Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=O)=[CH:3][CH:2]=1.Cl.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C@H:26]([NH2:28])[CH3:27])=[N:24][CH:25]=1.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:2]=[CH:3][C:4]([CH2:7][C:8]([NH:28][C@@H:26]([C:23]2[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][N:24]=2)[CH3:27])=[O:10])=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: COc1ccc([C@@H](C)N)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([C@@H](C)NC(=O)Cc2ccc(-c3ccccc3)cc2)nc1
Reaction time: 18 h

Procedure:
To a mixture of 4-biphenylacetic acid (2.00 g, 9.42 mmol), (1R)-1-(5-methoxypyridin-2-yl)ethanamine hydrochloride (1.96 g, 10.36 mmol), 1-hydroxy-7-azabenzotriazole (1.70 g, 12.49 mmol) and diisopropyl-ethyl amine (5.20 ml, 31.46 mmol) in DMF (55 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.40 g, 12.52 mmol) at room temperature. The reaction was stirred for 18 hours and then washed with saturated sodium bicarbonate solution and brine. Organics were extracted with EtOAc, dried over Na2SO4, filtered and concentrated in vacuo. Purification by normal phase chromatography (0-80% EtOAc/Hex) afforded 2-(1,1′-biphenyl-4-yl)-N-[(1R)-1-(5-methoxypyridin-2-yl)ethyl]acetamide as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.16 (s, 1H); 7.58 (m, 4H); 7.44 (m, 2H); 7.34 (m, 3H); 7.14 (m, 2H); 6.78 (d, J=6.80 Hz, 1H); 5.10 (m, 1H); 3.83 (s, 3H); 3.63 (s, 2H); 1.41 (d, J=6.80 Hz, 3H). MS (Electrospray): m/z 347.1 (M+H).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:15][C:14]=2[F:27])=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[CH:15][C:14]=1[F:27])[N:10]=2
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(N)cn2)c(F)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc3nc(N)sc3n2)c(F)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
To a solution of potassium thiocyanate (6.1 g, 62.6 mmol) in acetic acid (60 mL) was added a solution of tert-butyl {4-[(5-aminopyridin-2-yl)oxy]-3-fluorophenyl}carbamate (5.0 g, 15.7 mmol) in acetic acid (40 mL) at 0° C. A solution of bromine (3.25 g, 20.4 mmol) in acetic acid (20 mL) was added at 0° C., and the mixture was stirred at room temperature for 6 hr. Acetic acid was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate alone) to give the title compound (2.07 g, 35%).
Reaction SMILES: C(I)I.[Si:4]([N:11]1[C@H:14]([CH:15]=O)[CH2:13][C:12]1=[O:17])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5].[CH2:18](OCC)C.Cl>O1CCCC1.[Zn].CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Si:4]([N:11]1[C@H:14]([CH:15]=[CH2:18])[CH2:13][C:12]1=[O:17])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1C=O
Reactant: CCOCC
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: ICI
Solvent: C1CCOC1
Product: C=C[C@@H]1CC(=O)N1[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h

Procedure:
To a mixture of zinc (11.9 g) in tetrahydrofuran (215 ml) was added titanium (IV) isopropoxide (6.0 ml) at ambient temperature and the resultant mixture was stirred for 1 hour. A solution of methyleneiodide (8.1 ml) was then added to the mixture was stirred for 30 minutes. To the resultant mixture was added dropwise a solution of (S)-N-tert-butyldimethylsilyl-4-formyl-2-azetidinone (4.3 g) in tetrahydrofuran (130 ml) and stirred for 2 hours. The mixture was poured into a mixture of diethyl ether (500 ml) and 1N HCl (300 ml). The organic layer was washed with water, saturated aqueous NaHCO3 solution and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatograph on silica gel eluting with (EtOAc:n-hexane=1:10) to give (S)-N-tert-butyldimethylsilyl-4-vinyl-2-azetidinone (2.13 g) as a colorless oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH2:21])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH:22]1[CH:27]=[C:26]2[O:28][S:29]([C:32]3=[CH:33][CH:34]=[CH:35][C:24](=[C:25]23)[CH:23]=1)(=[O:31])=[O:30]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH:21][S:29]([C:32]3[C:25]4[C:24](=[CH:23][CH:22]=[CH:27][C:26]=4[OH:28])[CH:35]=[CH:34][CH:33]=3)(=[O:31])=[O:30])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC1CCN(C(=O)C(N)Cc2ccc3[nH]cnc3c2)CC1
Reactant: O=S1(=O)Oc2cccc3cccc1c23
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2cccc3cccc(O)c23)CC1
Temperature: 100 °C

