Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(N=O)C(=N)N[N+]([O-])=O.[OH-].[K+].[N+](=[CH2:15])=[N-].[F:16][C:17]1[CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:20]=[C:21]([F:24])[C:22]=1[OH:23]>CCOCC.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:16][C:17]1[CH:18]=[C:19]([CH:25]2[CH2:15][CH:26]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:20]=[C:21]([F:24])[C:22]=1[OH:23]
Reactant: C=[N+]=[N-]
Reactant: CCOC(=O)/C=C/c1cc(F)c(O)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(N=O)C(=N)N[N+](=O)[O-]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C1CC1c1cc(F)c(O)c(F)c1
Temperature: 0 °C

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-methyl-1-nitro-3-nitrosoguanidine (1.25 g, 8.50 mmol, 6.80 equiv) in ether (19 mL). This was followed by the addition of a solution of potassium hydroxide (1.57 g, 27.98 mmol, 22.40 equiv) in water (2.5 mL) dropwise with stirring at 0° C. the mixture were stirred at 0 degree for 2 min, the diazomethane was made. The ether phase was separated and dried over anhydrous sodium sulfate. Then it was used for the reaction directly. 100-mL round-bottom flask, was placed ethyl (2E)-3-(3,5-difluoro-4-hydroxyphenyl)prop-2-enoate (285 mg, 1.25 mmol, 1.00 equiv), Pd(OAc)2 (47 mg, 0.21 mmol, 0.17 equiv), ether (12 mL). The mixture was cooled to 0 degree C., the ether solution of diazomethane which got above was added dropwise with stirring at 0° C. The resulting solution was stirred overnight at 0° C. in a water/ice bath. The reaction was then quenched by the addition of acetic acid. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (30/70). The collected fractions were combined and concentrated under vacuum. This resulted in 130 mg (39%) of ethyl 2-(3,5-difluoro-4-hydroxyphenyl)cyclopropane-1-carboxylate as colorless oil. Mass spectrum (ESI, m/z): Calcd. for C12H12F2O3, 243.1 (M+H). found 243.1
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6](N)[O:5][N:4]=1.[ClH:17].[N+]([O-])([O-])=O.[Na+]>O>[F:1][C:2]([F:16])([F:15])[C:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([Cl:17])[O:5][N:4]=1
Reactant: Nc1onc(C(F)(F)F)c1-c1ccccc1
Reactant: Cl
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1noc(Cl)c1-c1ccccc1
Reaction time: 1 h
Yield: 16.9 %

Procedure:
To 2.28 g (10.0 mmole) of 3-trifluoromethyl-4-phenyl-5-aminoisoxazole were added 20 ml of conc. HCl and 1.09 g (11. 0 mmole) of cuprous chloride and 4.2 ml of aqueous sodium nitrate (2.76 g, 40 mmole) was added dropwise to the reaction mixture, keeping the temperature at 20°-25° C. After addition, the temperature was raised to 40°-45° C. and the mixture was stirred for 1 hour. To the mixture was added 16 ml of water, extracted with methylene chloride, dried with anhydrous sodium sulfate, evaporated under reduced pressure. The residue was purified by chromatography on silica gel to give 0.5651 g of colorless liquid. This was distilled under reduced pressure to give 0.4193 g of the titled compound as colorless liquid, yield 16.9%, b.p. 80.0°-83.0° C./0.50 mmHg.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8][CH:7]=1>OS(O)(=O)=O.O>[Br:5][C:6]1[C:15]2[C:10](=[C:11]([N+:1]([O-:4])=[O:2])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Brc1cncc2ccccc12
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cccc2c(Br)cncc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under argon, at room temperature, 65% HNO3 (200 mmol, 13.85 ml) is added in small portions to a solution of 4-bromoisoquinoline (100 mmol, 21.24 g) in 36N H2SO4 (50 ml). The reaction mixture is stirred for 3 h at room temperature. It is cooled to 0° C. and is then diluted with water. A yellow precipitate forms. It is filtered. The pH of the filtrate is adjusted to pH 10 by slow addition of 5N NaOH. The white precipitate which appears is extracted with CH2Cl2. This organic solution is washed with brine, dried over Na2SO4 and then evaporated under vacuum. The residue is purified by eluting on silica gel with an AcOEt/petroleum ether mixture. The purified product is recrystallized from absolute ethanol (EtOH).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([CH2:14][N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: BrCc1ccccc1
Product: c1ccc(Cn2c3ccccc3c3ccccc32)cc1

