Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[C:27]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:23]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:66][C:67]1[CH:74]=[C:73]([O:75][CH3:76])[CH:72]=[CH:71][C:68]=1[CH:69]=[O:70].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)(Cl)Cl>[CH3:76][O:75][C:73]1[CH:72]=[CH:71][C:68]([CH:69]=[O:70])=[C:67]([O:66][CH2:23][C:22]2[CH:21]=[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[C:26]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH:25]=2)[CH:74]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Reactant: COc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(COc2cc(OC)ccc2C=O)cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Temperature: 80 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
3,4,5-Tri(octadecyloxy)benzylchloride (93.6 g, wet, <90.8 mmol), 2-hydroxy-4-methoxybenzaldehyde (15.2 g, 0.10 mol) and potassium carbonate (31.4 g, 0.23 mol) were suspended in DMF (830 ml), and the suspension was stirred at 80° C. overnight. The reaction mixture was dissolved in chloroform (1600 ml), and the mixture was washed 3 times with 1N hydrochloric acid (800 ml), once with 5% aqueous sodium hydrogen carbonate solution (800 ml), and once with 20% brine (800 ml). The solvent was evaporated, and the residue was precipitated with methanol (800 ml) and washed with acetonitrile (800 ml) to give 4-methoxy-2-[3′,4′,5′-tris(octadecyloxy)benzyloxy]benzaldehyde (93.5 g, 89.2 mmol, 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C(C)=CC=CC=1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22](Cl)=[CH:21][CH:20]=1)([O-:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.O>[CH:5]1[CH:6]=[CH:7][C:2]([NH:1][C:22]2[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=2)=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Temperature: 96 °C
Yield: 129.4 %

Procedure:
186 g of aniline, 60 ml of xylene, 4.5 g of 1,10-phenanthroline, 157.5 g of 4-nitrochlorobenzene, 2 g of CuO and 76.3 g of potassium carbonate are heated to 195° C. for 7 hours in a water separator. The reaction mixture is cooled to 96° C. After the precipitated salts have been separated off by filtration, the filter cake is thoroughly washed with 200 ml of hot xylene. The filtrate and the washing liquid are combined, and after the solution has been cooled to 0° C., 127 g of 4-nitrodiphenylamine of melting point 128°-130° C. crystallize out and are separated off by filtration. 93 g of aniline, 157.5 g of p-nitrochlorobenzene and 76.3 g of potassium carbonate are added to the mother liquor produced in this procedure, and the mixture is freed from excess xylene by distillation, and heated at 195° C. for 11 hours in a water separator. After the salts have again been filtered off, the filtrate is worked up by steam distillation, as described in Example 7. 277 g of 4-nitrodiphenylamine of melting point 107°-111° C. are obtained.
Reaction SMILES: [NH2:1][CH:2]([C:9]1([CH3:14])[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:15][C:16]1[C:21]([C:22]#[N:23])=[CH:20][C:19]([F:24])=[C:18](Cl)[N:17]=1.C(N(CC)CC)C>C1COCC1>[Cl:15][C:16]1[N:17]=[C:18]([NH:1][C@@H:2]([C:9]2([CH3:14])[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:19]([F:24])=[CH:20][C:21]=1[C:22]#[N:23]
Reactant: CCOC(=O)CC(N)C1(C)CCCC1
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@@H](Nc1nc(Cl)c(C#N)cc1F)C1(C)CCCC1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a solution of racemic ethyl 3-amino-3-(1-methylcyclopentyl)propanoate, 33a, (0.40 g, 2.01 mmol) and 2,6-dichloro-5-fluoro-pyridine-3-carbonitrile (0.46 g, 2.41 mmol) in THF (20 mL) was added triethylamine (0.67 mL, 4.82 mmol). The reaction mixture was stirred at 90° C. in a pressure tube for 18 hours. The reaction mixture was filtered and the resulting filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (25% EtOAc/Hexanes) to afford 380 mg of the desired product as a racemic mixture: 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J=9.7 Hz, 1H), 5.56 (d, J=8.9 Hz, 1H), 4.68 (td, J=9.6, 3.6 Hz, 1H), 4.07 (q, J=7.1 Hz, 2H), 2.68 (dd, J=14.8, 3.7 Hz, 1H), 2.46 (dd, J=14.8, 9.3 Hz, 1H), 1.77-1.62 (m, 4H), 1.61-1.49 (m, 2H), 1.47-1.37 (m, 1H), 1.35-1.26 (m, 1H), 1.19 (t, J=7.1 Hz, 3H), 1.01 (s, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.81 minutes (M+H) 354.98. The racemic mixture was submitted to SFC chiral separation to give the individual enantiomers, 143a and 143b. The (R)-enantiomer, 143a, was taken forward into the next synthetic step.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH3:21])[C:7]([NH:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=O)=[O:8])[CH3:2].[CH2:22]([C:29]1[S:33][C:32]([NH2:34])=[N:31][C:30]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(#N)C.O>[CH2:22]([C:29]1[S:33][C:32]([NH:34][C:11]([C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH3:21])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)([CH3:15])[CH3:14])=[O:13])=[N:31][C:30]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1nc(-c2ccccc2)c(Cc2ccccc2)s1
Reactant: CCOc1ccc(C(=O)NC(C)(C)C(=O)O)cc1OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: CCOc1ccc(C(=O)NC(C)(C)C(=O)Nc2nc(-c3ccccc3)c(Cc3ccccc3)s2)cc1OCC
Temperature: 50 °C
Reaction time: 48 h

