Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([OH:18])=O)[O:9][N:8]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[OH:30][CH:31]([C:45]1[CH:50]=[CH:49][C:48](/[C:51](=[N:53]/O)/[NH2:52])=[CH:47][CH:46]=1)[CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][C@H:35]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:34]1>ClCCl>[OH:30][CH:31]([C:45]1[CH:50]=[CH:49][C:48]([C:51]2[N:53]=[C:16]([C:10]3[O:9][N:8]=[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[C:11]=3[C:12]([F:13])([F:14])[F:15])[O:18][N:52]=2)=[CH:47][CH:46]=1)[CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][C@H:35]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:34]1
Reactant: O=C(O)c1onc(-c2ccccn2)c1C(F)(F)F
Reactant: CCOC(=O)C[C@H]1CCCN(CC(O)c2ccc(/C(N)=N/O)cc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CCCN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccn5)c4C(F)(F)F)n3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under an argon atmosphere, 3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-5-carboxylic acid, Int-IV (40 mg, 0.155 mmol) was suspended in dichloromethane (1.5 mL) with sonication and DMF (5 μl, 0.065 mmol) was added. Oxalyl chloride (54.3 μl, 0.620 mmol) was added dropwise over 1-2 minutes. The reaction vial was flushed with argon and sealed. After 3 h, the contents were concentrated in vacuo. The material was re-constituted in dichloromethane and a solution of ethyl 2-((3R)-1-(2-hydroxy-2-(4-((Z)—N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidin-3-yl)acetate (54.1 mg, 0.155 mmol) in DCM (1-2 mL) was added. The reaction mixture was stirred for 3 days at room temperature and then purified by Prep HPLC to afford ethyl 2-((3R)-1-(2-hydroxy-2-(4-(5-(3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetate which was suspended in dioxane (2-3 mL) and 3N aq HCl (1 mL) was added. The mixture was placed in a sand bath heated to 50° C. overnight. The solution was evaporated, re-evaporated from chloroform-d and then placed under high vacuum to give 2-((3R)-1-(2-hydroxy-2-(4-(5-(3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid as a clear colorless film. 1H NMR (500 MHz, MeOD) δ ppm 8.69 (1 H, d, J=4.72 Hz), 8.14 (2H, d, J=8.32 Hz), 7.95 (1H, td, J=7.70, 1.80 Hz), 7.86 (1H, d, J=7.77 Hz), 7.61 (2H, d, J=8.32 Hz), 7.49-7.56 (1H, m), 5.17 (1H, dd, J=9.71, 4.16 Hz), 3.80 (1H, br. s.), 3.52-3.67 (4H, m), 2.89 (1H, br. s.), 2.73 (1H, t, J=11.93 Hz), 2.18-2.39 (3H, m), 1.79-1.94 (3H, m). HPLC RT=0.77 min, MH+=544. Waters Masslynx instrument equipped with a BEH 2.1×50 mm 17 uM C18 column and a method of 2-98% B solvent over 1.6 min at a flow rate of 0.8 mL/min. Solvent A is water; solvent B is acetonitrile and both contain 0.5% TFA.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]([CH3:40])([CH3:39])[C:9]([O:11][CH2:12][N:13]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][C:18]([OH:38])=[CH:19][C:20]=2[O:24][CH2:25][C@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:15]=[CH:14]1)=[O:10].S(OC)(OC)(=O)=O>CN(C)C=O>[CH3:7][C:8]([CH3:40])([CH3:39])[C:9]([O:11][CH2:12][N:13]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][C:18]([O:38][CH3:1])=[CH:19][C:20]=2[O:24][CH2:25][C@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:15]=[CH:14]1)=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(O)cc2ncn(COC(=O)C(C)(C)C)c(=O)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COc1cc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)c2c(=O)n(COC(=O)C(C)(C)C)cnc2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 47.9 %

