Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16](O)[C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=[O:21])=[CH:12][CH:11]=2)=[C:6]([CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].ClCCl.CN(S(F)(F)[F:38])C.Cl>[OH-].[Na+].O1CCCC1>[C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([F:38])[C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=[O:21])=[CH:12][CH:11]=2)=[C:6]([CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CN(C)S(F)(F)F
Reactant: CC(=O)c1ccc(OCc2ccc(C(O)c3cccc(C(=O)O)c3)cc2)c(C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)c1ccc(OCc2ccc(C(F)c3cccc(C(=O)O)c3)cc2)c(C)c1O
Temperature: -78 °C
Yield: 69.7 %

Procedure:
A suspension of 3-{[4-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzoic acid (100 mg, 0.246 mmol) and dichloromethane (5 mL) is stirred at −78° C. Dimethylamino sulfur trifluoride (35 μL, 0.271 mmol) is added and the mixture is warmed to room temperature. An additional portion of dimethylamino sulfur trifluoride (35 μL, 0.271 mmol) is added and suspension becomes a solution. The reaction mixture is diluted with aqueous 2N sodium hydroxide (5 mL) and tetrahydrofuran (2 mL) and stirred 10 min. The pH is adjusted to 2 with aqueous 5N hydrochloric acid and extracted with ethyl acetate (2×20 mL). The combined extracts are concentrated and the resulting residue is purified via silica chromatography eluting with hexanes to 1:1 hexanes:ethyl acetate to give the title compound (70 mg, 70%) as a white solid. 1H NMR (DMSO-d6) δ 13.12 (s, 1H), 12.86 (s, 1H), 7.93-7.95 (m, 2H), 7.82 (d, 1H), 7.68 (d, 1H), 7.44-7.59 (m, 5H), 6.75-6.90 (d, 1H), 6.72 (d, 1H), 5.29 (s, 2H), 2.59 (s, 3H), 2.06 (s, 3H). LCMS M−1 407.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[C:27]=1[N:35]=[C:36]=[O:37])([CH3:25])[CH3:24]>>[CH2:1]([N:8]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:14]=1)[C:36]([NH:35][C:27]1[C:26]([CH:23]([CH3:24])[CH3:25])=[CH:31][CH:30]=[CH:29][C:28]=1[CH:32]([CH3:34])[CH3:33])=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCOc1ccc(NCc2ccccc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CCCCCCCOc1ccc(N(Cc2ccccc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 39.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using benzyl(4-heptyloxyphenyl)amine (2.1 g) and 2,6-diisopropylphenyl isocyanate (1.61 g) as starting materials, N-benzyl-N′-(2,6-diisopropylphenyl)-N-(4-heptyloxyphenyl)urea (1.4 g) was obtained.
Reaction SMILES: BrC1C=[CH:6][C:5]([C@H:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[C@@H:11]3[CH2:19][CH2:20][C:21](=O)[N:10]3[CH2:9]2)=[CH:4][CH:3]=1.C1([C@H:29]2[C:38]3[C:33](=CC=C(O)C=3)[C@@H:32]3[CH2:40][CH2:41][C:42](=O)[N:31]3[CH2:30]2)C=CC=CC=1>>[N:31]1([CH2:42][CH2:41][CH2:40][O:18][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[C@@H:11]2[CH2:19][CH2:20][CH2:21][N:10]2[CH2:9][C@H:8]3[C:5]2[CH:4]=[CH:3][C:8]([C:9]#[N:10])=[CH:5][CH:6]=2)[CH2:30][CH2:29][CH2:38][CH2:33][CH2:32]1
Reactant: O=C1CC[C@H]2c3ccc(O)cc3[C@H](c3ccc(Br)cc3)CN12
Reactant: O=C1CC[C@H]2c3ccc(O)cc3[C@H](c3ccccc3)CN12
Product: N#Cc1ccc([C@@H]2CN3CCC[C@H]3c3ccc(OCCCN4CCCCC4)cc32)cc1

