Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[Cl:14][C:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=1.N1C=CC=CC=1>O1CCCC1.O>[Cl:14][C:15]1[C:20]([NH:21][C:7](=[O:8])[C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[N+:11]([O-:13])=[O:12])=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: Nc1cccnc1Cl
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)Cl)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(C(=O)Nc2cccnc2Cl)c1
Reaction time: 2 h
Yield: 98.7 %

Procedure:
A solution of 5-methyl-2-nitrobenzoyl chloride (3.77 g, 18.9 mmol) in tetrahydrofuran (25 mL) was treated with a solution consisting of 2-chloropyridin-3-amine (2.6 g, 20.22 mmol), pyridine (6 mL) and tetrahydrofuran (15 mL). The reaction mixture was stirred for 2 hours then diluted with water (150 mL) and extracted with dichloromethane (3×70 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (100 mL) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford N-(2-chloropyridin-3-yl)-5-methyl-2-nitrobenzamide (5.44 g) that was used without further purification. LCMS [M+H]: 292.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23]2[O:27][C:26](=[O:28])[N:25]([C@H:29]3[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40]C)=[O:39])[CH2:30]3)[N:24]=2)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[C:11]=1[NH:12]C(OCC1C=CC=CC=1)=O>Cl>[NH2:12][C:11]1[C:6]2[O:7][CH2:8][CH2:9][O:10][C:5]=2[C:4]([C:23]2[O:27][C:26](=[O:28])[N:25]([C@H:29]3[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])[CH2:30]3)[N:24]=2)=[CH:3][C:2]=1[Cl:1]
Reactant: COC(=O)CCCCN1CC[C@H](n2nc(-c3cc(Cl)c(NC(=O)OCc4ccccc4)c4c3OCCO4)oc2=O)C1
Agent: Cl
Product: Nc1c(Cl)cc(-c2nn([C@H]3CCN(CCCCC(=O)O)C3)c(=O)o2)c2c1OCCO2

Procedure:
0.50 g (0.85 mmol) of methyl (S)-3-[5-[7-chloro-8-[[(phenylmethoxy)carbonyl]amino]-2,3-dihydro-1,4-benzodioxin-5-yl]2-oxo-2,3-dihydro-1,3,4-oxadiazol-3-yl]pyrrolidine-l-pentanoate dissolved in 5 ml of concentrated aqueous hydrochloric acid is placed in a 25 ml round-bottomed flask and the reaction medium is refluxed for 22 h.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:4]=1.[OH:16][CH2:17][CH2:18][C:19]1[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=1>>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[N:4]=[C:3]([CH2:2][O:16][CH2:17][CH2:18][C:19]3[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=3)[CH:8]=[CH:7][CH:6]=2)=[CH:10][CH:11]=1
Reactant: Nc1cccc(CCO)c1
Reactant: Fc1ccc(-c2cccc(CCl)n2)cc1
Product: Nc1cccc(CCOCc2cccc(-c3ccc(F)cc3)n2)c1

Procedure:
Using a similar procedure to step 1 of Example 1 222 mg (1 mmol) of the product of step 3 above was reacted with 137 mg (1 mmol) of 3-(2-hydroxy ethyl)phenyl amine. After purification on silica with 40% ethyl acetate:hexane elution, recovered 0.21 g (65%) of an oil. NMR (200 MHz, CDCl3) δ 8.11 (m, 2H, ArH), 7.79 (m, 2H, ArH), 7.18-7.38 (m, 6H, ArH), 7.08 (d, J=8 Hz, 1H, ArH), 4.63 (s, 2H, OCH2), 4.53 (bs, 2H, NH2), 3.78 (t, J=7 Hz, 2H, OCH2), 2.92 (t, J=7 Hz, 2H, ArCH2).
Reaction SMILES: OO.[OH-].[Na+].CC([O:8][C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][C@@H:16]3[C:25]4[C:20](=[CH:21][C:22]([OH:27])=[C:23]([OH:26])[CH:24]=4)[CH2:19][CH2:18][C@H:17]3[C@@H:12]2[CH2:11][CH2:10]1)=O>>[CH3:28][C@@:13]12[C@@H:9]([OH:8])[CH2:10][CH2:11][C@H:12]1[C@H:17]1[C@@H:16]([C:25]3[CH:24]=[C:23]([OH:26])[C:22]([OH:27])=[CH:21][C:20]=3[CH2:19][CH2:18]1)[CH2:15][CH2:14]2
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)c(O)cc4[C@H]3CC[C@]12C
Agent: OO
Agent: [Na+]
Agent: [OH-]
Product: C[C@]12CC[C@@H]3c4cc(O)c(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Yield: 77 %

