy-1-ethylpiperidine-2,4-dione (Referential Example 35) was 300 ml of a 10% aqueous solution of hydrochloric acid. The resultant mixture was refluxed for 40 minutes. After allowing the reaction mixture to cool down, it was extracted with chloroform. The chloroform layer was washed with water, dried and then concentrated, thereby obtaining 16.6 g of 1-ethylpiperidine-2,4-dione as a light yellowish oily substance (yield: 70%).
Reaction SMILES: F[C:2]1[C:3]([C:16]#[N:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.[CH:18]1([NH2:21])[CH2:20][CH2:19]1>>[CH:18]1([NH:21][C:2]2[C:3]([C:16]#[N:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[CH:7]=2)[CH2:20][CH2:19]1
Reactant: N#Cc1ncc(Cc2ccc(F)cc2)cc1F
Reactant: NC1CC1
Product: N#Cc1ncc(Cc2ccc(F)cc2)cc1NC1CC1
Temperature: 75 °C
Reaction time: 0.2 h
Yield: 66 %

Procedure:
3-Fluoro-5-[(4-fluorophenyl)methyl]-2-pyridinecarbonitrile (546 mg, 2.4 mmol) was taken up in cyclopropylamine (8 mL) and heated at 75° C. in a microwave for 10 minutes and then again for 12 minutes. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography to give 3-(cyclopropylamino)-5-[(4-fluorophenyl)methyl]-2-pyridinecarbonitrile (417 mg, 66%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J=1.9 Hz, 1 H), 7.19 (dd, J=8.2, 5.9 Hz, 2 H), 7.19 (d, J=2.4 Hz, 1 H), 7.06 (t, J=8.6 Hz, 2 H), 5.02 (s, 1 H), 4.00 (s, 2 H), 2.48 (m, 1 H), 0.86 (m, 2 H), 0.61 (m, 2 H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@@H:12]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:13]([N:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH:16]1[C:21]#[N:22])=[O:14].S(=O)(=O)(O)O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[C:21]([C@H:16]1[N:15]2[C:13](=[O:14])[CH:12]([N:3]3[C:4](=[O:11])[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:2]3=[O:1])[CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[CH:20]2[CH2:19][CH2:18][CH2:17]1)#[N:22]
Reactant: N#CC1CCC=CN1C(=O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#C[C@@H]1CCCC2c3ccccc3CC(N3C(=O)c4ccccc4C3=O)C(=O)N21
Reaction time: 24 h

Procedure:
Combine N-[2(S)-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-2-cyano-1,2,3,4-tetrahydro-pyridine (100 mg, 0.26 mmol), sulfuric acid (3 mL, 99.999%), and trifluoroacetic anhydride (0.03 mL). After 24 hours, the title compound is obtained as a solution.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:32][CH2:33][CH3:34])[CH2:29][CH2:30][CH3:31])=[CH:18][CH:17]=1)[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:43](OC(=O)C)(=[O:45])[CH3:44].O>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:35])[N:7]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:29][CH2:30][CH3:31])[CH2:32][CH2:33][CH3:34])[C:43]([CH3:44])=[O:45])=[CH:20][CH:21]=1)[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCN(CCC)CCCCNCc1ccc(CN(Cc2nccn2C)C(=O)OC(C)(C)C)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)CCCCN(Cc1ccc(CN(Cc2nccn2C)C(=O)OC(C)(C)C)cc1)C(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 127.6 %

Procedure:
The compound (182.6 mg) obtained in Example 21-4 was dissolved in chloroform (7.0 ml) and added with triethylamine (0.133 ml) and acetic anhydride (73.5 mg) and the whole was stirred at room temperature for 24 hours. The reaction solution was added with water, subjected to extraction with chloroform, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (253.2 mg) as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C(=O)([O-])O.[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>O1CCCC1.O>[F:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[NH:1][C:16](=[O:17])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc(O)cc1F
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(O)cc1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 920.4 %