Procedure:
Cis-6-(4-Bromo-phenyl)-8-hydroxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one. Prepared as described in Example 42, Step 11, on a 1.89 mmol scale, to yield 654.3 mg of a mixture of the desired product and cis-6-phenyl-8-hydroxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one, the product of debromination under the reaction conditions. The crude product was taken on to the next step without purification or characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]([CH2:15][CH:16]([OH:19])[CH2:17]O)[C:13]2[C:20]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:21][CH:22]=[CH:23][C:12]=2[N:11]=1.CS(Cl)(=O)=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2=[N:11][C:12]3[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH2:25][CH3:26])[CH2:27][CH3:28])[C:13]=3[N:14]2[CH2:15][CH:16]([OH:19])[CH2:17]1
Reactant: CCN(CC)c1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CC(O)CO)c12
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCN(CC)c1cccc2nc3n(c12)CC(O)CN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 47 %

Procedure:
To a solution of 3-[2-[(2,4-dichlorophenyl)amino]-7-(diethylamino)-1H-benzimidazol-1-yl]propane-1,2-diol (Reference Example 88; 46.2 mg, 0.109 mmol) in pyridine (1 mL) was added methanesulfonyl chloride (0.0127 mL, 0.164 mmol) at 0° C. After 5 hr, the mixture was warmed up to room temperature. After 1 hr, methanesulfonyl chloride (0.0042 mL, 0.0545 mmol) was added, and the mixture was stirred for additional 1 hr. The reaction mixture was quenched with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on NH-silica gel eluting with a 20-80% ethyl acetate/n-hexane gradient mixture, to give the title compound as a colorless solid (20.6 mg, 0.0512 mmol, 47%). Analytically pure material was obtained by recrystallization from methanol/ethyl acetate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19]>CC(C)=O>[CH2:19]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)[CH:18]=[CH2:17]
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.8 %

Procedure:
To a slurry of 2.92 g (22 mmol) 5-hydroxyindole and 12.43 g (90 mmol) K2CO3 in 110 mL acetone was added 2.07 mL (24 mmol) allyl bromide. The reaction was stirred at room temperature over 2 days upon which time TLC indicated that the reaction was not complete. Additional 0.66 mL allyl bromide was added and the reaction was heated to reflux for 1.5 hr and stirred at room temperature over night. The reaction was filtered to remove precipitate and concentrated. The crude product was chromatographed on silica gel using 20–33% EtOAc-hexane to afford 3.128 g (18 mmol) 5-allyloxyindole as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH:34]([CH2:38][CH2:39][OH:40])[CH2:35][CH2:36][OH:37]>C1COCC1.CCOC(C)=O>[OH:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][OH:40])[S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:26][CH:25]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:22])=[O:21]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: OCCNCCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N(CCO)CCO)c3)n2)n1
Yield: 50 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.210 g, 0.429 mmol) by treatment with excess diethanolamine in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with n-heptane/diethyl ether to give the title compound (0.120 g, 50%) as a white solid. MS (ISP) 557.6 [(M+H)+]; mp 176° C.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O.CCOCC>[CH2:18]([O:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccc2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: c1ccc(COc2cccc3c2CCCC3)cc1
Yield: 99.1 %

Procedure:
5,6,7,8-tetrahydro-1-naphthol (5.9 g, 39mM) was added to a suspension of potassium carbonate (8.3 g, 60mM) in acetone (100 ml) and heated under reflux for 0.5 hour. Benzyl bromide (7.5 g, 43.8mM) was then added and the mixture was heated under reflux for a further 3 days with stirring. The resulting suspension was filtered and the filtrate was evaporated under reduced pressure to give an oil. This oil was dissolved in ether, washed with water, dried (sodium sulphate) and evaporated to giving an oil which was distilled under high vacuum to give the benzyl ether (3) (9.4 g, b.p. 170°-176° C. at 0.8 mm Hg).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[C:14]([CH3:26])([CH3:25])[C:13](=[O:27])[C:12]=1[C:28](OCC)=[O:29].Cl.[C:34]([O:38][C:39](=[O:42])[CH2:40][NH2:41])([CH3:37])([CH3:36])[CH3:35]>O1CCOCC1>[F:22][C:21]([F:24])([F:23])[C:17]1[CH:16]=[C:15]2[C:20]([C:11]([OH:10])=[C:12]([C:28]([NH:41][CH2:40][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:42])=[O:29])[C:13](=[O:27])[C:14]2([CH3:26])[CH3:25])=[CH:19][CH:18]=1
Reactant: CCOC(=O)C1=C(O)c2ccc(C(F)(F)F)cc2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(C(F)(F)F)cc2C(C)(C)C1=O
Temperature: 75 °C
Reaction time: 15 h
Yield: 21.4 %