Procedure:
The following section describes the process for the manufacture of catechol estrogen glycosides from estradiol as starting material. The first step is that estradiol was reacted with acetic anhydride in pyridine at room temperature for overnight, yielding estradiol diacetate stoichiometrically. Estradiol diacetate was heated at 80° C. in nitrobenzene for 1 hour in tile presence of 2 mol equivalent of aluminum chloride and 0.4 mol equivalent of acetyl chloride, and then 2-acetylestradiol 17-acetate was obtained by 85% yield. 2-Acetylestradiol 17-acetate was reacted with hydrogen peroxide at room temperature for 2 hours maintaining pH in a range between 12.0 and 12.5 by the addition of sodium hydroxide and 2-hydroxyestradiol 17-acetate thus obtained was hydrolyzed by conventional method either in acidic or alkaline condition to form 2-hydroxyestradiol by overall yield of 77%.
Reaction SMILES: C[Li].[CH2:3](OCC)C.[C:8]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:34])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)(=[O:27])=[O:26])[CH:20]=2)=[CH:13][CH:12]=1)(=[O:10])[CH3:9]>O>[OH:10][C:8]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:34])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([N:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)(=[O:27])=[O:26])[CH:20]=2)=[CH:13][CH:12]=1)([CH3:3])[CH3:9]
Reactant: CCOCC
Reactant: CC(=O)c1ccc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)cc1
Agent: [Li]C
Solvent: O
Product: CC(C)(O)c1ccc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
With cooling with ice, methyllithium (0.66 mL, 0.98 M diethyl ether solution) was dropwise added to a diethyl ether (1.0 mL) solution of the compound (50.0 mg) obtained in Example 92, and stirred for 1 hour with cooling with ice. After heated up to room temperature, water was added to the reaction liquid, and then extracted three times with ethyl acetate. This was dried with sodium sulfate, then the drying agent was removed through filtration, and the solvent was evaporated off under reduced pressure. The residue was purified through silica gel column chromatography (ethyl acetate/hexane=from 0% to 80%, gradient) to give the entitled compound (51.1 mg, 99%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([C@@H:4]1[C:27](=[O:28])[C:26]([C:29]([NH2:31])=[O:30])=[C:25]([OH:32])[C@:24]2([OH:33])[C@H:5]1[CH2:6][C@H:7]1[C:21]([C:22]2=[O:23])=[C:20]([OH:34])[C:10]2[C:11]([OH:19])=[C:12]([NH2:18])[CH:13]=[C:14]([N:15]([CH3:17])[CH3:16])[C:9]=2[CH2:8]1)[CH3:3].ClCC(OC)(OC)OC.Cl[CH2:45][C:46]1O[C:48]2[CH:54]=CC=C[C:49]=2[N:50]=1.C(N)CC.C(NCC1OC2C=CC=CC=2N=1)CC.N>CN(C=O)C>[CH3:17][N:15]([CH3:16])[C:14]1[C:9]2[CH2:8][C@@H:7]3[C:21](=[C:22]([OH:23])[C@@:24]4([OH:33])[C@@H:5]([CH2:6]3)[C@H:4]([N:2]([CH3:1])[CH3:3])[C:27]([OH:28])=[C:26]([C:29]([NH2:31])=[O:30])[C:25]4=[O:32])[C:20](=[O:34])[C:10]=2[C:11]2[O:19][C:45]([CH2:46][NH:50][CH2:49][CH2:48][CH3:54])=[N:18][C:12]=2[CH:13]=1
Reactant: ClCc1nc2ccccc2o1
Reactant: CN(C)c1cc(N)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]3(O)C(=O)C1=C2O
Agent: CCCNCc1nc2ccccc2o1
Agent: COC(CCl)(OC)OC
Agent: N
Solvent: CCCN
Solvent: CN(C)C=O
Product: CCCNCc1nc2cc(N(C)C)c3c(c2o1)C(=O)C1=C(O)[C@]2(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]2C[C@@H]1C3
Temperature: 25 °C

