Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:57])[C@H:4]([CH:54]([CH3:56])[CH3:55])[NH:5][C:6](=[O:53])[C@@H:7]([CH:50]([CH3:52])[CH3:51])[NH:8][C:9](=[O:49])[CH:10]([CH:12]1[CH2:18][CH2:17][N:16]([C@@H:19]([NH:21][C:22](=[O:33])[C@H:23]([CH3:32])[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH3:20])[CH2:15][CH:14]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:13]1[O:41][Si](C(C)(C)C)(C)C)[CH3:11].[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].CCOCC>C1COCC1>[CH3:1][O:2][C:3](=[O:57])[C@H:4]([CH:54]([CH3:56])[CH3:55])[NH:5][C:6](=[O:53])[C@@H:7]([CH:50]([CH3:52])[CH3:51])[NH:8][C:9](=[O:49])[CH:10]([CH:12]1[CH2:18][CH2:17][N:16]([C@@H:19]([NH:21][C:22](=[O:33])[C@H:23]([CH3:32])[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH3:20])[CH2:15][CH:14]([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:13]1[OH:41])[CH3:11]
Reactant: COC(=O)[C@@H](NC(=O)[C@H](NC(=O)C(C)C1CCN([C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)CC(Cc2ccccc2)C1O[Si](C)(C)C(C)(C)C)C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)[C@@H](NC(=O)[C@H](NC(=O)C(C)C1CCN([C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)CC(Cc2ccccc2)C1O)C(C)C)C(C)C

Procedure:
One isomer of the protected alcohol (66) is dissolved in THF and treated with n-Bu4NF (1M in THF, 2 equivalents) at room temperature. After all of the ether disappears (tlc), the reaction mixture is evaporated at reduced pressure and the residue is purified by flash chromatography to give the title compound (67).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([CH3:19])([CH3:18])[OH:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH2:20][NH2:21].[N+:22]([O-])([O-])=O.[Na+]>O.C(O)(=O)C>[CH3:18][C:16]([CH3:19])([OH:17])[CH2:15][N:14]1[C:10]2[C:9]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[N:20]3[N:21]=[N:22][N:3]=[C:2]3[C:11]=2[N:12]=[CH:13]1
Reactant: CC(C)(O)Cn1cnc2c(Cl)nc3ccccc3c21
Reactant: NN
Reactant: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(O)Cn1cnc2c1c1ccccc1n1nnnc21

Procedure:
A suspension of 4-chlorO-α,α-dimethyl-1H-imidazo-[4,5-c]quinoline-1-ethanol (1.0 g, 3.6 mmole, U.S. Pat. No. 4,689,338 Example 189 Part D) in hydrazine (3 mL, 6.9 mmole) was heated on a steam bath for 1 hour then diluted with water. The resulting precipitate was isolated by filtration. The solid was dissolved in a mixture of acetic acid (2 mL) and water (15 mL) then combined with a solution of sodium nitrate (0.5 g) in water. The resulting precipitate was isolated by filtration, washed with water and dried to provide 0.71 g of α,α-dimethyl-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline-6-ethanol as a white solid, m.p. 246-247° C. (shrunk at 230° C.). Analysis: Calculated for C14H14N6O: %C, 59.56; %H, 5.00; %N, 29.77; Found: %C, 59.45; %H, 5.06; %N, 29.51.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[C:17](/[CH:19]=[CH:20]/[CH:21]([C:26]2[CH:31]=[C:30]([Cl:32])[C:29]([Cl:33])=[C:28]([Cl:34])[CH:27]=2)[C:22]([F:25])([F:24])[F:23])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])=[O:5].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:18]=[C:17](/[CH:19]=[CH:20]/[CH:21]([C:26]2[CH:31]=[C:30]([Cl:32])[C:29]([Cl:33])=[C:28]([Cl:34])[CH:27]=2)[C:22]([F:24])([F:25])[F:23])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5]
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a stirred solution of (E)-tert-butyl 2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamido)acetate (440 mg, 0.734 mmol) in CH2Cl2 (36.0 ml), was added TFA (4.0 mL) and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was concentrated under reduced pressure to obtain residue which was washed with n-pentane to afford the title compound as an off-white solid (310 mg, 78%): 1H NMR (400 MHz, CDCl3) δ 13.0 (s, 1H), 8.75 (t, J=5.7 Hz, 1H), 7.93 (m, 2H), 7.62 (d, J=7.5 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H), 6.96 (dd, J=15.3, 9.3 Hz, 1H), 6.78 (d, J=15.3 Hz, 1H), 4.83 (m, 1H), 3.90 (d, J=5.7 Hz, 2H); ESIMS m/z 543.61 ([M+H]+); IR (thin film) 3429, 1635, 1114, 772 cm−1.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[O:15][CH3:16].[N:17]([O-:19])=[O:18].[Na+].C(O)(=O)C.[N+]([O-])(O)=O>O>[CH3:16][O:15][C:7]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[C:9]([CH:8]=1)[C:10]([OH:12])=[O:11]
Reactant: COc1cc(C(=O)O)ccc1OCCCCl
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: O=[N+]([O-])O
Product: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OCCCCl
Temperature: 40 °C
Yield: 944.9 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer and a dropping funnel were placed 16.2 g (65.4 mmol) of 4-(3-chloropropoxy)-3-methoxybenzoic acid (purity: 98%) obtained in Reference Example III-7, 0.45 g (6.54 mmol) of sodium nitrite, and 20 mL of acetic acid. The resulting mixture was heated to 40° C. under stirring. To the reaction mixture was dropwise added slowly 27.6 g (262.0 mmol) of nitric acid (60 wt. %), and the mixture was heated at the same temperature for 5 hours. After the reaction was complete, 20 mL of water was added to the reaction mixture, and the aqueous mixture was cooled to 20° C., precipitating a crystalline product. The crystalline product was collected by filtration, washed with 30 mL of water, and dried under reduced pressure, to give 17.9 g (isolated yield: 93.0%, purity: 99% in terms of area percentage determined by high performance liquid chromatography) of 5-methoxy-4-(3-chloropropoxy)-2-nitrobenzoic acid as a white crystalline product.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Br[CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:25]>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH3:25])[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Reactant: CC(Br)c1ccccc1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)N(C(C)c3ccccc3)C(C)(C)C2=O)cn1