Procedure:
Carbazole (5 g; 0.03 mol) was reacted with benzyl bromide (7.11 ml; 0.06 mol) by working in a manner similar to that described in Example 1a).
Reaction SMILES: CC(OC(=O)[NH:7][CH:8]([C:17]([N:19]1[CH2:24][CH2:23][C:22]2([C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26](=[O:33])[CH2:25]2)[CH2:21][CH2:20]1)=[O:18])[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])(C)C.[C:35]([NH:42][C:43]([CH3:48])([C:45]([OH:47])=O)[CH3:44])([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>>[O:33]=[C:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:22]2([CH2:21][CH2:20][N:19]([C:17]([CH:8]([NH:7][C:45](=[O:47])[C:43]([NH:42][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])([CH3:44])[CH3:48])[CH:9]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH3:10])=[O:18])[CH2:24][CH2:23]2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: CC(c1ccccc1)C(NC(=O)OC(C)(C)C)C(=O)N1CCC2(CC1)CC(=O)c1ccccc12
Product: CC(c1ccccc1)C(NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)N1CCC2(CC1)CC(=O)c1ccccc12
Yield: 64.8 %

Procedure:
The title compound (236 mg, 0.431 mmol) was prepared from 316 mg (0.665 mmol) of the intermediate from Step A and 148 mg (0.731 mmol) of Boc alpha methyl alanine according to the procedure described in Example 1 (Step A).
Reaction SMILES: F[B-](F)(F)F.[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11]([N+:14]#[N:15])=[CH:10][CH:9]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1>C(O)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([O:28][CH3:29])[CH:25]=[CH:26][C:27]=1/[N:15]=[N:14]/[C:11]1[CH:12]=[CH:13][C:8]([S:7]([F:16])([F:17])([F:18])([F:19])[F:6])=[CH:9][CH:10]=1
Reactant: COc1cccc(OC)c1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Agent: F[B-](F)(F)F
Solvent: CCO
Product: COc1ccc(/N=N/c2ccc(S(F)(F)(F)(F)F)cc2)c(OC)c1
Yield: 97.7 %

Procedure:
Diazonium salt 1 (9.8 mg, 0.030 mmol) in 1 mL of 95% aqueous ethanol was added to a solution of 1,3-dimethoxybenzene (8.7 mg, 0.063 mmol) in 0.5 mL of 95% aqueous ethanol. After 2 weeks, the solvent was evaporated to give a red oil, whose purification by SiO2 column chromatography (1:1 hexane/CH2Cl2) afforded 27a as orange crystals (10.8 mg, 98%); m.p. 88.0-88.5° C. IR (ATR): {tilde over (v)}=2943, 1600, 1496, 1471, 1294, 1253, 1211, 767 cm−1. MS (GC, EI): m/z=368 [M+], 241 [M+-SF5], 165 [M+-C6H4SF5]. 1H NMR (500 MHz, CDCl3): δ=7.89 (d, J=9.0 Hz, 2H), 7.86 (d, J=9.0 Hz, 2H), 7.78 (d, J=9.0 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 6.56 (dd, J=9.0, 2.4 Hz, 1H), 4.03 (s, 3H), 3.91 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ=164.8 (C), 159.5 (C), 154.4 (C), 154.1 (C), 136.7 (C), 126.9 (2CH), 122.5 (2CH), 118.2 (CH), 105.9 (CH), 98.9 (CH), 56.3 (CH3), 55.7 (CH3) ppm. 19F NMR (470 MHz, CDCl3): δ=84.3 (quint, J=150 Hz, 1 F), 63.2 (d, J=150 Hz, 4 F) ppm.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][N:20]3[CH:24]=[C:23]([CH2:25][C:26]([O:28]CC)=[O:27])[C:22]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:21]3)=[CH:15][CH:14]=2)[N:10]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][N:20]3[CH:24]=[C:23]([CH2:25][C:26]([OH:28])=[O:27])[C:22]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[N:21]3)=[CH:15][CH:14]=2)[N:10]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)nc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccco2)nc1COc1ccc(Cn2cc(CC(=O)O)c(-c3ccccc3)n2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
After a mixture of ethyl [1-[6-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]acetate (578 mg), 1N sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml), and ethanol (6 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (3 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain [1-[6-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]acetic acid (467 mg, yield: 86%). This was recrystallized from acetone-hexane. Melting point: 135–136° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CI.[C:14](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:14])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(C(C)(C)C)cc1
Yield: 94.5 %