Procedure:
150 mg of 2-(3,4-Diethoxy-benzoylamino)-2-methyl-propionic acid and 130 mg of 5-Benzyl-4-phenyl-thiazol-2-ylamine (WO2006082952) were stirred in 2 ml of acetonitrile at room temperature. 120 mg of EDCl and 100 mg of HOBT were added and the reaction mixture was stirred at 50° C. for 2 days and cooled to room temperature. It was diluted with water and the resulting precipitates were collected by filtration followed by washing with water. The filter cake was then purified by column chromatography (heptane/ethyl acetate=3/1) to provide the title compound. 1H NMR (400 MHz. CD3OD) δ 1.34-1.54 (m, 3H) 1.44 (d, J=5.31 Hz, 3H) 1.65 (s, 7H) 4.14 (qd, J=6.95, 2.53 Hz, 4H) 4.23 (s, 2H) 7.01 (d, J=8.46 Hz, 1H) 7.16-7.26 (m, 3H) 7.26-7.45 (m, 6H) 7.47-7.67 (m, 4H). m/z 545.1 (MH+).
Reaction SMILES: CO.S(=O)(=O)(O)O.[CH:8]([O:13][CH3:14])([O:11]C)OC.[C:15]([C:23]1C(=O)[O:25][C:26]([CH3:30])=[CH:27][C:28]=1[OH:29])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH3:14][O:13][C:8]([C:23]1[C:28](=[O:29])[CH:27]=[C:26]([CH3:30])[O:25][C:15]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:11]
Reactant: COC(OC)OC
Reactant: Cc1cc(O)c(C(=O)c2ccccc2)c(=O)o1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)oc(C)cc1=O
Yield: 75.8 %

Procedure:
A flask fitted with a reflux condenser and calcium chloride drying tube is charged with 70 ml dry methanol, 7.3 gms of 96% sulfuric acid and 10.15 gms of trimethyl orthoformate. 3-Benzoyl-4-hydroxy-6-methyl-2-pyrone (22 gms) is then added in small portions and the resulting reaction mixture is refluxed for 24 hours. The mixture is cooled and poured into water. Extraction with methylene chloride yields 17.7 gms of crude 3-methoxycarbonyl-6-methyl-2-phenyl-4-pyrone. mp (from methylene chloride/ether=101-2.5
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]([OH:15])=[O:14])[C@H:10]([C:16]([OH:18])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1.[Cl:48][C:49]1[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][CH:50]=1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([C:16](=[O:18])[NH:53][C:52]2[CH:54]=[CH:55][C:49]([Cl:48])=[CH:50][CH:51]=2)[C@H:11]([C:13]([OH:15])=[O:14])[CH2:12]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](C(=O)O)C1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](C(=O)Nc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 1c (2.25 g; 9 mmol) is suspended in acetonitrile (30 ml) and N,N-diisopropyl ethyl amin (3.03 ml; 17 mmol) is added at 25° C. After 20 min a clear solution is obtained and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDCI (2.0 g; 10 mmol) and 1-hydroxybenzotriazole HOBt (1.41 g; 10 mmol) is added. After stirring for 30 min at 25° C. 4-chloroaniline (1.11 g; 9 mmol) is added to the reaction mixture. The mixture is stirred for 18 h at 25° C., evaporated to dryness and dissolved in ethyl acetate (100 ml). The organic phase is washed with 0.1 N HCl (2×100 ml), water and brine and dried over Na2SO4. The organic phase is filtered and the filtrate is evaporated to dryness. Yield: 1.08 g (33.7%), ESI-MS: m/z=368 [M−H]−, Cl-pattern
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C@@H:7]1[NH:11][C@H:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8]1)([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>O1CCCC1>[Cl:23][CH2:24][C:25]([N:11]1[C@@H:7]([C:6]#[C:5][Si:2]([CH3:3])([CH3:4])[CH3:1])[CH2:8][CH2:9][C@H:10]1[C:12]([O:14][CH3:15])=[O:13])=[O:26]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)[C@@H]1CC[C@H](C#C[Si](C)(C)C)N1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CC[C@H](C#C[Si](C)(C)C)N1C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl (5R)-5-((trimethylsilyl)ethynyl)-L-prolinate (2.76 g, 12.2 mmol) and triethylamine (2.13 mL, 15.3 mmol) in dry tetrahydrofuran (50 mL) at 0° C. was gradually added a solution of chloroacetyl chloride (0.97 mL, 12.2 mmol) in dry tetrahydrofuran (10 mL). After stirring at room temperature for 2 hours, the mixture was filtered. The solid cake was washed with THF, and the filtrate and washings were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue taken up in toluene and concentrated to dryness under reduced pressure to provide the titled compound. MS (CI) m/z 302 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:26]1([CH2:32][S:33][CH:34]([C:38](O)=[O:39])[C:35](O)=[O:36])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[OH:39][C:38]1[CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])[O:10][C:35](=[O:36])[C:34]=1[S:33][CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccccc1O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccccc2O)cc(O)c1SCc1ccccc1

