Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]=[C:3]1[C:8](=[O:9])[CH:7]=[CH:6][C:5]([CH3:12])([CH:10]=[CH2:11])[CH2:4]1.Cl.[NH2:14]O>C(O)C.O>[CH3:12][C:5]1([CH:10]=[CH2:11])[CH2:4][C:3]2[CH:2]=[N:14][O:9][C:8]=2[CH:7]=[CH:6]1
Reactant: C=CC1(C)C=CC(=O)C(=CO)C1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCO
Product: C=CC1(C)C=Cc2oncc2C1
Temperature: 115 °C
Yield: 91.8 %

Procedure:
To a stirred solution of 21 (177 mg, 1.078 mmol) in ethanol (15 mL) under a nitrogen atmosphere was added a solution of hydroxylamine hydrochloride (741 mg, 10.66 mmol, 10 eq.) in water (1 mL). The reaction mixture was heated to reflux at 115° C. for 1 hour. Water was then added to the mixture until it became cloudy and the aqueous mixture was extracted with methylene chloride/ethyl ether (1:2, 4×). The organic layers were then combined and washed with saturated sodium bicarbonate solution (1×) and brine (1×), dried over magnesium sulfate, filtered and concentrated in vacuo to give 23 (159.7 mg, 0.99 mmol, 92%) as an oil. The product was used in the next reaction without further purification: 1H NMR (CDCl3) δ 8.03 (1H, s), 6.52 (1H, dd, J=0.6, 10 Hz), 5.87 (1H, d, J=10 Hz), 5.81 (1H, d, J=10.6 Hz), 5.04 (1H, dd, J=0.6, 18.3 Hz), 5.00 (1H, dd, J=1.2, 11.4 Hz), 2.69 (2H, dd, J=16.2, 34.8 Hz) 1.23 (3H, s); 13C NMR (CDCl3) δ 165.0, 148.8, 143.6, 141.6, 114.4, 112.7, 109.5, 40.4, 31.4, 26.0; MS (ESI+) m/z 162.1 [M+H]+, HRMS (ESI+) calcd for C10H11NO+H 162.0919. found 169.0913.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14]
Reactant: CN(C)CCCl
Reactant: Oc1cccc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCOc1cccc(Br)c1

Procedure:
3-Bromophenol (0.870 g, 5.00 mmol), (2-chloro-ethyl)-dimethylamine hydrochloride (0.792 g, 5.50 mmol) and Cs2CO3 (8 g, 25 mmol) were combined in DMF (20 mL) and the mixture was heated at reflux over night. H2O (20 mL) was added and the mixture was extracted with EtOAc, then washed with 2N NaOH and brine. The organic layers were combined, dried over Na2SO and concentrated to a brown oil which was then purified by flash chromatography (eluent: 20% EtOAc in hexanes).
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:30])=[C:13]([C:25]([O:27]CC)=O)[C:14](=[O:24])[N:15]2[CH2:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31]1([NH2:35])[CH2:34][CH2:33][CH2:32]1>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:30])=[C:13]([C:25]([NH:35][CH:31]3[CH2:34][CH2:33][CH2:32]3)=[O:27])[C:14](=[O:24])[N:15]2[CH2:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[N:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2nccs2)c1=O
Reactant: NC1CCC1
Product: O=C(NC1CCC1)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2nccs2)c1=O

Procedure:
This compound was prepared from ethyl 7-benzyl-4-hydroxy-2-oxo-1-(1,3-thiazol-2-ylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclobutylamine employing methods similar to those described in Example 5 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.27 (1H, d, J=7), 8.56 (1H, s), 8.13 (1H, s), 7.70 (1H, d, J=3.2 Hz), 7.67 (1H, d, J=3.2 Hz), 7.28-7.16 (5H, m), 5.78 (2H, s), 4.41 (1H, m), 4.09 (2H, s), 2.29 (2H, m), 2.05 (2H, m), 1.71 (2H, m); HRMS calcd for C24H22N4O3S+H+: 447.1491. Found: 447.1487.
Reaction SMILES: [CH:1]([C:4]1[C:13]([N+:14]([O-])=O)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Sn](Cl)Cl>Cl>[CH:1]([C:4]1[C:13]([NH2:14])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2cccnc2c1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Product: CC(C)c1ccc2cccnc2c1N
Yield: 73 %