Procedure:
Potassium carbonate (1.60 g, 12.6 mmol) was added to a solution of tert-butyl (2R)-2-{[(3-{[(2,2-dimethylpropanoyl)oxy]methyl}-7-hydroxy-4-oxo-3,4-dihydroquinazolin-5-yl)oxy]methyl}pyrrolidine-1-carboxylate (1.50 g, 3.2 mmol) in dimethylformamide (10 ml) and the mixture stirred at 0° C. for 5 minutes. Dimethyl sulphate (0.6 ml, 6.3 mmol) was added and the reaction stirred at 0° C. for a further 5 minutes and then warmed to room temperature and stirred for 1 hour. The reaction mixture was evaporated under reduced pressure and the residue dissolved in dichloromethane (20 ml) and washed with water (2×20 ml). The organics were dried over magnesium sulphate, filtered and evaporated under reduced pressure to give tert-butyl (2R)-2-{[(3-{[(2,2-dimethylpropanoyl)oxy]methyl}-7-methoxy-4-oxo-3,4-dihydroquinazolin-5-yl)oxy]methyl}pyrrolidine-1-carboxylate (0.750 g, 48% yield) which was used in the next stage without further purification.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17].[Cl:19][C:20]1[CH:25]=[C:24]([C:26](Cl)=[O:27])[CH:23]=[CH:22][N:21]=1>C(Cl)Cl>[Cl:19][C:20]1[CH:25]=[C:24]([C:26]([NH:13][C:12]2[CH:14]=[CH:15][C:9]([CH3:8])=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[O:27])[CH:23]=[CH:22][N:21]=1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccnc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1[N+](=O)[O-]
Yield: 26.8 %

Procedure:
Triethylamine (31.8 ml) was added to a stirred mixture of 4-methyl-3-nitroaniline (15.8 g), 2-chloropyridine4-carbonyl chloride (20 g) and methylene chloride (1 liter) and the resultant mixture was stirred at ambient temperature for 16 hours. The precipitate was isolated, washed with a saturated aqueous sodium bicarbonate solution and with methylene chloride and dried under vacuum at 40° C. There was thus obtained 2-chloro-N-(4-methyl-3-nitrophenyl)pyridine-4-carboxamide (10.2 g). The organic filtrate was washed with a saturated aqueous sodium bicarbonate solution, dried (MgSO4) and evaporated. The residue was triturated under methylene chloride and the resultant solid was isolated and dried under vacuum at 40° C. There was thus obtained a second crop (8.13 g) of 2-chloro-N-(4-methyl-3-nitrophenyl)pyridine-4-carboxamide; NMR Spectrum: (DMSOd6) 2.48 (s, 3H), 7.51 (d, 1H), 7.86 (m, 1H), 7.96 (m, 2H), 8.49 (m, 1H), 8.64 (m, 1H), 10.85 (s, 1H); Mass Spectrum: M+H+ 292 and 294.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:38]=[C:39]([O:41][CH3:42])[CH:40]=1)[CH2:36]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:36][C:35]2[CH:38]=[C:39]([O:41][CH3:42])[CH:40]=[C:33]([O:32][CH3:31])[CH:34]=2)[CH:6]=1
Reactant: COC(=O)Cc1cccc(OCCCNCC(c2ccccc2)c2ccccc2)c1
Reactant: COc1cc(CBr)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cccc(OCCCN(Cc2cc(OC)cc(OC)c2)CC(c2ccccc2)c2ccccc2)c1
Temperature: 45 °C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
To a solution of {3-[3-(2,2-diphenyl-ethylamino)-propoxy]-phenyl}-acetic acid methyl ester (3) (0.30 g, 0.00074 mol) in DMF (10 mL), was added 3,5-dimethoxy-benzyl bromide (0.23 g, 0.0011 mol) and powdered potassium carbonate (0.96 g, 0.007 mol), the reaction mixture was heated and stirred at 45° C. for 18 hours. After cooling, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, concentrated to an oil, which was purified by flash chromatography (8:2 Hexanes/EtOAc) to give the desired product as oil 0.30 g in 92% yield. 1H NMR (CDCl3) δ 7.20 (m, 9H), 7.11 (t, 2H), 6.83 (d, 1H), 6.64 (s, 1H), 6.62 (d, 1H), 6.26 (s, 3H), 4.18 (t, 1H), 3.67 (s, 3H), 3.63 (s, 6H), 3.61 (s, 2H), 3.56 (s, 2H), 3.54 (t, 2H), 3.08 (d, 2H), 2.60 (t, 2H), 1.79 (t, 2H). 