Procedure:
The title compound was prepared by Method A using 2'-hydroxyacetophenone (0.722 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (1.95 g, 11.6 mmol), chlorotrimethylsilane (1.48 mL, 11.6 mmol), THF (116 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 189° C.; 1H NMR (400 MHz, DMSO-d6) δ 4.01 (s, 2 H), 6.97 (s, 1 H), 7.25 (m, 7 H), 7.71 (d, 1 H), 10.75 (s, 1 H), 11.85 (bs, 1 H).
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][CH2:7][C@@H:8]([OH:9])[C@H:4]2[CH2:3][NH:2]1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]=1.C(N(CC)CC)C>C(O)C>[F:18][C:17]([F:20])([F:19])[C:13]1[N:12]=[C:11]([N:2]2[CH2:3][C@@H:4]3[C@H:8]([OH:9])[CH2:7][CH2:6][C@@H:5]3[CH2:1]2)[CH:16]=[CH:15][CH:14]=1
Reactant: FC(F)(F)c1cccc(Br)n1
Reactant: O[C@@H]1CC[C@@H]2CNC[C@@H]21
Solvent: CCN(CC)CC
Solvent: CCO
Product: O[C@@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Temperature: 80 °C

Procedure:
(3aR,4R,6aS)-Octahydrocyclopenta[c]pyrrol-4-ol (1.65 g, 12.97 mmol) from Example 29, 2-bromo-6-(trifluoromethyl)pyridine (3.66 g, 16.22 mmol) and triethylamine (7.23 mL, 51.9 mmol) were combined in ethanol (7.23 mL). The reaction was heated at 80° C. for 24 hours and the solvent was concentrated in vacuo. The resulting residue was purified by silica gel chromatography using 0-40% ethyl acetate/hexane as eluent to give the title compound and the title compound of Example 31: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.47 (t, J=7.9, 1H), 6.94 (d, J=7.2, 1H), 6.53 (d, J=8.6, 1H), 6.38 (d, J=4.1, 1H), 4.47-4.38 (m, 1H), 4.12 (dd, J=11.0, 4.3, 1H), 3.70-3.63 (m, 1H), 3.53 (t, J=10.0, 1H), 3.38 (dd, J=10.4, 4.6, 1H), 2.80-2.73 (m, 1H), 2.72-2.64 (m, 1H), 1.97-1.74 (m, 3H), 1.64-1.56 (m, 1H); MS (ESI+) m/z 273 (M+H)+.
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:19][C:18]([NH2:20])=[N:17][N:16]=3)=[CH:11][CH:10]=2)[CH:3]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>N1C=CC=CC=1.CO>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:20][C:18]2[O:19][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][C:4]4[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=4)=[CH:14][CH:13]=3)=[N:16][N:17]=2)=[O:27])=[CH:24][C:23]=1[C:31]([F:32])([F:33])[F:34]
Reactant: Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1
Reactant: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1
Agent: Br
Solvent: c1ccncc1
Solvent: CO
Product: O=C(Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1)c1ccc(F)c(C(F)(F)F)c1
Reaction time: 18 h
Yield: 47.3 %