Procedure:
9-aminominocycline sulfate salt (1.0 g, 1.50 mmol) is dissolved in DMF (50 mL) and treated with a solution of 2-chloro-1,1,1-trimethoxyethane (0.463 g, 3.00 mmol, 2 equivalents). The reaction is stirred at room temperature until mass spectrometry shows conversion to the chloromethylbenzoxazole derivative. The solution is then treated with n-propylamine (10 mL, excess) and stirred until mass spectrometry shows conversion to the n-propylaminomethyl benzoxazole. The mixture is concentrated under reduced pressure to remove excess n-propylamine, and then poured slowly into ether (1 L) and HCl/ether is added to precipate the salt. The solid is rinsed with fresh ether and dried under vacuum. The crude solid is dissolved in water (100 mL) giving a solution at pH 2. The pH is raised successively by 0.5 units with aqueous ammonia, and extracted with dichloromethane. The fractions extracted at pH 4-4.5 are combined, dried (Na2SO4), filtered and concentrated nearly to dryness. A small volume of methanol is added and the solution is treated with 1M HCl in ether. The precipitated solid is collected by filtration, washed with fresh ether and dried under vacuum to yield 0.067 g of the product as its HCl salt.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[OH:28][C:29]([CH3:33])([CH3:32])[C:30]#[CH:31]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCN(CC)CC>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:31]#[C:30][C:29]([OH:28])([CH3:33])[CH3:32])=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C#CC(C)(C)O
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[C@@H](c1ccc(C#CC(C)(C)O)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Yield: 88.6 %

Procedure:
A microwave vial was charged with (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (216 mg, 0.50 mmol), 3-hydroxy-3-methyl-1-butyne (0.24 mL, 2.50 mmol), CuI (9.5 mg, 0.05 mmol) and Et3N (4 mL). The mixture was sparged with N2 for 5 min and PdCl2(PPh3)2 (21 mg, 0.03 mmol) was added. The mixture was sparged with N2 for 5 min and heated at 100° C. for 2 h in the microwave. The mixture was diluted with EtOAc (200 mL), washed with 5% aq HCl (2×30 mL), satd aq NaHCO3 (30 mL) and brine (30 mL), and dried over Na2SO4. Removal of the solvent left a dark oil (379 mg) which was applied to a 2 g silica SPE Cartridge. The cartridge was eluted with 0, 25, 50 and 75% EtOAc in hexanes (20 mL) of each and EtOAc (2×20 mL) to give six fractions. Fractions 4 and 5 were pooled and concentrated to afford the title compound (193 mg, 89%) as an oil. LC-MS Method 1 tR=1.53 min, m/z=436, 378; 1H NMR (CDCl3) 1.12 (s, 3H), 1.18 (s, 3H), 1.52 (d, 3H), 1.60 (s, 6H), 2.15 (m, 1H), 2.19 (s, 2H), 2.20-2.45 (2H), 2.80 (m, 1H), 5.66 (q, 1H), 6.86 (d, 2H), 7.17 (d, 2H), 7.30-7.40 (5H)
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:15])[CH:9]([Cl:14])[C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(C)C>[Cl:14][C@@H:9]([C@H:8]([OH:15])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(Cl)C(=O)Cc1ccccc1
Reactant: [H][H]
Solvent: CC(C)O
Product: COC(=O)[C@@H](Cl)[C@H](O)Cc1ccccc1
Yield: 98.6 %

Procedure:
In a 200 ml Hastelloy autoclave was put 50 g (GC p=93.2%, 220 mmol) of methyl 4-phenyl-2-chloro-3-oxobutyrate (compound (III)), 99.4 mg (0.055 mmol) of Ru2Cl4 [(R)-T-BINAP]2NEt3, and 100 ml of isopropyl alcohol (IPA) under a nitrogen stream. After heating the solution, a hydrogen pressure of 30 atm was introduced into the autoclave at 100° C. to initiate the reaction. Then, it was confirmed by GC that no unreacted matter remained to complete the reaction (for 1 to 2 hours). IPA was recovered under reduced pressure at not higher than 50° C. to obtain 50.3 g [GC p=92.2%, HPLC o.p. syn 87% (80.5% ee), anti 13% (94.6% ee)] of compound (IV) in a yield of 98.6%.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[OH-].C([Sn+2]Cl)CCC.[NH3:18]>>[C:1]([NH2:18])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: N
Agent: CCCC[Sn+2]Cl
Agent: [OH-]
Product: NC(=O)c1ccccc1
Temperature: 165 °C