Procedure:
Prepared as in Example 16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 16a) and (1-bromoethyl)benzene. MS 408 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.15 μM.
Reaction SMILES: [CH2:1]([N:8]([CH2:29][CH:30]1[CH2:35][CH2:34][CH:33]([CH2:36][OH:37])[CH2:32][CH2:31]1)[S:9]([NH:12][C:13](=[O:28])[C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([C:42]1[CH:47]=[CH:46]C=C(C(C)(C)C)N=1)(C)(C)[CH3:39].ICCCCC>ClCCl.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[CH2:1]([N:8]([CH2:29][CH:30]1[CH2:31][CH2:32][CH:33]([CH2:36][O:37][CH2:39][CH2:38][CH2:42][CH2:47][CH3:46])[CH2:34][CH2:35]1)[S:9]([NH:12][C:13](=[O:28])[C:14]1[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[C:16]([C:24]([F:25])([F:26])[F:27])[CH:15]=1)(=[O:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)n1
Reactant: O=C(NS(=O)(=O)N(Cc1ccccc1)CC1CCC(CO)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCCCCI
Product: CCCCCOCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Yield: 73.9 %

Procedure:
Intermediate (4) (27.6 mg, 50 μmole, 1.0 eq) was dissolved in dichloromethane (250 μL), after which 2,6-di-t-butyl pyridine (36 μL, 160 μmole, 3.2 eq), silver triflate (38.5 mg, 150 μmole, 3.0 eq) and iodopentane (23 μL, 175 μmole, 3.5 eq) were added. After 45 minutes the reaction mixture was directly purified to give 23 mg of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 8.45 (s, 2H), 8.15 (s, 1H), 7.36 (d, 2H), 7.24 (t, 2H), 7.17 (t, 1H), 4.39 (s, 2H), 3.30 (water), 3.23 (t, 2H), 3.01 (d, 2H), 2.92 (d, 2H), 2.48 (DMSO), 1.61 (m, 2H), 1.54 (m, 2H), 1.41 (m, 2H), 1.34-1.19 (m, 6H), 0.82 (t, 3H), 0.62 (m, 4H).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([C:7]2[C:11]([C:12]([OH:14])=[O:13])=[CH:10][S:9][N:8]=2)=[CH:3][CH:2]=1.B(F)(F)F.[CH3:20][CH2:21]OCC>C(O)C>[C:1]1([CH3:15])[CH:2]=[CH:3][C:4]([C:7]2[C:11]([C:12]([O:14][CH2:20][CH3:21])=[O:13])=[CH:10][S:9][N:8]=2)=[CH:5][CH:6]=1
Reactant: CCOCC
Reactant: Cc1ccc(-c2nscc2C(=O)O)cc1
Agent: FB(F)F
Solvent: CCO
Product: CCOC(=O)c1csnc1-c1ccc(C)cc1
Yield: 89.7 %