Procedure:
In a similar fashion using route 1 general procedure 4, 7-isopropyl-8-nitroquinoline (Intermediate 59) (670 mg, 3.09 mmol), tin (II) chloride (1.8 g, 9.3 mmol) and 6 N HCl (6 drops) gave the title compound (420 mg, 73%) which was used in the next step without purification.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:18]1([CH2:28][NH2:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.O>C1(C)C(C)=CC=CC=1>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:29][C:28]([C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(C)cc1
Reactant: NCc1cccc2ccccc12
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)c1nc(-c2cccc3ccccc23)[nH]c1-c1ccc(C)cc1
Reaction time: 9 h
Yield: 12 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-methylphenyl)-3-oxopropionate (13.7 g) and 1-naphthalenemethylamine (11.0 g) were dissolved in xylene (137 ml), andrefluxed underheating for 9 hr whiledehydrating with Dean-stark trap. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was concentrated under reduced pressure and isopropyl alcohol was added to the obtained residue to allow crystallization. The crystals were collected by filtration to give ethyl 5-(4-methylphenyl)-2-(1-naphthyl)-imidazole-4-carboxylate (2.5 g), melting point 190-192° C.
Reaction SMILES: C[N:2]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@:3]([CH3:17])([C:14]([OH:16])=[O:15])[CH2:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1.O.[OH-].[Li+].O1CCOCC1>O>[C:18]([NH:2][C@:3]([CH3:17])([C:14]([OH:16])=[O:15])[CH2:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: CN(C(=O)OCc1ccccc1)[C@@](C)(Cc1cc2ccccc2s1)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@](Cc1cc2ccccc2s1)(NC(=O)OCc1ccccc1)C(=O)O
Yield: 82.8 %