Procedure:
5-[4-(Pyridin-3-yloxy)phenyl]-1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. Neat 4-fluoro-3-trifluoromethylbenzoyl chloride (200 uL) was added directly into the solution. It was left to stir for 18 hours. The reaction mixture formed a red solution with a yellow precipitate. Then it was diluted with ca. 1 mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (105.1 mg). Yield 47.3%.
Reaction SMILES: [NH2:1][O:2][CH2:3][C:4]([NH:6][CH3:7])=[O:5].C(Cl)Cl.[F:11][C:12]1[C:13]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=2[F:36])=[C:14]([CH:22]=[C:23]([CH:26]=O)[C:24]=1[F:25])[C:15]([NH:17][O:18][CH2:19][CH2:20][OH:21])=[O:16]>C1COCC1>[F:11][C:12]1[C:13]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=2[F:36])=[C:14]([CH:22]=[C:23](/[CH:26]=[N:1]/[O:2][CH2:3][C:4](=[O:5])[NH:6][CH3:7])[C:24]=1[F:25])[C:15]([NH:17][O:18][CH2:19][CH2:20][OH:21])=[O:16]
Reactant: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: CNC(=O)CON
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)CO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reaction time: 15 h
Yield: 76.9 %

Procedure:
To a solution of 2-aminooxy-N-methyl-acetamide (1.71 g, 16.4 mmol) obtained in Step B in a mixed solvent of methylene chloride (50 ml) and THF (25 ml) was added 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide (3.94 g, 8.20 mmol) obtained in Step F of Example 1 at room temperature, and the mixture was stirred for 15 hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride (40 ml) was added to the resultant residue to precipitate a solid, which was filtered and washed with methylene chloride. The resultant solid was dried under reduced pressure to give (E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[methylcarbamoylmethoxyimino-methyl]-benzamide (3.57 g, 77%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([CH:12]=[O:13])=[CH:11][C:4]=2[NH:3]1.CI.[C:16](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:16][N:3]1[C:2](=[O:1])[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([CH:12]=[O:13])=[CH:11][C:4]1=2
Reactant: O=Cc1ccc2c(c1)NC(=O)CO2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)COc2ccc(C=O)cc21
Yield: 85.3 %

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde (0.5 g, 2.82 mmol), methyl iodide (0.6 g, 4.23 mmol) and cesium carbonate (1.37 g, 4.23 mmol) were dissolved in dry dimethylformamide (2 mL). The reaction mixture was irradiated by microwave at 100° C. for 30 minutes. The solvent was removed and the residue was washed with water and extracted with dichloromethane. Purification by silica chromatography (ISCO) produced 4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde (0.46 g, 85%). 1H NMR (400 MHz, DMSO-d6): δ 9.95 (s, 1H), 7.62 (s, 1H), 7.59 (d, 1H), 7.20 (d, 1H), 4.80 (s, 2H), 3.34 (s, 3H); MS (ESI) m/z: Calculated for C10H9NO3: 191.1. found: 192.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27].[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[C:9]([O:15][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:8][CH:7]=1
Reactant: CCOC(Cc1ccc(O)c2sccc12)C(=O)OC
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c2sccc12)C(=O)OC

Procedure:
In analogy to the procedure described in example 108 c], [rac]-2-ethoxy-3-(7-hydroxy-benzo[b]thiophen-4-yl)-propionic acid methyl ester was treated with 4-chloromethyl-5-methyl-2-phenyloxazole and sodium hydride in N,N-dimethylformamide to yield [rac]-2-ethoxy-3-[7-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzo[b]thiophen-4yl]-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-ethoxy-3-[7-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzo[b]thiophen-4-yl]-propionic acid as colorless solid.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:7]([NH2:10])[CH:8]=[CH2:9]>O1CCCC1>[CH2:7]([NH:10][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH:8]=[CH2:9]
Reactant: CCCC(=O)Cl
Reactant: C=CCN
Solvent: C1CCOC1
Product: C=CCNC(=O)CCC
Temperature: 15 °C
Reaction time: 0.25 h
Yield: 101.6 %