Procedure:
3-(p-Tolyl)-4-isothiazolecarboxylic acid (1.5 g, 0.0068 mol), 20 ml of absolute ethanol, and boron trifluoride etherate (4.3 ml, 0.034 mol) were heated at reflux for 24 hours. Volatile materials were removed under reduced pressure. Water (25 ml) was added and the material extracted four times with ether. The ether was back-extracted with 5% NaHCO3, dried (CaSO4) and concentrated under reduced pressure to yield 1.51 g (0.0061 mol, 89.9%) of oil, nD25 = 1.5671.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH2:13]([Mg]Br)[CH3:14].B(F)(F)F.CCOCC>CCOCC.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([C:7]2([NH2:8])[CH2:14][CH2:13]2)=[CH:5][CH:4]=1
Reactant: CC[Mg]Br
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: CCOCC
Product: NC1(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
To a cold solution of 4-(trifluoromethyl)benzonitrile (1.03 g, 5.84 mmol) in ether (50 mL) was added titanium isopropoxide (1.50 mL, 5.83 mmol) and ethyl magnesium bromide (3.0M in ether) (1.55 g, 11.67 mmol) at −70° C. The reaction mass was stirred at RT for 1 h and boron trifluoride etherate (4.0 mL) was added. The reaction mass was stirred at RT for 1 h. The reaction mass was quenched in HCl:NaOH (30 mL). The reaction mass was extracted with ether and the organic layer was concentrated to afford 0.420 g of the desired product. 1HNMR (CDCl3): δ 1.05 (s, 2H), 1.60 (s, 2H), 1.78 (s, 2H), 7.36 (d, J=7.8 Hz, 2H), 7.55 (d, J=8.1 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@H:4](/[CH:5]=[C:6](\[F:12])/[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([OH:15])=[O:14].[C:17]([C@@H:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)#[N:18]>C(Cl)(Cl)Cl>[CH3:16][C:2]1([CH3:1])[C@H:4](/[CH:5]=[C:6](\[F:12])/[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([O:15][C@H:19]([C:17]#[N:18])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:21]=1)=[O:14]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)/C(F)=C/[C@@H]1[C@@H](C(=O)O)C1(C)C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)/C(F)=C/[C@@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Example 1, the acid of Step A and (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,trans) 2,2-dimethyl-3(Z)-[2-fluoro-3-oxo-3-ethoxy-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+15°±2° (c=0.5% in chloroform).
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5](Br)=[C:4]([F:12])[CH:3]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[C:22]([CH3:28])([CH3:27])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([OH:26])([C:5]2[C:6]3[O:10][CH:9]=[CH:8][C:7]=3[C:2]([F:1])=[CH:3][C:4]=2[F:12])[C:22]([CH3:28])([CH3:27])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Fc1cc(F)c2ccoc2c1Br
Reactant: CC1(C)CN(Cc2ccccc2)CCC1=O
Product: CC1(C)CN(Cc2ccccc2)CCC1(O)c1c(F)cc(F)c2ccoc12
Yield: 52.1 %