Procedure:
To 15.0 g of 4-tert-butylphenol dissolved in 100 ml of acetone were added 37.5 ml of methyl iodide and 83.0 g of potassium carbonate and heated at reflux for 20 hours. The reaction mixture was filtered and the filtrate was concentrated at reduced pressure. Diethyl ether was added to the residue to remove the insoluble matters by the filtration and the filtrate was concentrated at reduced pressure. The residue was purified by vacuum distillation to give 15.5 g of the title compound having the following physical properties.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[O:8]=[CH:9][C:10]1[CH:18]=[CH:17][C:15]([OH:16])=[C:12]([O:13][CH3:14])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CCO>[CH:2]1([O:16][C:15]2[CH:17]=[CH:18][C:10]([CH:9]=[O:8])=[CH:11][C:12]=2[O:13][CH3:14])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1cc(C=O)ccc1O
Reactant: BrC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(C=O)ccc1OC1CCCCC1
Reaction time: 64 h
Yield: 36.2 %

Procedure:
Bromocyclohexane (8.0 mL, 66 mmol) was added to a suspension of vanillin (5.0 g, 33 mmol), potassium carbonate (13.6 g, 99 mmol) and sodium iodide (0.49 g, 3.3 mmol) in EtOH (75 mL) and treated according to Procedure 3 for 64 h. The crude product was purified by flash chromatography with 10-15% EtOAc/petrol as eluent to give 4-cyclohexyloxy-3-methoxybenzaldehyde (2.8 g, 37%) as a pale yellow oil; δH (400 MHz, CDCl3) 1.27-1.43 (m, 4H, CH2), 1.56 (m, 2H, CH2), 1.85 (m, 2H, CH2), 2.06 (m, 2H, CH2), 3.91 (s, 3H, OCH3), 4.37 (tt, J=9.4, 3.6 Hz, 1H, OCH), 6.98 (d, J5,6=8.0 Hz, 1H, H5), 7.40 (d, J2,6=2.0 Hz, 1H, H2), 7.42 (dd, J5,6=8.0, J2,6=2.0 Hz, 1H, H6), 9.83 (s, 1H, CHO); do (100 MHz, CDCl3) 23.9, 25.4, 31.6, 56.0, 76.9, 109.8, 113.2, 126.5, 129.7, 150.5, 153.0, 190.8; vmax 1133, 1263, 1504, 1581, 1680, 2857, 2933 cm−1.
Reaction SMILES: I[C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O)[CH3:15].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:11][C:10]1[CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]([O:12][CH3:13])=[CH:3][C:2]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:14][CH3:15]
Reactant: CCOc1ccccc1B(O)O
Reactant: COc1cc(I)c(Cl)cc1C(=O)O
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOc1ccccc1-c1cc(OC)c(C(=O)O)cc1Cl

Procedure:
To a stirred solution of 4-iodo-5-chloro-2-methoxy benzoic acid of Example 15, Step A (0.500 g, 1.6 mmol) in N,N-dimethylformamide (30 mL) was added 2-ethoxy phenyl boronic acid (0.8 g, 4.8 mmol) and potassium carbonate (2.04 g, 14.7 mmol). This mixture was purged with nitrogen and then treated with a catalytic amount of tetrakis(triphenylphosphine) palladium(0) (0.093 g, 0.08 mmol). The reaction was heated to reflux overnight, cooled, acidified with 2 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to yield the title acid which was used in the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])([O:13][CH3:14])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:22][C:16]1[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:15]=1[C:10]1([O:13][CH3:14])[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: COC1(c2cccc(F)c2F)CCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC1(c2cccc(F)c2F)CCNC1
Yield: 84.7 %

Procedure:
Preparation according to Preparation 15. Tert-butyl-3-(2,3-difluorophenyl)-3-methoxypyrrolidin-1-carboxylate (4.7 g, 15 mmol), methylene chloride (20 mL) and trifluoroacetic acid (5 mL). Purification on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) gave the title compound (2.71 g, 85%). MS m/z (rel. intensity, 70 eV) 198 (44), 183 (95), 171 (bp), 141 (61), 127 (44).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[C:9]([C:13]1[CH:17]=[C:16]([C:18](O)=[O:19])[NH:15][N:14]=1)([CH3:12])([CH3:11])[CH3:10].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[C:9]([C:13]1[CH:17]=[C:16]([C:18]([NH:8][CH2:7][CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:19])[NH:15][N:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1cc(C(=O)O)[nH]n1
Reactant: NCCc1ccco1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(=O)NCCc2ccco2)[nH]n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 38.3 %