13C NMR (CDCl3) δ 173.3, 161.9, 160.5, 144.9, 143.8, 136.6, 130.8, 129.7, 129.6, 127.6, 122.7, 116.9, 114.5, 107.8, 100.6, 67.1, 61.2, 60.8, 56.6, 53.4, 52.0, 51.2, 42.7, 28.2.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[CH3:21][O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH:12][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)CCCCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)CCCCCNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Benzenesulfonyl chloride (92a) (0.88 g, 5.0 mmol) was added to the mixture of methyl 6-aminohexanoate hydrochloride (91) (1.82 g, 10 mmol) in acetonitrile (10 ml) and sodium carbonate (2.6 g, 24.6 mmol) in water (10 ml). The mixture was stirred for 6 hours at ambient temperature, and the product was extracted with ethyl acetate (30 ml). The extract was dried (Na2SO4) and solvents were removed under reduced pressure. The product was chromatographed on silica gel with ethyl acetate-hexane (1:2) as eluent. The title compound was obtained as oil (1.28 g, 90%). 1H NMR δH (90 MHz, DMSO-d6) δ: 0.90-1.63 (6H, m, CH2); 2.21 (2H, t, J=7.0 Hz, CH2); 2.71 (2H, q, J=6.0 Hz, CH2N); 3.58 (3H, s, CH3); 7.40-7.72 (3H, m, C6H3); 7.72-7.89 (2H, m, C6H2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[C:10](#[N:13])[CH:11]=[CH2:12]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:12][CH2:11][C:10]#[N:13])=[CH:5][CH:4]=1
Reactant: C=CC#N
Reactant: COc1ccc(O)cc1
Solvent: CO
Product: COc1ccc(OCCC#N)cc1
Temperature: 78 °C
Yield: 89.48 %

Procedure:
A 740 g (5.96 mol, 1 eq.) sample of 4-methoxyphenol was charged to a 3 necked 5 L flask under nitrogen. Triton B (50 mL of a 30% wt. solution in methanol) was charged to the flask, and stirring initiated via an overhead stirrer. Acrylonitrile (2365 mL, 35.76 mol, 6 eq.) was then charged to the reaction flask in a single portion, and the reaction mixture heated at 78° C. for 36 h. HPLC analysis indicated that the reaction was complete at this point. Solvents were removed via rotary evaporation, and the resulting oil was chased with toluene to remove excess acrylonitrile. The crude material was recrystallized from TBME (tert-butyl methyl ether) 10 volumes relative to the crude weight), and dried in a vacuum oven to give 945 g of 1 as white crystals (Yield: 89.48%). 1H NMR (450 MHz, CDCl3): δ=2.72 (t, 2H; CH2CN); δ=3.83 (s, 3H; OCH3); δ=4.05 (t, 2H; OCH2); δ=6.70 (m, 4H; Ar—H); 13C NMR (112.5 MHz, CDCl3): d=18.843 (CH2CN); 55.902 (OCH3); 63.699 (OCH2); 114.947 (CH3OCCH); 116.183 (CH2OCCH); 117.716 (CN); 151.983 (CH3OC); 154.775 (CH2OC).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([C:19]([O:21]CC)=[O:20])[CH:18]=2)=[C:9]([C:24]2[S:25][CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:28]=2)[CH:8]=1)=[O:5])[CH3:2].[Li+].[OH-].C(#N)C>C1COCC1>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([C:19]([OH:21])=[O:20])[CH:18]=2)=[C:9]([C:24]2[S:25][CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:28]=2)[CH:8]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(-c3ccccc3)cs2)c(-c2cncc(C(=O)OCC)c2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(-c2nc(-c3ccccc3)cs2)c(-c2cncc(C(=O)O)c2)cn1
Temperature: 25 °C
Yield: 31 %

Procedure:
In a 25 mL round-bottomed flask ethyl 6′-{[(ethylamino)carbonyl]amino}-4′-(4-phenyl-1,3-thiazol-2-yl)-3,3′-bipyridine-5-carboxylate (Example 131, 0.20 g, 0.42 mmol) was suspended in THF (3 mL). 1N LiOH (1.20 mL, 1.21 mmol) was added and the solution was stirred at room temperature over night. The solvent was removed and the resulting residue was diluted with water. The pH was adjusted to 4 (pH paper) with 2N HCl. White solids formed. They were trichurated with acetonitrile for 30 minutes and then filtered, washed with acetonitrile and dried in vacuo to give 58 mg of the title compound. LC/MS (ES+)[(M+H)+]: 446 for C23H11N5O3S. 1H NMR (300 MHz, d6-DMSO): 1.10 (t, 3H), 3.21 (m, 2H), 7.32-7.40 (m, 3H), 7.65 (t, 1H), 7.70 (s, 1H), 7.72 (s, 1H), 8.22 (s, 1H), 8.23-8.26 (m, 2H), 8.31 (s, 1H), 8.73 (d, 1H), 9.08 (d, 1H), 9.45 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH2:4][N:5]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]=2)[NH:6][C:7]=1[CH:8]=O)#[N:2].C(O)(=O)[CH2:22][C:23]([OH:25])=[O:24]>N1CCCCC1.N1C=CC=CC=1>[C:1]([C:3]1[CH2:4][N:5]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]=2)[NH:6][C:7]=1[CH:8]=[CH:22][C:23]([OH:25])=[O:24])#[N:2]
Reactant: O=C(O)CC(=O)O
Reactant: N#CC1=C(C=O)NN(c2ncc(C(F)(F)F)cc2Cl)C1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: N#CC1=C(C=CC(=O)O)NN(c2ncc(C(F)(F)F)cc2Cl)C1

Procedure:
A stirred solution of 0.3 gram (0.001 mole) of 4-cyano-5-formyl-2-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazole, 0.2 gram (0.002 mole) of malonic acid, two drops of piperidine, and 3 mL of pyridine was heated at reflux for about 18 hours. After this time, the reaction mixture was cooled and was concentrated under reduced pressure to a residue. The residue was stirred with excess aqueous 2N hydrochloric acid and ethyl acetate. The organic layer was separated and washed with aqueous 2N hydrochloric acid and then with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was triturated several times with petroleum ether, and each time the supernatent liquid was discarded. The resultant solid was dried, yielding 3-[4-cyano-2-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylic acid. The nmr spectrum was consistent with the proposed structure and was identical to the nmr spectrum of this compound prepared by the method of Example 4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]([CH3:26])[NH:21][CH2:20][CH2:19]2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][CH:25]=[C:16]([O:15][CH3:14])[CH:17]=4)[CH:22]3[CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: COc1ccc2c(c1)CCNC2C
Product: COc1ccc2c(c1)CCN(C(=O)c1cc3ncc(Cl)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Methoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [OH:1][CH:2]([CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:23]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](O)=[O:4].Cl.[CH2:35]([O:37][NH2:38])[CH3:36]>>[CH2:35]([O:37][NH:38][C:3](=[O:4])[CH:2]([OH:1])[CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:23]1)[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:36]
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Reactant: CCON
Agent: Cl
Product: CCONC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 2-hydroxy-4-phenyl-3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)butanoic acid with O-ethylhydroxylamine hydrochloride. ESI-MS [M+H]+: 486.2
Reaction SMILES: C(O[CH:5]([C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][N:15]=[CH:16]2)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)C>C(O)C>[CH:16]1[C:17]2[C:12](=[C:11]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:14][N:15]=1
Reactant: CCOC(=O)C(OC(C)=O)c1cccc2cnccc12
Solvent: CCO
Product: CCOC(=O)Cc1cccc2cnccc12
Temperature: 60 °C
Reaction time: 6 h
Yield: 82.6 %

Procedure:
The product of Example 70C (1.43 g, 5.23 mmol) in absolute ethanol (200 mL) was treated with dry 10% Pd/C (0.122 g) and triethylamine (10.4 mL). The reaction mixture was stirred at 60° C. for 6 hours under H2 (60 psi), filtered and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (5% methanol/CH2Cl2) to provide the title compound as light brown oil (0.93 g, 67%). MS (ESI+) m/z 216 (M+H)+, (ESI−) m/z 214 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 1.17 (t, J 7.1, 3H), 4.09 (q, J 7.1, 2H), 4.17 (s, 2H), 7.64 (m, 1H), 7.72 (d, J 6.2, 1H), 7.81 (d, J 5.7, 1H), 8.07 (d, J 7.9, 1H), 8.54 (d, J 6.1, 1H), 9.33 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](O)=[O:5].[CH2:12]([O:14][C:15](=[O:26])[CH:16]=[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:18])[CH3:13].[H-].[Na+]>C(#N)C>[CH2:12]([O:14][C:15]([C:16]1[C:2]2[C:3](=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[N:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:17]=1[CH3:18])=[O:26])[CH3:13]
Reactant: Cc1cccc(Br)c1C(=O)O
Reactant: CCOC(=O)C=C(C)Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1c(C)n(-c2ccccc2)c(=O)c2c(C)cccc12
Temperature: 0 °C
Yield: 22.3 %

Procedure:
To a cold (ice/water bath) solution of 2-bromo-6-methyl-benzoic acid (650 mg, 3.023 mmol) and 3-phenylamino-but-2-enoic acid ethyl ester (750 mg, 3.65 mmol) in acetonitrile (10 ml), sodium hydride (267 mg, 6.67 mmol, 60% dispersion in mineral oil) was added in portions. The cold bath was removed and the mixture was sonicated at ambient temperature until gas evolution ceased (10 min). Copper (I) bromide was added (957 mg, 6.67 mmol) and the obtained suspension was flushed with argon, sealed and heated under microwave irradiation at +80° C. for 30 min. LC-MS indicated a full conversion to 2-(1-ethoxycarbonyl-2-phenylamino-propenyl)-6-methyl-benzoic acid (LC-MS (m/z) 340.4 (MH+); tR=1.59. The obtained suspension was heated at +160° C. under microwave irradiation for 30 min. It was diluted with ethyl acetate (50 ml) and filtered. The obtained organic solution was washed with 1M HCl (3×50 ml), water (2×10 ml) and sat. aq. NaHCO3 solution (30 ml), absorbed on SiO2 (3 g) and flash chromatographed on SiO2 (50 g, gradient heptane-30% ethyl acetate in heptane) to give 217 mg of yellow oil. Yield 22%. LC-MS (m/z) 322.2 (MH+); tR=1.62. 1H NMR (500 MHz, DMSO-d6): 1.32 (t, 3H), 1.91 (s, 3H), 2.74 (s, 3H), 4.39 (q, 2H), 7.3 (d, 1H), 7.36 (overlapping m, 3H), 7.49 (m, 1H), 7.55 (t, 2H), 7.61 (t, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[O:7]=[C:8]1[CH:12]([NH:13][C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:21])[CH2:11][CH2:10][O:9]1.Cl>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]([N:13]([CH:12]1[CH2:11][CH2:10][O:9][C:8]1=[O:7])[C:14]1[C:15]([CH3:21])=[CH:16][CH:17]=[CH:18][C:19]=1[CH3:20])=[O:5]
Reactant: Cc1cccc(C)c1NC1CCOC1=O
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1C
Product: COCC(=O)N(c1c(C)cccc1C)C1CCOC1=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
Over 2 hours, 113 g (1.04 moles) of methoxyacetyl chloride are added at 60°-70° C. and under a pressure of 70°-80 mbar to a suspension of 205 g (1.0 mole) of N-(2-oxotetrahydro-3-furyl)-2,6-dimethylaniline in 500 ml of xylene. Towards the end of the addition of methoxyacetyl chloride the reaction mixture begins to boil, with hydrogen chloride gas evolving. When the addition of methoxyacetyl chloride is complete, the reaction mixture is stirred for 3 hours under weak reflux at 60°-65° C. and under a pressure of 70-80 mbar, and the hydrogen chloride evolving during the reaction is removed. Subsequently, half of the xylene is distilled off, the reaction mixture is cooled to 20° C., the precipitated product is filtered off, washed with xylene and dried, affording 263 g (95% of theory) of N-methoxyacetyl-N-(2-oxotetrahydro-3-furyl)-2,6-dimethylaniline with a melting point of 118°-120° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].OS(O)(=O)=O.