Procedure:
To a suspension of 4-amino-3-fluorophenol (50 g, 39.3 mmol) in tetrahydrofuran/water (=1/1, 500 mL) was added sodium hydrogen carbonate (36.3 g, 39.3 mmol), and benzyl chloroformate (62 mL, 43.3 mmol) was added dropwise at room temperature. The mixture was stirred at room temperature for 16 hr, and extracted with ethyl acetate (1000 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with hexane/diethyl ether (=1/1) and collected by filtration to give the title compound (94.5 g, 92%).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CO.[CH2:9]([O:16][C:17](=[O:30])[CH:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:20]=O)C1C=CC=CC=1.COP(C(=[N+]=[N-])C(=O)C)(=O)OC>C(OCC)C>[CH3:9][O:16][C:17](=[O:30])[CH:18]([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19][C:20]#[CH:1]
Reactant: CC(C)(C)OC(=O)NC(CC=O)C(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: C#CCC(NC(=O)OC(C)(C)C)C(=O)OC
Reaction time: 0.17 h

Procedure:
Potassium carbonate (1.687 g, 12.2 mmol) was added to an anhydrous methanol (91.5 mL) solution of 2-tert-butoxycarbonylamino-4-oxo-butyric acid benzyl ester (1.875 g, 6.10 mmol) and the reaction stirred 10 minutes. (1-Diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (1.407 g, 7.32 mmol) was added and the reaction was stirred at room temp temperature 1 hour. The reaction was poured into diethyl ether and washed 4 times with 5% sodium bicarbonate, dried over magnesium sulfate and concentrated (1.05 g, crude product mixture). The crude product was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ5.39 -5.31 (m, 1H), 4.49-4.41 (m, 1H), 3.77 (s, 3H), 2.79-2.65 (m, 2H), 2.03 (s, 1H), 1.59 and 1.44 (2 singlets, rotamers, 3H).
Reaction SMILES: [OH:1][C@:2]1([C@@H:17]2[CH2:21][S:20][C:19](=[O:22])[N:18]2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH2:7][C@H:6]([OH:8])[CH2:5][C@@H:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:3]1.O[C@:33]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@@H](O)C[C@@H](CCCC=C)O1>>[OH:8][C@@H:6]1[CH2:5][C@@H:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:3][C@:2]([C@@H:17]2[CH2:21][S:20][C:19](=[O:22])[N:18]2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)([O:1][CH3:33])[CH2:7]1
Reactant: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(O)C[C@H](O)C[C@@H](CCc3ccccc3)O2)cc1
Reactant: C=CCCC[C@@H]1C[C@H](O)C[C@](O)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Product: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H](O)C[C@@H](CCc3ccccc3)O2)cc1

Procedure:
Application of the method shown in Example 13, with the modification that (R)-4-((2R,4R,6R)-2,4-dihydroxy-6-phenethyl-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one is substituted for (R)-4-((2R,4S,6R)-2,4-dihydroxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, affords the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:32]2[CH:33]=[CH:34][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=2)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]3)=[CH:20][CH:19]=1)([CH3:23])([CH3:22])[CH3:24]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Product: CC(C)(C)c1ccc(-c2ccc3c(c2)cc(C(=O)O)n3-c2ccc(S(C)(=O)=O)cc2)cc1

Procedure:
The title compound was prepared in accordance with Example 8(c) using 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester and 4-(methylsulfonyl)phenylboronic acid, followed by hydrolysis in accordance with the procedure described in Example 1(c).
Reaction SMILES: [CH2:1]([P:3]([CH2:10][CH2:11][CH:12]=[O:13])(=[O:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2].CC(C)=[O:16].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[CH2:1]([P:3]([O:4][CH2:5][CH2:6][CH2:7][CH3:8])([CH2:10][CH2:11][C:12]([OH:16])=[O:13])=[O:9])[CH3:2]
Reactant: CC(C)=O
Reactant: CCCCOP(=O)(CC)CCC=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CCCCOP(=O)(CC)CCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
20.6 g (0.1 mop of butyl ethyl-(2-formylethyl)phosphinate (produced as in Example 10) in 500 ml of acetone are mixed with 0.11 mol of Jones reagent (12.7 g of chromium trioxide in 36.7 ml of water and 11.0 ml of concentrated sulfuric acid) at 0° C. by dropwise addition. The reaction mixture is additionally stirred for 3½ hours with ice cooling and 1 hour at room temperature. After 12 ml of isopropanol have been added, the mixture is poured onto ice-water. Volatile constituents are subsequently distilled off in vacuo. The residue is taken up in tetrahydrofuran and extracted, Insoluble salts were filtered, off. The solvent of the filtrate was removed in vacuo and the residue was recrystallized from acetone to obtain 17.3 g (78% of theory) of 3-(ethylbutoxyphosphinyl)propionic acid as oil,
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1ccc(-c2ccc(N)cc2)cc1
Reaction time: 4 h
Yield: 100.7 %