Procedure:
Beginning with 1.17 gm (5.01 mMol) 4,6-difluoro-7-bromobenzofuran and 1.14 gm (5.26 mMol) 1-benzyl-3,3-dimethyl-4-oxopiperidine, 0.97 gm (52%) of the desired compound were prepared essentially as described in EXAMPLE 19.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C@@H:21]([OH:26])[CH2:22][C@H:23]([OH:25])[CH3:24].C(OC(N=NC(OC(C)C)=O)=O)(C)C.C1(C)C=CC=CC=1.[N+]([C:51]1[CH:59]=[CH:58][C:54]([C:55](O)=[O:56])=[CH:53][CH:52]=1)([O-])=O>C1COCC1.O>[C:55]([O:25][C@@H:23]([CH3:24])[CH2:22][C@H:21]([OH:26])[CH3:20])(=[O:56])[C:54]1[CH:58]=[CH:59][CH:51]=[CH:52][CH:53]=1
Reactant: C[C@@H](O)C[C@@H](C)O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)C[C@H](C)OC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
After triphenylphosphine (566 mg, 2.16 mmol), (2R,4R)-2,4-pentanediol (225 mg, 2.16 mmol), and THF (6 ml) were added to a 50 mL flask, a 40% azodicarboxylic acid diisopropyl ester-toluene solution (1.13 mL, 2.16 mmol) dissolved in THF (6 mL) was added dropwise thereto at 20° C. Subsequently, 4-nitrobenzoic acid (300 mg, 1.80 mmol) dissolved in THF (6 mL) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for one hour. Water (0.5 ml) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 mL, ×2). Then, the organic layer was washed with water (10 ml) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 40% ethyl acetate-hexane solution) to give (4S,2R)-4-benzoyloxypentane-2-ol containing 1,2-hydrazinedicarboxylic acid diisopropyl ester as 593 mg of a pale yellow solid substance. Measurement of 1H-NMR showed that 379 mg of (4S,2R)-4-(4-nitrobenzoyloxy)pentane-2-ol (yield: 83%/4-nitrobenzoic acid), and 213 mg of 1,2-hydrazinedicarboxylic acid diisopropyl ester were contained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[CH:6][C:5]=1Br.[Cu][C:30]#[N:31].[C:32](=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[C:6]([CH3:32])[C:5]=1[C:30]#[N:31]
Reactant: N#C[Cu]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c(C)c1C#N
Temperature: 160 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-bromo-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzoic acid methyl ester (Example I13) (2.52 g) in dry N,N-dimethylformamide (75 ml) was added copper(I) cyanide (1.145 g). The reaction mixture was stirred at 160° C. for 40 minutes. The reaction mixture was allowed to cool to ambient temperature and was poured into a mixture of aqueous sodium carbonate (saturated) and water (1:2) (150 ml). The mixture was extracted with ethyl acetate (3×70 ml). The combined organic extracts were washed with water (2×70 ml) and brine (70 ml), dried over sodium sulfate and concentrated. The residue was re-crystallized from a mixture of diethyl ether and heptane (1:1) to give methyl 2-cyano-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzoic acid methyl ester (1.474 g). 1H-NMR (CDCl3, 400 MHz): 8.23-7.45 (m, 6H), 4.11 (d, 1H), 4.03 (s, 3H), 3.74 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].N1C=CC=CC=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[C:22](Cl)=[O:23]>ClCCl>[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[C:22]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[O:23]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Yield: 88.1 %

Procedure:
To a solution of 4-fluoro-3-nitro-phenylamine (3.0 g, 20 mmol) in dichloromethane (60 mL) was added pyridine (3.2 g, 40.0 mmol). The solution was cooled to 0° C. and 3,5-dichlorobenzoyl chloride (4.0 g, 20.0 mmol) was added. The ice bath was removed and the reaction was allowed to warm to room temperature over 18 h. The reaction was poured into water and a precipitate formed. The solid was collected and washed with excess water. This solid was than dried under vacuum at 50° C. for 18h. This solid was taken up in ethyl acetate. The ethyl acetate was washed with 5% HCl, water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound (5.8 g, 92%).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[C:21]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[C:9]([F:28])[CH:8]=1)C.[OH-].[Na+]>C1COCC1.C(O)C>[C:21]1(=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:10]2[CH:11]=[CH:12][C:7]([CH:6]=[CH:5][C:4]([OH:29])=[O:3])=[CH:8][C:9]=2[F:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCOC(=O)C=Cc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C=Cc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)c(F)c1
Temperature: 65 °C
Yield: 8.3 %

Procedure:
To a solution of 3-{4-[cycloheptylidene-(4-hydroxy-phenyl)-methyl]-3-fluoro-phenyl)-acrylic acid ethyl ester (176) (0.8 g, 2.15 mmol) in THF (10 mL) and ethanol (10 mL) was added 1 N sodium hydroxide (21 mL). The reaction mixture was heated at 65° C. for 2.5 h. The reaction mixture was partially concentrated to remove the EtOH and THF. To the basic aqueous mixture was added 1 N HCl to pH˜1 (according to litmus paper). The acidic aqueous solution was extracted with dichloromethane and the organic extract washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was triturated with dichloromethane, filtered and dried to give 0.065 g (10%) of compound 177 as a white powder. 1H NMR (400 MHz, DMSO-d6): δ 1.51 (b, 8 H), 2.09 (m, 2 H), 2.25 (m, 2 H), 6.52 (d, J=16.1 Hz, 1 H), 6.65 (d, J=8.4 Hz, 2 H), 6.92 (d, J=8.4 Hz, 2 H), 7.19 (t, J=7.8 Hz, 1 H), 7.43-7.49 (m, 1 H), 7.51-7.53 (m, 2 H), 9.32 (s, 1 H), 12.43 (s, 1 H). HRMS (ESI) Calcd for C23H22FO3: 365.1553 (M−H)−. Found: 365.1543.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:4]>O1CCOCC1.CO.[Pd]>[CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:4]
Reactant: COC(=O)C=Cc1c[nH]c2cc(C(=O)OC)ccc12
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)CCc1c[nH]c2cc(C(=O)OC)ccc12
Temperature: 20 °C
Reaction time: 6.5 h
Yield: 82.5 %