[N+:17]([O-])([OH:19])=[O:18]>O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[C:9]([N+:17]([O-:19])=[O:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C(C)(C)C)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
Nitration was performed as described in General Method 12 using tert-butyl-4-methylbenzene (25 g), concentrated H2SO4 (92 g), 70% HNO3 (82 g), and H2O (25 g). The crude product was purified via distillation under vacuum.
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[CH3:18]>CN(C)C=O>[CH2:10]([N:9]([CH3:18])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 39.5 %

Procedure:
60% dispersion of sodium hydride in mineral oil (2.37 g, 0.0592 mol) was added to a solution of N-phenyl-N-benzylamine (10.33 g, 0.0564 mol) in anhydrous N,N-dimethylformamide (200 mL) at 0° C. The reaction mixture was warmed up to ambient temperature and stirred for 45 min. Iodomethane (7.99 g, 0.0564 mol) was added dropwise and the stirring at ambient temperature was continued under an atmosphere of nitrogen for 20 hours. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate (250 mL) and water (200 mL). The organic phase was dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (2:98) as mobile phase to yield N-benzyl-N-methyl-N-phenylamine (4.4 g, 0.0223 mol) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:10](=[CH2:15])[C:11]([O:13]C)=[O:12].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:10](=[CH2:15])[C:11]([OH:13])=[O:12]
Reactant: C=C(Oc1ccccc1OC)C(=O)OC
Solvent: O
Solvent: C1CCOC1
Product: C=C(Oc1ccccc1OC)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(2-methoxyphenyloxy)propenoate (0.30 g, 1.4 mmol) in tetrahydrofuran (30 mL) and water (30 mL was added lithium hydroxide monohydrate 0.17 g, 4.0 mmol). After stirring at room temperature overnight, the reaction was quenched by addition of concentrated hydrochloric acid (final pH=2), and the product was extracted with ethyl acetate (3×100 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.42 (ddd, 1H), 7.22 (dd, 1H), 7.10 (dd, 1H), 6.97 (ddd, 1H), 5.48 (d, 1H), 4.51 (d, 1H), 3.64 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:4](=[O:12])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[Br:23]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:23][C:7]1[N:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[C:4](=[O:12])[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)[C:2]=1[CH3:1]
Reactant: COC(=O)c1ncc(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Br)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 18.5 °C

Procedure:
Methyl 5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (400 g, 1 eq) was dissolved in DMF (3 L) and stirred at 17-20° C. N-Bromosuccinimide (229.3 g, 1 eq) was dissolved in DMF (1 L), and added to the ester solution over 1 hour. Post-addition, the reaction was stirred at 17-20° C. for 10 hours. The reaction mixture was added to water (15 L) with stirring. The resulting slurry was stirred at 20-25° C. overnight. The title compound was collected by filtration. The cake was washed with water (1 L) and heptane (1 L) and then dried to constant weight at 40° C. to give 456 g (91%).