Procedure:
To a solution of the 4′-tert-Butyl-4-nitro-biphenyl (1.8 g) in ethanol (20 mL) is added palladium (10%) on carbon (0.15 g). The reaction is charged to 30 psi under a hydrogen atmosphere and allowed to stir for 4 h. The mixture is then filtered through a pad of Celite®. The solution is concentrated and purified by reverse phase HPLC using 0.1% TFA in water and acetonitrile to afford 1.6 g of the titled compound as a white solid. 1H-NMR.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[Cl:10][C:11]1[CH:12]=[C:13]([OH:32])[CH:14]=[CH:15][C:16]=1[CH:17]([CH3:31])[C:18]([OH:30])([C:23]1[CH:28]=[N:27][C:26]([CH3:29])=[CH:25][N:24]=1)[C:19]([F:22])([F:21])[F:20]>>[C:6]([O:5][C:3](=[O:4])[CH2:2][O:32][C:13]1[CH:14]=[CH:15][C:16]([CH:17]([CH3:31])[C:18]([OH:30])([C:23]2[CH:28]=[N:27][C:26]([CH3:29])=[CH:25][N:24]=2)[C:19]([F:20])([F:21])[F:22])=[C:11]([Cl:10])[CH:12]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Product: Cc1cnc(C(O)(C(C)c2ccc(OCC(=O)OC(C)(C)C)cc2Cl)C(F)(F)F)cn1

Procedure:
The title compound was prepared in analogy to Example 74 from tert-butyl bromoacetate and 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 72). MS (m/e)=461.1 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:5]=2[O:4][N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: COC(=O)c1ccc2c(C)noc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1noc2cc(C(=O)O)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
Methyl 3-methyl-1,2-benzisoxazole-6-carboxylate (170 mg, 0.89 mmole) is dissolved in 6 ml MeOH under nitrogen. The solution is treated with 2N aqueous NaOH (1 ml, 2 mmole) and the mixture is stirred 4 h at rt. The volatiles are removed in vacuo and the residue is dissolved in 4 ml water. The pH of the solution is adjusted to 3 with 10% aqueous HCl, the white precipitate is collected, is washed with water, and is dried to give 144 mg (92%) of 3-methyl-1,2-benzisoxazole-6-carboxylic acid as a white solid. MS m/z (ESI): 176.2 (M−H)−.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]C1)=[O:7])([CH3:4])[CH3:3].NC1(C(O)=O)CCC1.NC1(C(O)=O)CC1>>[CH3:4][C:2]([O:5][C:6]([NH:8][C:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC1
Agent: NC1(C(=O)O)CC1
Agent: NC1(C(=O)O)CCC1
Product: CC(C)(C)OC(=O)NC1(C(=O)O)CC1

Procedure:
The title compound (998 mg) was made in a similar fashion to the preparation of Intermediate 68 replacing 1-aminocyclobutanecarboxylic acid WITH 1-aminocyclopropanecarboxylic acid (550 mg).
Reaction SMILES: [CH:1]1([PH:6][CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN([CH2:15][C-:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:21]N(C)C)C.[CH-:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1.[Fe+2:30]>C(O)(=O)C>[CH:7]1([P:6]([CH2:15][C-:16]2[CH:20]=[CH:19][CH:18]=[C:17]2[CH2:21][P:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:8][CH2:9][CH2:10][CH2:11]1.[CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Fe+2:30]
Reactant: CN(C)Cc1ccc[c-]1CN(C)C
Reactant: C1CCC(PC2CCCC2)C1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CC(=O)O
Product: c1cc(CP(C2CCCC2)C2CCCC2)[c-](CP(C2CCCC2)C2CCCC2)c1