Procedure:
A solution of methyl N-CBZ-α-methyl-3-benzothiophenylalanine (0.6 g, 1.57 mmol), lithium hydroxide hydrate (0.14 g, 3.33 mmol) in water (20 mL), and dioxan (20 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water, washed with ether, acidified with 1N hydrochloric acid, and extracted with ethyl acetate three times. The combined extracts were washed with water, dried over magnesium sulphate, filtered, and evaporated to dryness. Crystallization from ether/hexane gave colorless crystals 0.48 g (83%);
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(P(=CC#N)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:11]=[CH:10][N:9]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cc[nH]n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(n2ccc(-c3ccccc3)n2)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
To a solution of 3-phenyl-1H-pyrazole (300 mg) in toluene (15 mL) were added tert-butyl 4-hydroxypiperidine-1-carboxylate (838 mg) and (tributylphosphoranylidene)acetonitrile (1.0 g), followed by stirring at 100° C. for 4 hours. The reaction liquid was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 50/50) and purified again by silica gel column chromatography (hexane/ethyl acetate=100/0 to 70/30) to obtain tert-butyl 4-(3-phenyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (475 mg) as a colorless oily substance.
Reaction SMILES: [Na].[O:2]=[C:3]1[NH:7][C:6](=[O:8])[CH:5](P(OCC)(=O)OCC)[NH:4]1.[CH3:17][CH:18]([N:20]1[CH2:24][CH:23]([CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([N+:35]([O-:37])=[O:36])=[C:31]([CH:34]=2)[CH:32]=O)[O:22][C:21]1=[O:38])[CH3:19]>C(O)C.O>[CH3:19][CH:18]([N:20]1[CH2:24][CH:23]([CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([N+:35]([O-:37])=[O:36])=[C:31]([CH:32]=[C:5]3[NH:4][C:3](=[O:2])[NH:7][C:6]3=[O:8])[CH:34]=2)[O:22][C:21]1=[O:38])[CH3:17]
Reactant: CCOP(=O)(OCC)C1NC(=O)NC1=O
Reactant: CC(C)N1CC(COc2ccc([N+](=O)[O-])c(C=O)c2)OC1=O
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CC(C)N1CC(COc2ccc([N+](=O)[O-])c(C=C3NC(=O)NC3=O)c2)OC1=O
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
Sodium (0.9 g, 0.04 g atom) was dissolved in ethanol (150 mL) and diethyl 2,4-dioxoimidazolidine-5-phosphonate (9.19 g, 40 mmol) added. After 30 minutes solid 5-[[[3-(1-methylethyl)-2-oxooxazolidin-5-yl]methyl]oxy]-2-nitrobenzaldehyde (10.0 g, 32 mmol) was added and the mixture stirred vigorously. After 30 minutes, the mixture was diluted with water (150 mL) filtered and the solid washed with water and air dried to give 5-[[5-[[[3-(1-methylethyl)-2-oxooxazolidin-5-yl]methyl]oxy]-2-nitrophenyl]methylene]-2,4-imidazolidinedione (9.80 g, 77%). An analytical sample was prepared by crystallization from dimethylformamide and wate and had an m.p. 285°-287° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:26][CH2:27][C:28](Cl)=[O:29]>C1COCC1>[Cl:26][CH2:27][C:28]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)=[CH:4][CH:3]=1)=[O:29]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(-c2nc(O)cc(C(F)(F)F)n2)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)Nc1ccc(-c2nc(O)cc(C(F)(F)F)n2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound of example 15 (0.10 g, 0.39 mmol) in THF (6 mL), at 0° C. was added triethylamine (0.059 g, 0.58 mmol) and chloroacetylchloride (0.066 g, 0.58 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×15 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 1% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][CH2:21][CH2:22][C@H:23]([O:42][CH2:43][CH2:44][CH3:45])[C@H:24]([C@@H:30]([O:32]CC1C=CC(OC)=CC=1)[CH3:31])[CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[OH-].[Na+]>O.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][CH2:21][CH2:22][C@H:23]([O:42][CH2:43][CH2:44][CH3:45])[C@H:24]([C@@H:30]([OH:32])[CH3:31])[CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCO[C@@H](CCC[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1)[C@@H](CCC(C)C)[C@H](C)OCc1ccc(OC)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCCO[C@@H](CCC[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1)[C@@H](CCC(C)C)[C@H](C)O
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of (2S,6S,7S)-benzyl 2-((tert-butoxycarbonyl)amino)-7-((S)-1-((4-methoxybenzyl)oxy)-ethyl)-10-methyl-6-propoxyundecanoate (1.10 g, 1.75 mmol) in H2O (0.531 mL) and DCM (5.31 mL) was added DDQ (0.418 g, 1.84 mmol) at 0° C. The mixture was stirred vigorously at this temperature for 1 h and then 1N NaOH (1.84 mL, 1.84 mmol) and H2O (20 mL) were added. The phases were separated and the aqueous phase was extracted with DCM (3×15 mL). The combined organic extracts were washed with brine (8 mL), dried over Na2SO4, filtered, and the filtrate was treated with Celite® (2 scoopula tip-fulls). The solvent was removed under reduced pressure and the resulting adsorbed material was directly loaded onto a column and purified using flash column chromatography (40 g SiO2, 0→60% EtOAc/hexanes) to afford the title compound (815 mg, 1.61 mmol, 92%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.41-7.30 (m, 5H), 5.17 (app q, J=12.4 Hz, 2H), 5.07 (d, J=8.5 Hz, 1H), 4.44-4.39 (m, 1H), 4.39-4.30 (m, 1H), 3.87-3.75 (m, 1H), 3.54 (app dt, J=9.0, 6.6 Hz, 1H), 3.42-3.33 (m, 1H), 3.26 (app dt, J=8.9, 6.6 Hz, 1H), 1.87-1.76 (m, 1H), 1.72-1.37 (m, 17H), 1.35-1.07 (m, 7H), 1.04-0.93 (m, 1H), 0.93-0.84 (m, 9H); 13C NMR (101 MHz, CDCl3) δ 172.66, 155.32, 135.39, 128.59, 128.42, 128.24, 82.50, 79.89, 71.42, 69.10, 66.99, 53.52, 45.46, 37.47, 32.82, 28.82, 28.31, 28.28, 25.27, 23.20, 22.68, 22.54, 22.44, 22.06, 10.66; ESIMS m/z 530 ([M+Na]+).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:15])([F:16])[F:17])=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: Cc1c(C(=O)O)cc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1C
Temperature: 60 °C
Yield: 90.2 %