Procedure:
To a solution of methyl 3-(2-methoxycarbonylethenyl)indole-6-carboxylate (213 mg) in a mixture of 1,4-dioxane (2 ml) and methanol (3 ml) was added 10% palladium on carbon (40 mg) and the mixture was stirred under hydrogen at 20° C. for 6.5 hours. The resulting mixture was filtered through celite and the filtrate was evaporated in vacuo. The residue was triturated with diisopropyl ether to give methyl 3-(2-methoxycarbonylethyl)indole-6-carboxylate (177 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[CH:30](=O)[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:30][CH3:31])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCN(Cc1cccc(-c2ccnc(Cl)n2)c1)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
Intermediate 1 was coupled with 4-Amino-piperidine-1-carboxylic acid tert-butyl ester following procedure B. When the starting aldehyde had been consumed, 2 equivalents each of acetaldehyde and sodium triacetoxyborohydride were added and the mixture stirred for another two hours. The organic layer was washed with water followed by sat. NaCl. The solvent was removed to give product LC-MS showed the product was >90% pure and had the expected M+H+ of 403, and it was used in the following reactions without purification.
Reaction SMILES: C([NH:8][CH2:9][CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=2)=[CH:16][CH:15]=1)=[O:12])C1C=CC=CC=1.[CH2:28]([C:31]1[CH:41]=[C:40]([CH2:42][CH2:43][O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:39]=[CH:38][C:32]=1[O:33][CH2:34][CH:35]1[O:37][CH2:36]1)[CH:29]=[CH2:30]>C(O)CC>[OH:37][CH:35]([CH:34]([CH2:20][C:17]1[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1)[O:33][C:32]1[CH:38]=[CH:39][C:40]([CH2:42][CH2:43][O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)=[CH:41][C:31]=1[CH2:28][CH:29]=[CH2:30])[CH2:36][NH:8][CH2:9][CH2:10][C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=2)=[CH:18][CH:19]=1)=[O:12]
Reactant: C=CCc1cc(CCOCC2CC2)ccc1OCC1CO1
Reactant: CC1CC(=O)NN=C1c1ccc(NC(=O)CCNCc2ccccc2)cc1
Solvent: CCCO
Product: C=CCc1cc(CCOCC2CC2)ccc1OC(Cc1ccccc1)C(O)CNCCC(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Yield: 89.9 %

Procedure:
A mixture of 6-[4-(3-benzylaminopropionamido)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (5.5 g; 0.015 mol), 1-[2-allyl-4-[2-(cyclopropylmethoxy)ethyl]phenoxy]-2,3-epoxypropane (8.65 g; 0.03 mol) and n-propanol (100 ml) was stirred under reflux for 24 hours. The mixture was cooled, filtered and the filtrate was evaporated under reduced pressure and chromatographed on a silica gel column, using ethyl acetate as eluant, to give as a glass 6-[4-[3-[2-hydroxy-3-[2-allyl-4-(2-(cyclopropylmethoxy)ethyl)phenoxy]-N-benzylpropylamino]propionamido]phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (4.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][S:8][C:9]2[C:10](F)=[C:11]([F:27])[C:12]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:5][CH:4]=1.[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C=O)C>[N:31]([C:10]1[C:9]([S:8][CH2:7][C:6]2[CH:29]=[CH:30][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[C:11]=1[F:27])=[N+:32]=[N-:33]
Reactant: COC(=O)c1cc(SCc2ccc(OC)cc2)c(F)c(F)c1Nc1ccccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(SCc2ccc(OC)cc2)c(N=[N+]=[N-])c(F)c1Nc1ccccc1Cl
Temperature: 90 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
To a solution of methyl 5-(4-methoxybenzylthio)-3,4-difluoro-2-((2-chlorophenyl)amino)benzoate (24.18 g, 53.75 mmol) in DMF (200 mL) was added NaN3 (4.19 g, 64.49 mmol) at ambient temperature. The mixture was stirred at 90° C. for 3 h. Then water (200 mL) was added. The solution was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 10:1, v/v) and gave the desired product (pale yellow solid, 21.63 g, 85.1% yield). 1H NMR (400 MHz, CDCl3): δ 9.01 (s, 1H), 7.80 (s, 1H), 7.33 (m, 4H), 7.15 (m, 1H), 6.90 (m, 1H), 6.85 (m, 2H), 4.05 (s, 2H), 3.92 (s, 3H), 3.81 (s, 3H).