Procedure:
The title compound was prepared in accordance with the procedure of Example 2 employing dicyclopentylphosphine (Strem 566 mg, 3.33 mmol), 1,2-bis(dimethylaminomethyl)ferrocene (0.5 g, 1.66 mmol) and anhydrous acetic acid (100 ml). Yield 0.432 g.
Reaction SMILES: [Na].Cl[C:3]1[N:7]([CH3:8])[N:6]=[C:5]([CH3:9])[C:4]=1[C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18].[NH:20]([CH2:27][CH2:28][OH:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH:20]([CH2:27][CH2:28][O:29][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([CH3:9])[C:4]=1[C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCCNc1ccccc1
Reactant: Cc1nn(C)c(Cl)c1C(=O)c1ccc(Cl)cc1Cl
Agent: [Na]
Product: Cc1nn(C)c(OCCNc2ccccc2)c1C(=O)c1ccc(Cl)cc1Cl

Procedure:
0.08 g of sodium metal was dissolved with heating in 2 ml of 2-anilinoethanol, and then 1 g of 5-chloro-4-(2,4-dichlorobenzoyl)-1,3-dimethylpyrazole was added. The resulting mixture was heated at 100° to 110° C. for 3 hours with stirring. Excess 2-anilinoethanol was distilled off under reduced pressure. The residue was then washed with chloroform and filtered. The chloroform solution was washed with water and dried over anhydrous sodium sulphate. Chloroform was distilled off and the residue was purified by silica gel chromatography (eluent, benzene:acetone at 7:1) to give 0.92 g of the desired product, Compound 1, having a refractive index nD24 1.6105 (yield 69%).
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[F:15])(=O)[CH2:2][CH2:3][CH2:4][CH3:5].O.NN.OC(O)C>>[CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[F:15])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)c1ccc(OC)cc1F
Agent: CC(O)O
Agent: NN
Solvent: O
Product: CCCCCc1ccc(OC)cc1F

Procedure:
4-Valeryl-3-fluoroanisole (14.1 g), hydrazine hydrate (8.6 ml) potassium hydroxide (4.4 g) and 1:1 dihydroxyethane (84 ml) were reacted together as described in Example 1. 4-Pentyl-3-fluoroanisole was isolated as a colourless oil b.pt 77° C. at 0.1 mm. The product showed 1 spot only on tlc using dichloromethanepetrol (1:1) as solvent.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCN(C(C)C)C(C)C.[NH2:34][C:35]1[CH:57]=[CH:56][C:38]([CH2:39][NH:40][C:41]2[C:46]3[CH:47]4[O:55][CH2:54][CH2:53][CH2:52][N:48]4[C:49](=[O:51])[NH:50][C:45]=3[N:44]=[CH:43][CH:42]=2)=[CH:37][C:36]=1[F:58]>CN(C=O)C>[F:58][C:36]1[CH:37]=[C:38]([CH2:39][NH:40][C:41]2[C:46]3[CH:47]4[O:55][CH2:54][CH2:53][CH2:52][N:48]4[C:49](=[O:51])[NH:50][C:45]=3[N:44]=[CH:43][CH:42]=2)[CH:56]=[CH:57][C:35]=1[NH:34][C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(CNc2ccnc3c2C2OCCCN2C(=O)N3)cc1F
Reactant: O=C(O)c1ccccc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(CNc2ccnc3c2C2OCCCN2C(=O)N3)cc1F)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.2 %

Procedure:
Benzoic acid (35 mg; 0.17 mmol), Bop-Cl (39 mg; 0.16 mmol), DIEA (0.04 mL; 0.25 mmol), and 45 (55mg, 0.26 mmol) were suspended in DMF (2 mL), and stirred overnight at room temperature. The crude reaction mixture was purified directly via HPLC to provide 52 (7 mg, 10% yield) as a solid. LC-MS (M+H=448, obsd.=448).