Procedure:
DIPEA (1870 μL, 10738 μmol, 2.5 eq) was added to a mixture of ethyl 4-hydroxy-1,1-dimethyl-2-oxo-7-(trifluoromethyl)-naphthalene-3-carboxylate (1.41 g, 4295 μmol) and glycine tert-butyl ester hydrochloride (864 mg, 5154 μmol) in dioxane (50 mL). The reaction mixture was stirred at 75° C. for 15 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a yellow solid. The crude solid was purified by silica flash chromatography (0-40% DCM/hexane) to give the desired ester as a white solid (380 mg). MS (m/e)=358.1 (M+H-tBu)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[CH:14]=[C:15]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: COc1ccc(-c2ccccc2)cc1N
Product: COc1ccc(-c2ccccc2)cc1NC(=O)c1cc(Cl)ccc1O
Yield: 37 %

Procedure:
Using 5-chlorosalicylic acid and 3-amino-4-methoxybiphenyl as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]([CH3:30])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][C:9]=1[CH3:29])[CH3:6])C.[OH-].[Na+]>C1COCC1.CO>[CH3:30][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:20][C:21]=2[CH3:22])=[CH:10][C:9]=1[CH3:29])([CH3:6])[C:4]([OH:31])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCCc2nc(-c3ccccc3)oc2C)ccc1OC(C)(C)C(=O)O
Temperature: 55 °C

Procedure:
A solution of 2-methyl-2-{2-methyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}propionic acid ethyl ester (5.00 g, 11.8 mmol) in THF (30 mL) and MeOH (60 mL) was treated with 5N aqueous NaOH (20 mL). The solution was heated at 55° C. for 1 h, cooled to ambient temperature, and concentrated in vacuo. The residue was treated with ice water (20 mL), acidified with 5N aqueous HCl (25 mL), and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (40 mL), dried (Na2SO4), and concentrated to a white solid (4.46 g, 96%): mp 117° C.; 1H NMR (400 MHz, CDCl3) δ 1.53 (s, 6H), 2.19 (s, 3H), 2.38 (s, 3H), 2.98 (t, 2H, J=6.6 Hz), 4.15 (t, 2H, J=6.6 Hz), 6.58 (dd, 1H, J=3.4, 8.8 Hz), 6.70 (d, 1H, J=2.9 Hz), 6.80 (d, 1H, J=8.8 Hz), 7.38-7.45 (m, 3H), 7.97-8.00 (m, 2H); MS (FIA) m/e 394.2 [M−1].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:6]=[CH:5][N:4]=1>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:6]=[CH:5][N:4]=1
Reactant: COc1cc(/C=C/c2ccccn2)ccn1
Solvent: CO
Product: COc1cc(CCc2ccccn2)ccn1
Reaction time: 24 h
Yield: 718 %

Procedure:
(E)-2-Methoxy-4-(2-(pyridin-2-yl)vinyl)pyridine (290 mg, 0.13 mmol) was dissolved in MeOH (15 mL) and degassed with a nitrogen stream for 10 minutes. Palladium on charcoal (10%, wet, 5 g) was added and the reaction mixture stirred under an atmosphere of hydrogen for 24 h. The reaction mixture was degassed again and the catalyst removed by filtration. Concentration of the filtrate provided the title compound (200 mg, 90%) as a green oil: 1H NMR (500 MHz, CD3OD) δ 8.56 (d, J=5.1 Hz, 1H), 8.03 (d, J=5.1 Hz, 1H), 7.59-7.55 (dt, J=7.9, 19 Hz, 1H), 7.14-7.10 (dd, J=7.2, 5.1 Hz, 1H), 7.08 (d, J=7.6 Hz, 1H), 6.71 (d, J=5.4 Hz, 1H), 6.56 (s, 1H), 3.90 (s, 3H), 3.10-3.06 (m, 2H), 3.04-3.00 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH2:24])=[CH:19][CH:18]=2)[N:3]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[N:3]=[C:4]([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH3:24])=[CH:21][CH:22]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: C=Cc1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1
Yield: 23.5 %