Procedure:
Prepared from 1-(1H-benzimidazol-5-yl-methyl)-2-(4-methyl-piperidin-1-yl)-2-oxo-ethylamine and 1,8naphthalene sultone by heating to 100° C. for 30 minutes and subsequently heating to 140° C. for 20 minutes. After cooling, the product obtained is purified over a silica gel column (eluant: ethyl acetate/methanol=9:1).
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:29]([OH:31])=[O:30])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]1[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=1.C(Cl)Cl.C(NCC)C>C(#N)C>[NH2:1][C@H:2]([C:29]([OH:31])=[O:30])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]1[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=1
Reactant: COc1ccc(C(NCCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCNCC
Solvent: CC#N
Product: COc1ccc(C(NCCCC[C@H](N)C(=O)O)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of Fmoc-Lys(MMT) (9.7336 g) in 100 ml of mixture of methylene chloride and acetonitrile (1:1) at room temperature was added diethylamine (100 ml). The mixture was stirred at room temperature for 1.5 hrs. After removal of solvent, the residue was flushed with acetonitrile at 60° C. (90 ml×2), washed with acetonitrile (20 ml×3) and ether (20 ml×3). The solid was then dissolved as far as possible in 1:1 CH2Cl2/CH3OH (200 ml) and some solid byproduct was removed by filtering through filter paper. After removal of solvent and being dried in vacuo, 4.7707 g (82.2%, based on Fmoc-Lys) of pale yellow foam was obtained. ES(+)-MS: 147(Lys+1), 273(MMT).
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:10][C:11]=3[CH:12]=[C:13]2[F:16])=[CH:4][CH:3]=1.[CH2:26]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[F:16][C:13]1[C:14]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:10][C:11]=3[CH:12]=1)=[CH:4][CH:3]=[C:2]([C:35]1[CH:34]=[CH:33][C:32]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:37][CH:36]=1)[CH:15]=2
Reactant: CCCCCCc1ccc(B(O)O)cc1
Reactant: CCCCCCCCOc1ccc2c(c1)cc(F)c1cc(Br)ccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc2c(c1)cc(F)c1cc(-c3ccc(CCCCCC)cc3)ccc12

Procedure:
From 7-bromo-9-fluoro-2-octyloxyphenanthrene by reaction with 4-hexylphenyl-boronic acid, sodium carbonate and tetrakis(triphenylphosphine)palladium(O) in toluene/ethanol/H2O.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[CH2:25][NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])[C:5]1=[O:34])[CH:2]=[CH2:3].[CH3:36][S:37](Cl)(=[O:39])=[O:38].N1C=CC=CC=1>ClCCCl.CN(C1C=CN=CC=1)C>[CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[CH2:25][N:26]([CH2:27][C:28]([F:29])([F:31])[F:30])[S:37]([CH3:36])(=[O:39])=[O:38])[C:5]1=[O:34])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNCC(F)(F)F)C1=O
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(CC(F)(F)F)S(C)(=O)=O)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(2,2,2-trifluoroethylamino)butan-2-yl)piperidin-2-one prepared above in Step A (60.9 mg, 0.115 mmol) in DCE (770 μL) was added DMAP (70.5 mg, 0.577 mmol) and methanesulfonyl chloride (35.9 μL, 0.462 mmol) successively at rt. After being stirred at rt for 3 h, pyridine (46.7 μL, 0.577 mmol), methanesulfonyl chloride (35.9 μL, 0.462 mmol), and DCE (0.77 mL) were added and the resulting solution was stirred for 15 h.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[C:11](=[O:45])[C:12]([CH3:44])=[C:13]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([OH:43])=[C:24]([CH:42]=2)[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34]C(OC(C)(C)C)=O)=[CH:30][CH:29]=2)=[O:26])[C:14](=[O:18])[C:15]=1[O:16][CH3:17]>C(Cl)Cl>[CH3:8][O:9][C:10]1[C:11](=[O:45])[C:12]([CH3:44])=[C:13]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([OH:43])=[C:24]([CH:42]=2)[C:25]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([NH2:34])=[CH:32][CH:33]=2)=[O:26])[C:14](=[O:18])[C:15]=1[O:16][CH3:17]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(NC(=O)OC(C)(C)C)cc3)c2)=C(C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(N)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 114.9 %