Procedure:
To a solution of 2-methyl-3-nitro-5-(trifluoromethyl)benzoic acid (21.0 g, 84.3 mmol) in DMF (200 mL) was added potassium carbonate (35.0 g, 253 mmol) and methyl iodide (24.0 g, 169 mmol). The mixture was stirred at 60° C. and after stirring for 6 h the reaction mixture was cooled to 23° C. and was filtered. The filtrate was concentrated in vacuo and the residue was dissolved in EtOAc and water. The aqueous phase was extracted with EtOAc (2×250 mL and the combined organic layers were concentrated in vacuo. The residue was purified by column chromatography (SiO2 heptane-EtOac=4/1) to give the titled compound (20.0 g, 90% yield). 1H-NMR (400 MHz, CDCl3) δ (ppm); 8.27 (s, 1H), 8.11 (s, 1H), 3.99 (s, 3H), 2.71 (s, 3H); MS (ES) [M−H] 261.9.
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH:21]=4)[CH:17]=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[N:3]=1.[CH2:32]([Sn](CCCC)(CCCC)C=C)[CH2:33]CC.C1(C)C=CC=CC=1>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.CN(C=O)C>[O:29]1[CH2:30][CH2:31][N:26]([C:22]2[CH:21]=[C:20]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]([NH:13][C:10]4[CH:11]=[CH:12][C:7]([N:4]5[CH:5]=[N:6][C:2]([CH:32]=[CH2:33])=[N:3]5)=[CH:8][CH:9]=4)[N:19]=3)[CH:25]=[CH:24][CH:23]=2)[CH2:27][CH2:28]1
Reactant: Brc1ncn(-c2ccc(Nc3nccc(-c4cccc(N5CCOCC5)c4)n3)cc2)n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C=Cc1ncn(-c2ccc(Nc3nccc(-c4cccc(N5CCOCC5)c4)n3)cc2)n1
Temperature: 120 °C

Procedure:
A mixture of N-(4-(3-bromo-1H-1,2,4-triazol-1-yl)phenyl)-4-(3-morpholinophenyl)pyrimidin-2-amine (0.024 g, 0.05 mmol), tributyl(vinyl)stannane (0.032 g, 0.10 mmol), Pd(PPh3)4 (0.012 g, 0.01 mmol), toluene (0.4 mL) and DMF (0.1 mL) was heated in a sealed tube at 120° C. with microwave irradiation for 1 h. The reaction mixture was cooled down to room temperature. Purification of this material by column chromatography on silica gel (40% EtOAc/hexane) provided the desired product as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.43 (d, 1H), 8.36 (s, 1H), 7.80 (d, 2H), 7.59 (d, 2H), 7.37 (m, 4H), 7.14 (d, 1H), 7.01 (dd, 1H), 6.75 (dd, 1H), 6.27 (d, 1H), 5.51 (d, 1H), 3.84 (m, 4H), 3.20 (m, 4H). MS (ESI) 426.29 (M+H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH3:16])=[C:9]([F:17])[CH:8]=1.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.Cl>O1CCCC1>[F:17][C:9]1[CH:8]=[C:7]([B:18]([OH:23])[OH:19])[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCOc1ccc(Br)cc1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCOc1ccc(B(O)O)cc1F
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 60.9 %

Procedure:
A solution n-butyllithium (2.5 M in hexanes, 4.4 ml) was added dropwise over 5 minutes to a stirring solution of 1-bromo-3-fluoro-4-propoxybenzene (2.3 g) in tetrahydrofuran (10 ml) at -70° C. The solution was stirred at -70° C. for 15 minutes and then transferred by cannula to a solution of triisopropyl borate (4.14 g) in tetrahydrofuran (10 ml) at -78° C. Once addition was complete the mixture was stirred at room temperature for 30 minutes. A solution of dilute hydrochloric acid (2 M, 30 ml) was added and the mixture extracted with ethyl acetate (3×50 ml). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the sub-title compound as a white solid (1.19 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[CH:27]([CH3:29])[CH3:28]>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:3][C:2]=1[O:1][CH:27]([CH3:29])[CH3:28]
Reactant: COc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1O
Reactant: CC(C)Br
Product: COc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1OC(C)C

Procedure:
Using the compound obtained in Example 17 and 2-bromo propane, colorless oily N-[2-(4-methoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained following the procedure of Example 19.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:17].[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](=[NH:30])OCC)=[CH:21][CH:20]=1>C(O)C>[ClH:17].[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26](=[NH:30])[CH2:25][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=N)Cc1ccc(F)cc1
Reactant: Cc1ccccc1COc1cccnc1N
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1COc1cccnc1NC(=N)Cc1ccc(F)cc1
Yield: 5.2 %