Procedure:
A solution of 50 mF (0.16 mmol) 2-amino-4-furan-2-yl-6-(4-vinyl-benzylamino)-pyrimidine-5-carbonitrile in 10 ml ethanol was stirred with a spatula end of 10% palladium on charcoal under 1 atm of hydrogen for 16 h at room temperature. After filtration to remove the catalyst, the reaction mixture was concentrated in vacuo. Chromatography (ethyl acetate) followed by trituration in ether/hexane afforded 12 mg (24%) 2-amino-4-(4-ethyl-benzylamino)-6-furan-2-yl-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 320 (M+H+, 100).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([CH:14]2[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15]2)[CH2:4][CH:3]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[N+](C1C=CC=CC=1)([O-])=O>C1(C)C(C)=CC=CC=1.[C].[Pd]>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:4][CH:3]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C1C=CCCC1
Agent: [Pd]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: Cc1ccccc1C
Product: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2c1ccccc1
Yield: 83.5 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-5-(2-cyclohexen-1-yl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (500 mg) was suspended in xylene (20 ml), nitrobenzene (831 mg) and 10% palladium carbon (250 mg) were added therto, and the mixture was refluxed for 2 hours. The reaction mixture was allowed to cool, filtrated, and the filtrate was concentrated under reduced pressure. Diisopropyl ether was added to the residue, crystals so precipitated were collected by filtration, to thereby obtain 413 mg of the titled compound (Yield: 83%).
Reaction SMILES: C([Li])CCC.CO[C:8]([C:10]1[CH:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:22]=[CH:21][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:9]>C1COCC1>[O:28]1[CH2:27][CH2:26][N:25]([C:23]2[CH:22]=[CH:21][C:11]3[O:12][CH2:13][CH2:14][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8](=[O:9])[C:10]=3[CH:24]=2)[CH2:30][CH2:29]1
Reactant: CCOC(=O)CCCOc1ccc(N2CCOCC2)cc1C(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1CCOc2ccc(N3CCOCC3)cc2C1=O
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
In THF (15 ml) was dissolved diusopropylamine (1.018 ml), and to the mixture was added dropwise at 0° C. n-butyl lithium (4.2 ml). The mixture was stirred at the same temperature for 30 minutes. To the mixture was added dropwise a solution of ethyl 4-(2-methoxycarbonyl-4-morpholinophenoxy)butyrate (1829 mg, 5.18 mmol) in THF (5 ml) at −78° C., ice bath was removed, and the mixture was stirred for 7 hours. To the mixture was added at 0° C. 10% ammonium chloride solution (30 ml), and the mixture was extracted with ethyl acetate (30 ml×3). The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (silica gel 50 g, ethyl acetate/hexane=1/5), and the desired fraction was concentrated under reduced pressure to give ethyl 7-morpholino-5-oxo-2,3,4,5-tetrahydro-1-benzoxepine-4-carboxylate (924 mg, 2.89 mmol, 5.6%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[NH:12][CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1>Cl>[NH:16]1[CH2:17][CH2:18][CH:13]([NH:12][C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:27])[F:28])=[CH:5][CH:6]=2)=[O:26])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)Nc2ccc(OC(F)(F)F)cc2)CC1
Agent: Cl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)NC1CCNCC1

Procedure:
tert-butyl 4-(3-(4-(trifluoromethoxy)phenyl)ureido)piperidine-1-carboxylate (7.5 g, 18.6 mmol) was dissolved in HCl solution (2 M, MeOH, 100 mL). The resulting solution was refluxed for 2 h. The solvent was removed under vacuo and the crude was washed by dichloromethane twice and was basified to pH 10 by NaOH solution (6N). The final precipitates (5.6 g, 18.5 mmol, 99%) were filtered and dried under high vacuum. The final product (PTU/2) was served as a scaffold for the following urea inhibitors synthesis. 1H NMR (d6-DMSO, 300 Mhz): ∂ 1.19 (m, 2H), 1.74 (d, J=9 Hz, 2H), 2.10 (br, 1H), 2.48 (m, 2H), 2.87 (d, J=9 Hz, 2H), 2.90 (m, 1H), 6.18 (d, J=8 Hz, 1H), 7.20 (d, J=9 Hz, 2H), 7.46 (d, J=9 Hz, 2H), 8.52 (s, 1H). 19F NMR (d6-DMSO, 300 Mhz): ∂ 57.17.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:33][CH2:34]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: CCOC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: CCOC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ccnc23)CC1