Procedure:
Trifluoroacetic acid (0.5 ml) was added to a methylene chloride solution (10 ml) of N-[5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-hydroxybenzoyl]-4-tert-butoxycarbonylaminoaniline (0.205 g, 0.309 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was concentrated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=95:5) to obtain the titled compound (0.150 g, 0.355 mmol, 91%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1.C(O[CH:15]=[C:16]([C:22]#[N:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C.C(C(=CNC1C=CC(CCCC)=CN=1)C(OCC)=O)#N>>[C:22]([C:16](=[CH:15][NH:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:23]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: CCCCc1cccnc1N
Agent: CCCCc1ccc(NC=C(C#N)C(=O)OCC)nc1
Product: CCCCc1cccnc1NC=C(C#N)C(=O)OCC
Yield: 84 %

Procedure:
The title compound (m.p. 98.5°-99.5°, 84% yield) was prepared from 2-amino-3-n-butylpyridine and ethyl ethoxymethylenecyanoacetate in a manner similar to that described for the preparation of ethyl 2-cyano-3-(5-n-butyl-2-pyridylamino)acrylate in Preparation 3D of U.S. Pat. No. 4,122,274.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[CH:11]=[O:12].[F-:13].[K+]>CN(C)C=O>[F:13][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[CH:11]=[O:12]
Reactant: Cn1nc(C(F)F)c(C=O)c1Cl
Reactant: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nc(C(F)F)c(C=O)c1F
Temperature: 150 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Under argon 19.4 g (100 mmol) of 5-chloro-1-methyl-3-difluoromethyl-1H-pyrazole-4-carbaldehyde (II-1) were initially charged in dimethylformamide. This was followed by the addition of 8.6 g (150 mmol) of potassium fluoride (KF water content 0.05%), heating to 150° C. and subsequent stirring at that temperature for 8 hours. This was followed by dilution of the mixture with ethyl acetate, filtration and distillative removal of the solvent in vacuo at 0.5 mbar and 70° C. to obtain 16 g (90% of theory) of 5-fluoro-1-methyl-3-difluoromethyl-1H-pyrazole-4-carbaldehyde having a purity of 99% (melting point 68° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:13]([N:15]([CH2:24][CH3:25])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[CH3:14]>[N+](C1C=CC=CC=1)([O-])=O>[CH2:13]([N:15]([C:16]1[CH:17]=[CH:18][C:19]([C:20]2[NH:12][C:11]3[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=3[N:1]=2)=[CH:22][CH:23]=1)[CH2:24][CH3:25])[CH3:14]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: CCN(CC)c1ccc(C=O)cc1
Solvent: O=[N+]([O-])c1ccccc1
Product: CCN(CC)c1ccc(-c2nc3cc(C(=O)OC)ccc3[nH]2)cc1
Temperature: 145 °C
Yield: 81.9 %