Procedure:
2-(furan-2-yl)ethanamine (0.81 g, 7.30 mmol) was added to a premixed (10 min) solution of 3-tert-butyl-1H-pyrazole-5-carboxylic acid (0.61 g, 3.60 mmol), DCC (1.51 g, 7.30 mmol) and HOBt (0.99 g, 7.30 mmol) in DCM:DMF-solution (10 ml, 2:9, v/v). After stirring for 15 h at RT the reaction mixture was filtered through a pad of Celite and the filtrate was washed two times with water, evaporated to dryness and purified with CombiFlash to afford 0.36 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.27 (s, 9H), 2.84 (t, 2H), 3.46 (m, 2H), 6.17 (m, 1H), 6.35 (m, 2H), 7.52 (m, 1H), 8.08 (m, 1H), 12.89 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:31])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH:21]=[C:20]([CH3:28])[N:19]=3)[O:15][N:14]=2)=[CH:8][C:7]=1[CH2:29][CH3:30].C1C=CC2N(O)N=NC=2C=1.[C:42](O)(=[O:45])[CH2:43][OH:44].CCN=C=NCCCN(C)C.Cl>C1COCC1.C([O-])(O)=O.[Na+]>[CH2:29]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:24][CH:25]([CH3:26])[CH3:27])[CH:21]=[C:20]([CH3:28])[N:19]=3)[O:15][N:14]=2)[CH:10]=[C:11]([CH3:12])[C:6]=1[O:5][CH2:4][C@@H:3]([OH:31])[CH2:2][NH:1][C:43](=[O:44])[CH2:42][OH:45])[CH3:30]
Reactant: O=C(O)CO
Reactant: CCc1cc(-c2noc(-c3cc(CC(C)C)cc(C)n3)n2)cc(C)c1OC[C@@H](O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CCc1cc(-c2noc(-c3cc(CC(C)C)cc(C)n3)n2)cc(C)c1OC[C@@H](O)CNC(=O)CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.7 %

Procedure:
To a solution of (S)-1-amino-3-{2-ethyl-4-[5-(4-isobutyl-6-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-propan-2-ol (36 mg, 86 μmol), HOBt (14 mg, 103 μmol) and glycolic acid (8 mg, 103 μmol) in THF (3 mL), EDC HCl (20 mg, 103 μmol) is added. The mixture is stirred at rt for 18 h before it is diluted with sat. aq. NaHCO3-solution and extracted twice with EA. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by prep. TLC using DCM containing 11% of methanol to give the title compound (36 mg) as a pale yellow oil; LC-MS: tR=0.98 min, [M+H]+=483.21; 1H NMR (CDCl3): δ 0.98 (d, J=6.3 Hz, 6H), 1.31 (t, J=7.5 Hz, 3H), 1.97-2.08 (m, 1H), 2.38 (s, 3H), 2.59 (d, J=6.8 Hz, 2H), 2.69-2.78 (m, 5H), 2.81 (s br, 1H), 3.42 (s br, 1H). 3.48-3.57 (m, 2H), 3.74-3.93 (m, 2H), 4.17-4.25 (m, 3H), 7.05 (s br, 1H), 7.19 (s, 1H), 7.93 (s, 1H), 7.94 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH3:17])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)c(O)c1
Reaction time: 10 h
Yield: 94 %

Procedure:
3-Hydroxy-4-methylbenzoic acid (7.60 g) was dissolved in methanol (400 mL), and thereto was added sulfuric acid (15.0 g), and the mixture was allowed to stand at room temperature for 10 hours. The reaction solution was concentrated to 150 mL, and diluted with water, and extracted with toluene. The extract was washed with an aqueous sodium hydrogen carbonate solution, and concentrated to give methyl 3-hydroxy-4-methylbenzoate (7.76 g, 94%). This product was dissolved in THF (140 mL), and thereto was added NaH (60% dispersion in oil, 2.22 g), and the mixture was stirred at 50° C. for one hour. To the mixture was added allyl bromide (7.00 g), and the mixture was refluxed for 5 hours. Water was added to the reaction solution, and the mixture was extracted with toluene, dried, filtered, and concentrated. The residue was purified by silica gel column chromatography to give methyl [3-(allyloxy)-4-methyl]benzoate (8.92 g, 93%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:25]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)Nc2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(NC(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.5 %