Procedure:
Starting from 7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-N-piperidin-4-yl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f1) and commercially available ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:21][NH:22][CH2:23][CH3:24]>>[CH2:23]([N:22]([CH3:21])[CH:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:9][CH:10]=2)[CH2:15][CH2:16]1)[CH3:24]
Reactant: CCNC
Reactant: O=C1CCN(c2ccc(CN3CCOCC3)cc2)CC1
Product: CCN(C)C1CCN(c2ccc(CN3CCOCC3)cc2)CC1

Procedure:
Prepared from the product of Example 19 and N-methylethylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11]C)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].B(Br)(Br)Br>ClCCCl.C1COCC1>[NH2:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: COc1ccc(C(N)=O)c(N)c1
Agent: BrB(Br)Br
Solvent: C1CCOC1
Solvent: ClCCCl
Product: NC(=O)c1ccc(O)cc1N
Temperature: 40 °C
Yield: 31.3 %

Procedure:
To 2-amino-4-methoxybenzamide (7.0 g, 42 mmol) in 1,2-dichloroethane (100 mL) was added boron tribromide (25 g, 100 mmol) at rt. After heating for 40° C. for 20 h, 1 N boron tribromide in THF (40 mL) was added, and the reaction was heated to 50° C. for 20 h. The mixture was cooled and quenched by addition of aq. sodium bicarbonate. The resulting precipitate was collected by filtration to afford 2-amino-4-hydroxybenzamide as a white solid (2.0 g). The mother liquors were concentrated, diluted with MeOH., filtered and concentrated. The residue was again diluted with MeOH, filtered and concentrated, and the resulting residue was chromatographed on silica gel eluting with 5-15% MeOH/DCM to give 2-amino-4-hydroxybenzamide as a white solid (4.7 grams). The solids were combined for a total yield of 6.7 g (quantitative). 1H NMR (300 MHz, DMSO-d6) δ ppm 5.91 (dd, J=8.67, 2.26 Hz, 1 H) 6.03 (d, J=2.45 Hz, 1 H) 6.62 (br. s., 2 H) 7.38 (d, J=8.67 Hz, 1H) 9.45 (s, 1 H). LC-MS (ESI) m/z 153 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=[O:2].C(Cl)CCl.[CH:23]1[CH:24]=[CH:25]C2N(O)N=[N:29][C:27]=2[CH:28]=1.N1CCCCC1>C(Cl)Cl>[N:29]1([C:12]([C:11]2[CH:15]=[CH:16][C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:18][CH:17]=3)=[N:9][CH:10]=2)=[O:14])[CH2:25][CH2:24][CH2:23][CH2:28][CH2:27]1
Reactant: O=Cc1ccc(Oc2ccc(C(=O)O)cn2)cc1
Reactant: On1nnc2ccccc21
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=Cc1ccc(Oc2ccc(C(=O)N3CCCCC3)cn2)cc1
Yield: 45.1 %

Procedure:
Combine 6-(4-Formyl-phenoxy)-nicotinic acid (250.0 mg, 1.03 mmol), EDC (237.0 mg, 1.23 mmol), HOBt (166.2 mg, 1.23 mmol), and Piperidine (0.10 mL, 1.03 mmol) in CH2Cl2 (6 mL). After reaction stirs at room temperature under a Nitrogen atmosphere for 24 hours, concentrate the reaction mixture using a rotovap, add Ethyl acetate and wash with 0.1N HCl, 10% NaHCO3, Brine, and dry over Na2SO4. After concentrating the reaction mixture, flash chromatograph using 2:1 Ethyl acetate:Hexanes to afford 144.1 mg (45% yield) of the title compound as a white foam: 1H NMR (500 MHz, CDCl3); 1.5-1.8 (6H, m), 3.3-3.8 (4H, m), 7.0-7.1 (1H, m), 7.3-7.4 (2H, m), 7.8-8.0 (3H, m), 8.3 (1H, m), 9.9 (1H, s); MS m/z 311 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=3Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:31].[C:33]1(C)[C:38]([OH:39])=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:31][C:7]1[CH:8]=[C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][C:21]=3[O:39][C:38]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:14]=2)[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]([OH:2])=[O:32]
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: Cc1ccccc1O
Product: Cc1cc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Oc3ccccc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepare by reacting the compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester with o-cresol as in Example 45 to afford 0.229 g (21%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C30H25O5F3 522, found 523 (M+1, 100%).