Procedure:
Methyl 3,4-diaminobenzoate (0.73 g, 4.42 mmol), 4-(diethylamino)benzaldehyde (3.0 g, 16.9 mmol) were dissolved in nitrobenzene (30 mL) and refluxed on a 145° C. oil bath overnight. The nitrobenzene was then removed in vacuo using a Kugelrohr apparatus (60° C., 0.1 mm Hg). The remaining oily residue was dissolved in CHCl3 and washed with water (3×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude oil was then purified through colurnn chromatography using a solvent system of 1% MeOH/CHCl3 to give methyl 2-(4-(N,N-diethyl)aminophenyl)benzimidazole-6-carboxylate as a yellowish solid (1.17 g, 82% yield). TLC (2.5% MeOH/CHCl3) Rf=0.26; 1H-NMR (500 MHz, CDCl3) 9.87 (s br, 1H), 8.30 (s br, 1H), 7.94 (dd, 1.5, 8.5, 1H), 7.91 (d, 8.5, 2H), 7.60 (s br, 1H), 6.72 (d, 8.5, 2H), 3.42 (q, 7.0, 4H), 1.21 (t, 7.0, 6H); IR (neat) 3508, 2063, 2920, 1712, 1611, 1504, 1434, 1360, 1307, 1269, 1205, 1157, 1082, 1008, 821, 751.
Reaction SMILES: C(OC(=O)[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:29])[NH2:28])=[C:23]([OH:30])[CH:22]=2)=[C:16]([F:31])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.[ClH:33]>ClCCl.O1CCOCC1>[ClH:33].[F:31][C:16]1[CH:15]=[C:14]([CH2:13][NH:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:19]=[CH:18][C:17]=1[O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH2:28])=[O:29])=[C:23]([OH:30])[CH:22]=1
Reactant: CC(C)CCN(Cc1ccc(Oc2ccc(C(N)=O)c(O)c2)c(F)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)CCNCc1ccc(Oc2ccc(C(N)=O)c(O)c2)c(F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
[4-(4-Carbamoyl-3-hydroxy-phenoxy)-3-fluoro-benzyl]-(3-methyl-butyl)-carbamic acid tert-butyl ester (I-1e-1: 15 g) was dissolved in 150 mL of dichloromethane and treated with 50 mL of a 4.0 M hydrogen chloride solution in dioxane. After stirring 24 hours at room temperature, the volatiles were removed under reduced pressure and the resulting crude material was suspended in methanol, heated at reflux for 20 minutes, and stirred overnight at room temperature. The resulting slurry was collect via filtration, rinsed with chilled methanol, and dried under vacuum to provide the title compound (1A).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[CH:20][C:19]([N:22]=C(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:18][CH:17]=2)=[C:12]([O:36][CH3:37])[CH:11]=1.CC([O-])=O.[Na+].Cl.NO>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)=[C:12]([O:36][CH3:37])[CH:11]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1-c1ccc(N=C(c2ccccc2)c2ccccc2)cn1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: COc1cc(-c2nc3ccccc3o2)ccc1-c1ccc(N)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-[4-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]-N-(diphenylmethylene)pyridin-3-amine (61 mg, 0.13 mmol) was dissolved in MeOH (2 mL) and NaOAc (25 mg, 0.31 mmol) and hydroxylamine hydrochloride (16 mg, 0.23 mmol) were added. The resulting suspension was stirred at rt for 1 h. The mixture was partitioned between CH2Cl2 and 0.1N aqueous NaOH. Aqueous layer was extracted with CH2Cl2 (3×15 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. Crude mixture was adsorbed onto silica gel and purified by automated flash chromatography using an EtOAc/hexanes gradient to afford the desired 6-[4-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]pyridin-3-amine: 1H NMR (CDCl3, 300 MHz) δ 8.25–8.24 (d, 1H), 7.95 (s, 2H), 7.86 (s, 1H), 7.80–7.76 (m, 2H), 7.62–7.59 (m, 1H), 7.38–7.35 (m, 2H), 7.07–7.04 (m, 1H), 4.01 (s, 3H). MS (ESI) 318 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([Cl:12])([Cl:11])[C:8]([OH:10])=[O:9].[CH2:13](O)[CH3:14]>Cl>[CH2:13]([O:9][C:8](=[O:10])[C:7]([Cl:11])([Cl:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH3:14]
Reactant: CCO
Reactant: O=C(O)C(Cl)(Cl)CCCCCBr
Agent: Cl
Product: CCOC(=O)C(Cl)(Cl)CCCCCBr
Temperature: 0 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
19.5 g 5 was dissolved in 300 ml ethanol, saturated at 0° C. with hydrochloric acid gas and stirred for a further 5 hours at 0° C. After removing the major amount of ethanol in a vacuum, the residue was taken up in ether, washed with water, dried over magnesium sulfate and the solvent was removed. 21.2 g (98%) 7-bromo-2,2-dichloroheptanoic acid ethyl ester 6 was obtained as a colourless oil.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([C:24]([NH:30][C:31]([NH:33][C:34]4[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:41])=[O:32])=[N:25][CH:26]=[N:27]3)=[CH:22][C:21]=2[O:42][CH3:43])[CH2:12][CH2:11]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([C:24]([NH:30][C:31]([NH:33][C:34]4[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:41])=[O:32])=[N:25][CH:26]=[N:27]3)=[CH:22][C:21]=2[O:42][CH3:43])[CH2:12][CH2:11]1
Reactant: COc1cc2c(NC(=O)Nc3c(C)cccc3Cl)ncnc2cc1OCCCN1CCC(CNC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(NC(=O)Nc3c(C)cccc3Cl)ncnc2cc1OCCCN1CCC(CN)CC1