Procedure:
To demonstrate the ability to conduct the amidation in an inert reaction medium 400 gms. benzoic acid was dissolved in 400 mls. mineral spirits with 2 gms. butylchlorotin dihydroxide. The solution was then heated with agitation to 165° C. while introducing ammonia below the surface ofthe liquid through a dispersion tube at a rate of 0.5 SCFH. As the reactionprogressed the amide product came out of solution. An acid value of 12 was achieved after only 7 hours reaction. At the completion of the reaction the insoluble amide product was recovered by filtration, washed and dried.Benzamide (melt point 133°-135° C.) obtained by this process is substantially free of undesirable nitrile by-product.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].[CH2:33]([N:40]1[CH2:44][CH2:43][CH2:42][C@@H:41]1[CH2:45][OH:46])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+]>C(OCC)(=O)C.O.O1CCOCC1>[CH2:33]([N:40]1[CH2:44][CH2:43][CH2:42][C@@H:41]1[CH2:45][O:46][C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1Cl
Reactant: OC[C@H]1CCCN1Cc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1OC[C@H]1CCCN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 50.1 %

Procedure:
A mixture of 5-chloro-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (300 mg), [(2R)-1-benzylpyrrolidin-2-yl]methanol (251 mg), 18-crown-6 (346 mg), potassium t-butoxide (147 mg), and dioxane (3 mL) was stirred at 100° C. for 5 hours. To the mixture were added water and ethyl acetate, followed by liquid separation. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH2 type: eluent; ethyl acetate:chloroform=1:1) to obtain 5-{[(2R)-1-benzylpyrrolidin-2-yl]methoxy}-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (201 mg) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:6]=1.Br[CH2:22][CH:23]1[CH2:26][CH2:25][CH2:24]1.[OH-].[K+].O>CS(C)=O>[CH3:1][O:2][C:3](=[O:20])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][CH2:15][C:16]([F:17])([F:19])[F:18])[CH:6]=1)[CH2:22][CH:23]1[CH2:26][CH2:25][CH2:24]1
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])c(OCC(F)(F)F)c1
Reactant: BrCC1CCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C(CC1CCC1)c1ccc([N+](=O)[O-])c(OCC(F)(F)F)c1
Reaction time: 16 h
Yield: 43.9 %

Procedure:
[4-Nitro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid methyl ester (33 g, 94.5 mmol) and (bromomethyl)cyclobutane (17 g, 114.1 mmol) were mixed in DMSO (50 mL) and KOH (6.4 g, 114.1 mmol) was added in portions over 15 min. The reaction mixture was stirred for 16 h and water (100 mL) was added. The reaction mixture was extracted with EtOAc (3×50 mL). The combined organic phases were dried over MgSO4 and evaporated to give a crude yellow oil, which was purified by silica gel gradient column chromatography using Heptane-EtOAc (9:1-4:1) to give 15 g (40%) of the product as a yellow oil. (The synthesis was repeated with temperature kept at 40° C. over 16 h to give the product in quantitative yield). 1H NMR (300 MHz, CDCl3/TMS): δ 7.86 (d, J=8.0 Hz, 1H), 7.12-7.09 (m, 2H), 4.50 (q, J=7.7 Hz, 2H), 3.68 (s, 3H), 3.55 (t, J=7.3 Hz, 1H), 2.22-2.10 (m, 2H), 2.03-1.75 (m, 5H), 1.70-1.55 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 172.9, 150.5, 146.4, 139.4, 126.0, 122.7, 122.6 (d, 1JCF=277.6 Hz), 116.0, 67.5 (q, 1JCF=36.7 Hz), 52.3, 49.6, 40.7, 33.9, 28.2, 27.9, 18.4.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([N:18]2[CH:22]=[N:21][N:20]=[CH:19]2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[CH3:23][Si](C=[N+]=[N-])(C)C>CO.CCCCCC>[CH3:23][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:11]([N:18]2[CH:22]=[N:21][N:20]=[CH:19]2)[C:12]([C:14]([F:17])([F:15])[F:16])=[CH:13][C:5]=1[NH:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(C(F)(F)F)c(-n2cnnc2)cc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1cc(-n2cnnc2)c(C(F)(F)F)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
A solution of 1.3 g (4.14 mmol) of 2-acetylamino-5-[1,2,4]triazol-4-yl-4-trifluoromethyl-benzoic acid in 15 ml of methanol is treated dropwise with 3.1 ml (6.21 mmol) of a 2M solution of trimethylsilyl diazomethane in hexane. The mixture is stirred for 1 hour at room temperature and another 1.5 ml (3.00 mmol) of a solution of trimethylsilyl diazomethane in hexane (2M) is added. After 1 hour, the reaction is quenched by adding glacial acetic acid until no more gas evolution is observed. The mixture is concentrated in vacuo and the residue taken up in ethyl acetate, washed with water, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, gradient 100% ethyl acetate to ethyl acetate/methanol 9:1) afforded 456 mg (34%) of 2-acetylamino-5-[1,2,4]triazol-4-yl-4-trifluoromethyl-benzoic acid methyl ester as yellow crystals, m.p. 180-184° C.
Reaction SMILES: [C:1]1([C:11](O)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>C1COCC1>[C:1]1([CH2:11][OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2ccccc12
Solvent: C1CCOC1
Product: OCc1cccc2ccccc12
Temperature: 25 °C