Procedure:
A suspension of 4-(2-tert-butylphenyl)-N-(4-hydroxyphenyl)piperazine-1-carboxamide (Example 174, 0.290 g, 0.82 mmol), methyl bromoacetate (0.163 g, 1.07 mmol), and potassium carbonate (0.227 g, 1.64 mmol) in DMF (3 mL) was stirred at room temperature for 24 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 solution and brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to give the crude product, which was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=90:10 to 50:50) to provide methyl [4-({[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}amino)phenoxy]acetate (0.260 g, 75%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([CH2:19][CH2:20]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([CH2:19][CH2:20][NH:1][C:2]2[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Product: O=C(O)c1cc(NCCc2ccc([N+](=O)[O-])cc2)ccc1O
Yield: 90.3 %

Procedure:
By following the similar procedure in Synthesis Example 1 by using 5-aminosalicylic acid (500 mg, 3.26 mmole) and 4-nitrophenethyl bromide (900 mg, 3.92 mmole), 890 mg (50% yield) of 5-(4-nitrophenethyl)aminosalicylic acid was obtained as a pale yellow solid.: mp 234-236° C.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])=[CH:4][CH:3]=1.[C:19](Cl)(=[O:29])[C:20]1[CH:28]=[CH:27][CH:26]=[C:22]([C:23](Cl)=[O:24])[CH:21]=1>>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:19](=[O:29])[C:20]2[CH:28]=[CH:27][CH:26]=[C:22]([C:23]([O:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])=[CH:17][CH:18]=3)=[O:24])[CH:21]=2)=[CH:18][CH:17]=1)=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCOC(=O)c1ccc(O)cc1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Product: CCCCCCCCOC(=O)c1ccc(OC(=O)c2cccc(C(=O)Oc3ccc(C(=O)OCCCCCCCC)cc3)c2)cc1

Procedure:
Octyl p-hydroxybenzoate and isophthalic dichloride are made to react and treated in a similar procedure to Example 4 to yield di(p-octyloxycarbonylphenyl)isophthalate in a pale yellow oily state.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][C:14]1=[O:22])C1C=CC=CC=1.Cl>CS(C)=O.CO>[NH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:22])[CH2:1]1
Reactant: O=C1Nc2ccccc2C1CCCCNCc1ccccc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CO
Product: O=C1Nc2ccccc2C12CCCCNC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-(4-(Benzylamino)-butyl)-indolin-2-one. Conc hydrochloric acid (90 mL) was added to a solution of the compound from the previous step in DMSO (38 mL) and MeOH (8 mL). After stirring for 30 min at 0° C. and 30 min at room temperature the mixture was poured onto ice followed by extractive work-up. The title compound was obtained as a crude orange oil (16.2 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][N:22]=3)=[C:16]([F:30])[CH:15]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.CCOC(C)=O>C(#N)C.O>[CH2:28]([O:27][C:24]1[CH:23]=[N:22][C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([CH:10]3[O:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[CH:15][C:16]=2[F:30])=[N:26][CH:25]=1)[CH3:29]
Reactant: CCOc1cnc(Nc2ccc(C3CN(C(=O)OC(C)(C)C)CCO3)cc2F)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOc1cnc(Nc2ccc(C3CNCCO3)cc2F)nc1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 109.5 %

Procedure:
To a stirred solution of (RS)-2-[4-(5-ethoxy-pyrimidin-2-ylamino)-3-fluoro-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (12 mg) in acetonitrile (1.5 ml) and water (3 ml) was added trifluoroacetic acid (22.0 μl). The reaction mixture was then capped and the mixture was shaken at 80° C. for 3.5 h. The reaction mixture was then cooled to room temperature and poured into EtOAc and washed with 1 M aq. NaOH. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/EtOAc/MeOH) to afford (RS)-(5-ethoxy-pyrimidin-2-yl)-(2-fluoro-4-morpholin-2-yl-phenyl)-amine (10 mg, quant.) as an off-white solid. MS (ISP): 319.2 ([ M+H]+).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[N:22]=[C:23](/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])[O:24][CH:25]=1>>[F:35][C:29]1[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=1/[CH:27]=[CH:26]/[C:23]1[O:24][CH:25]=[C:21]([CH2:20][O:16][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[N:2]3)=[CH:15][CH:14]=2)[N:22]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)c(F)c1
Agent: [H-]
Agent: [Na+]
Product: Fc1ccc(/C=C/c2nc(COc3ccc(CCCCn4ccnn4)cc3)co2)c(F)c1
Yield: 83.2 %

Procedure:
Using 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol (152 mg), 65% oily sodium hydride (28 mg) and 4-(chloromethyl)-2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazole (188 mg), the same reaction as Example 2 was carried out to yield the titled compound (254 mg).