Procedure:
Butyroyl chloride (194.7 g, 1.83 mol) in 1 L of tetrahydrofuran was added to a three neck round bottom flask equipped with a thermometer, stir bar, and dropping funnel. The contents of the flask were then cooled to 15° C. in an ice bath while stirring. Allylamine (208.7 g, 3.65 mol) in 50 mL of tetahydrofuran was then added slowly through the dropping funnel while maintaining stirring. Throughout the addition, the temperature was maintained at 15° C. . After addition was complete, stirring continued for an additional 15 minutes, after which the solid allylamine chloride precipitate was filtered off. The filtrate was concentrated under vacuum to yield 236.4 g of N-allyl butyramide as a colorless viscous liquid.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH:10](OCC)=[O:11].O1CCCC1.CC(C)([O-])C.[K+]>O>[OH:11]/[CH:10]=[C:4]1/[C:5](=[O:8])[CH2:6][CH2:7][C:2]([CH3:9])([CH3:1])[CH2:3]/1
Reactant: CC1(C)CCC(=O)CC1
Reactant: CCOC=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(=O)/C(=C/O)C1
Temperature: 2.5 °C
Reaction time: 12 h

Procedure:
4,4-Dimethylcyclohexanone (20 g), ethyl formate (15.8 g, 1.35 eq) and tetrahydrofuran (100 ml) were charged in a 250 ml flask and the mixture was cooled to 0-5° C. Potassium t-butoxide (1M in tetrahydrofuran 191 mL, 1.2 equiv) was slowly added while maintaining the temperature below 0° C. The reaction mixture was mixed at −5 to +5° C. and monitored for completion by GC analysis. After mixing overnight, no starting material was observed. Water (140 mL) was slowly added, and the resulting mixture was extracted with heptane (150 mL). The pH of the aqueous layer was adjusted with 6 M HCl to pH=1-2 (˜40 g HCl) and the extracted with toluene (80 mL). The organic layer was washed with 20% aqueous NaCl (2×140 mL). The product solution in toluene was used directly in the next step within 12 hours (storage at 0° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([O:23][CH3:24])[CH:17]=1.[CH2:25]([N:27]1[C:32](=[O:33])[N:31]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[C:30](=[O:41])[C:29]([C:42](O)=[O:43])=[N:28]1)[CH3:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:42]([C:29]2[C:30](=[O:41])[N:31]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[C:32](=[O:33])[N:27]([CH2:25][CH3:26])[N:28]=2)=[O:43])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N
Reactant: CCn1nc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Product: CCn1nc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2OC)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 4-(6,7-dimethoxy-quinolin-4-yloxy)-2-methoxy-phenylamine and 2-ethyl-4-(4-fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid using the procedure for example 1. mp=264-6° C.; LCMS m/z=588 (M+1);); 1H NMR (DMSO): 11.00 (s, 1H), 8.47-8.52 (m, 2H), 7.51 (s, 1H), 7.38-7.46 (m, 5H), 7.10 (m, 1H), 6.88 (m, 1H), 6.53 (d, 1H, J=5 Hz), 4.10 (q, 2H, J=7 Hz), 3.94 (s, 3H), 3.93 (s, 3H), 3.84 (s, 3H), 1.35 (t, 3H, J=7 Hz).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[C:7]([CH:8]=O)[C:6]([OH:11])=[CH:5][CH:4]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]([F:33])([F:32])/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28]>O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:25]([C:24]([F:23])([F:33])[F:32])[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:8][C:7]=2[CH:10]=1
Reactant: CSc1ccc(O)c(C=O)c1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1=Cc2cc(SC)ccc2OC1C(F)(F)F
Temperature: 65 °C

Procedure:
5-Methylthiosalicylaldehyde (Step 1) (2.516 g, 14.96 mmole) was added to dimethylformamide (3.5 mL), potassium carbonate (2.27 g, 16.45 mmole) and ethyl 4,4,4-trifluorocrotonate (3.3 mL, 3.8 g, 22.4 mmole). The mixture was heated to 65° C. for 3 h. The reaction was cooled to room temperature, poured into H2O (50 mL), and extracted with diethyl ether (2×75 mL). The combined ethereal phases were washed with aqueous NaHCO3 solution (3×50 mL), aqueous 2 N HCl solution (3×50 mL), and brine (3×50 mL), dried over MgSO4, filtered, diluted with isooctane and partially concentrated in vacuo causing the precipitation of the ethyl ester (2.863 g, 60%) as a yellow powder: mp 87.8–89.6° C. This ester was of suitable purity to use without further purification.