Procedure:
Naphthalene-1-carboxylic acid is dissolved in dry THF and 5 equiv. of borane dimethylsulfide complex are added. The mixture obtained is stirred at rt, diluted with EtAc, washed with 1N HCl and 5% NaHCO3 solution, dried and solvent is evaporated. (Naphthalene-1-yl)-methanol is obtained, which is dissolved in CH2Cl2. To the solution obtained 1.5 equiv. of Dess-Martin reagent are added at rt. The mixture obtained is diluted with EtAc, extracted with 1N HCl and 5% NaHCO3-solution, dried and solvent is evaporated. Naphthalene-1-carboxaldehyde is obtained and dissolved with 1 equiv. of racemic-Boc-α-phosphonoglycine trimethylester in CH2Cl2 and 1.1 equiv. of DBU are added. The mixture obtained is stirred at rt and treated in sequence with 1N HCl and 5% NaHCO3 solution. The phases obtained are separated, the organic phase obtained is dried and solvent is evaporated. 2-Boc-amino-3-(naphthalene-1-yl)-acrylic acid methyl ester (cis/trans mixture) is obtained, is dissolved in MeOH/H2O at pH 6.5 (phosphate buffer) and 20 w/w % of 10% Pd/C are added. The mixture obtained is hydrogenated at rt and 50 bar, the catalyst is filtered off and from the filtrate obtained solvent is evaporated. Racemic naphythylalanine methylester is obtained, dissolved in methanolic NH3 and stirred. The mixture obtained is subjected to extractive work up. Racemic naphythylalanine amide is obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1Br)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].[C:17]1([CH3:26])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[CH:13]=[CH:14][C:15]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH3:26])(=[O:3])[CH3:2]
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(Br)c(COC(C)=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccccc2C)c(COC(C)=O)c1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A mixture of methyl 3-[(acetyloxy)methyl]-4-bromobenzoate (4.7 g; 16.4 mmol; 1 eq.), o-tolylboronic acid (2.45 g; 18 mmol; 1.1 eq.), potassium carbonate (11.3 g; 82 mmol; 5 eq.) and Pd(PPh3)4 (1.89 g; 1.64 mmol; 0.1 eq.) in toluene (23.5 mL) and water (23.5 mL) was refluxed for 2 hours. After cooling to RT, the reaction mixture was filtered through a pad of Celite® which was further washed with toluene (50 mL). The filtrate was concentrated in vacuo, the residue taken up in EtOAc (250 mL) and washed with sat. aq. NaHCO3 (100 mL), water (100 mL) and brine (100 mL), dried over magnesium sulphate and concentrated in vacuo to afford the title compound (4.9 g, quantitative) as a brown oil. HPLC (Method A) Rt 5.23 min (Purity 62.3%).
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH:41]1[CH:45]=[CH:44][N:43]=[CH:42]1>COCCOC>[C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])[C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([N:41]1[CH:45]=[CH:44][N:43]=[CH:42]1)[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: Cc1cc2nc(OS(=O)(=O)C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: c1c[nH]cn1
Solvent: COCCOC
Product: Cc1cc2nc(-n3ccnc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 95 °C
Yield: 19.2 %

Procedure:
To a solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate (compound of Example 26) (200 mg, 0.332 mmol) in 1,2-dimethoxyethane was added imidazole (226 mg, 3.32 mmol) and the reaction was sealed and heated to 95° C. overnight. The crude reaction mixture was absorbed onto silica gel and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a yellow oil (33.2 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C30H35ClN3O3: 520.23. found: 520.35.