Procedure:
A mixture of 2-amino-3-(2-methylbenzyloxy)pyridine (5.2 g, 24.2 mmol) and ethyl 4-fluorophenylacetimidate hydrochloride (5.8 g, 26.7 mmol) in ethanol (80 ml) was heated under reflux for 2 hours, then the solvent evaporated. The residue was purified by flash chromatography (chloroform/methanol) to obtain the product as a foam (0.49 g), m.p. 59°-64° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=1.[C:14]1(N)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C.Cl>[Cl:1][C:2]1[C:7]([C:8]2[NH:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:9]=2)=[CH:6][CH:5]=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=1
Reactant: Nc1ccccc1N
Reactant: CC(C)(C)c1ccc(C#N)c(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1ccc(-c2nc3ccccc3[nH]2)c(Cl)n1
Temperature: 220 °C
Reaction time: 0.5 h

Procedure:
A mixture, homogenised in a mortar, of 19.5 g (100 mmol) of 2-chloro-3-cyano-6-tert-butylpyridine (S28), 36.2 g (200 mmol) of o-phenylenediamine and 38.0 g (200 mmol) of p-toluenesulfonic acid monohydrate is heated at 220° C. (oil-bath temperature) for 3 h. After cooling, the black, glassy sinter cake is taken up in a mixture of 100 ml of ethanol and 100 ml of 1N hydrochloric acid with vigorous stirring. After stirring for 30 min., the grey-green solid is filtered off with suction, washed three times with 50 ml of water each time and dried in vacuo. The solid is taken up in 200 ml of ethyl acetate, chromatographed on silica gel (ethyl acetate/heptane 1:1, Rf about 0.7) in order to remove 2-tert-butyl-6,11-dihydrobenzo[b]pyrido[2,3-e]-1,4-diazepin-5-one and brown by-products. The crude product obtained in this way is dissolved in ethyl acetate at the boiling temperature, and four times the amount of cyclohexane is added dropwise. After stirring at room temperature for 18 h, the crystals formed are filtered off with suction, washed with n-heptane and dried in vacuo. Yield: 7.5 g (26 mmol), 26%. Purity: >95% according to 1H-NMR.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:31][Si](C)(C)C>C(Cl)Cl.CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14]([NH2:31])=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C#N
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(N)=O)cc1C#N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71 %

Procedure:
A mixture of 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (200 mg, 0.62 mmol) in methylene chloride (2 mL) cooled to 0° C. was treated with N,N-dimethylformamide (2 drops). The reaction mixture was then slowly treated with oxalyl chloride (60 μL, 0.69 mmol). The reaction mixture was stirred at 0° C. for 10 min and then stirred at 25° C. for 1.5 h. The resulting reaction mixture was then treated dropwise with 1,1,1,3,3,3-hexamethyldisilazane (395 μL, 1.87 mmol) and subsequently stirred at 25° C. for 15 h. The reaction mixture was then partitioned between methylene chloride (20 mL), methanol (15 mL), and a 5% aqueous sulfuric acid solution (25 mL). The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate) afforded 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (141 mg, 70%) as a white foam: mp 67-70° C. (foam to gel); EI-HRMS m/e calcd for C16H20N2O3S (M+) 320.1195, found 320.1195.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9](Br)=[CH:8][CH:7]=[CH:6][C:5]=12.C([O:13][B:14](OCC)[O:15]CC)C.[Li]CCCC.[Cl-].[NH4+]>O1CCCC1.CCCCC>[N:1]1[O:2][N:3]=[C:4]2[C:9]([B:14]([OH:15])[OH:13])=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Brc1cccc2nonc12
Reactant: CCOB(OCC)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc2nonc12
Reaction time: 0.08 h
Yield: 32 %

Procedure:
To a solution of 4-benzo[c]furazanyl bromide (4 g, 0.020 mol) in tetrahydrofurane (80 ml) and n-pentane (20 ml) is added triethylborate (3.8 ml, 0.022 mol) and N,N,N,N-tetraethylendiamine (3 ml, 0.02 mol). Then, n-BuLi (8.8 ml, 2.5N in hexane, 0.022 mol) is added dropwise at -100° C. and the solution is stirred for 5 minutes more. The reaction mixture is poured into an aqueous solution of saturated ammonium chloride and the water phase is extracted with ethyl acetate. The organic solvent is removed and the crude product is taken up in dichloromethan/n-hexane (5:6). The suspension is filtered to yield the title compound (1.05 g) which is used without further purification.