Procedure:
Using an analogous procedure to that described in Example 21, 1-{7-[3-(4-tert-butoxycarbonylaminomethylpiperidin-1-yl)propoxy]-6-methoxyquinazolin-4-yl}-3-(2-chloro-6-methylphenyl)urea was reacted with trifluoroacetic acid to give the title compound; NMR Spectrum: (DMSOd6) 1.0-1.3 (m, 3H), 1.63 (d, 2H), 1.7-2.0 (m, 4H), 2.28 (s, 3H), 2.4 (m, 2H), 2.86 (d, 2H), 3.1-3.5 (partially obscured by a water signal) 3.94 (s, 3H), 4.19 (t, 2H), 7.1-7.4 (m, 4H), 8.06 (s, 1H), 8.66 (s, 1H), 11.85 (s, 1H); Mass Spectrum: M+H+ 513 and 515.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[Br:9][C:10]1[CH:26]=[CH:25][C:13]([CH:14]=[N:15][C@@H:16]([CH3:24])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1.[OH-].[Na+]>>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:14]2[C:19]3[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][C@H:16]([CH3:24])[NH:15]2)=[CH:25][CH:26]=1
Reactant: C[C@@H](Cc1ccccc1)N=Cc1ccc(Br)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: C[C@H]1Cc2ccccc2[C@@H](c2ccc(Br)cc2)N1
Temperature: 120 °C
Reaction time: 19 h

Procedure:
To a flask with trifluoromethanesulfonic acid (3.00 mL, 34 mmol) at 0° C. was added dropwise the (S)—N-(4-bromobenzylidene)-1-phenylpropan-2-amine and the reaction was heated to 120° C. and stirred 19 h under N2. The reaction was poured into ice water (20 mL) and basisified with 5 N NaOH (6 mL). The aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with saturated NaCl (20 mL), dried (MgSO4), and concentrated to give a yellow/brown oil (410 mg). 1H-NMR shows 92:8 diastereomeric ratio. The residue was purified by ISCO (40 g SiO2, 0-100% EtOAc/hexane) to give the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:36][C:37]1[CH:38]=[C:39]([CH:44]=[CH:45][C:46]=1O)[C:40]([O:42][CH3:43])=[O:41].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[Cl:36][C:37]1[CH:38]=[C:39]([CH:44]=[CH:45][C:46]=1[O:14][CH:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:13][CH2:12]1)[C:40]([O:42][CH3:43])=[O:41]
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: COc1ccc(CN2CCC(O)CC2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OC2CCN(Cc3ccc(OC)cc3)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 8.6 %

Procedure:
To a stirred solution of 1-(4-methoxybenzyl)piperidin-4-ol (0.33 g, 1.49 mmol) in toluene (10 mL) at room temperature was added triphenylphosphine (0.44 g, 1.67 mmol) and methyl 3-chloro-4-hydroxybenzoate (0.42 g, 2.25 mmol). The reaction was stirred at room temperature for 5 min. After this time, diisopropyl azodicarboxylate (0.33 g, 1.67 mmol) was added dropwise and the reaction was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the resulting residue was purified by flash chromatography (silica gel, methylene chloride/methanol/30% ammonium hydroxide=25/1/0.05) to afford methyl 3-chloro-4-(1-(4-methoxybenzyl)piperidin-4-yloxy)benzoate as a white solid (0.05 g, 10%). MS (ESI): 390.1 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:14]([OH:16])=[O:15].[C:17]([C:21]1[N:22]=[C:23]([C:26]2[O:27][C:28]3[CH:34]=[CH:33][C:32]([CH2:35]Cl)=[CH:31][C:29]=3[CH:30]=2)[S:24][CH:25]=1)([CH3:20])([CH3:19])[CH3:18].O>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:35][C:32]1[CH:33]=[CH:34][C:28]3[O:27][C:26]([C:23]4[S:24][CH:25]=[C:21]([C:17]([CH3:19])([CH3:18])[CH3:20])[N:22]=4)=[CH:30][C:29]=3[CH:31]=1)[N:9]=[C:8]2[C:14]([OH:16])=[O:15]
Reactant: CC(C)(C)c1csc(-c2cc3cc(CCl)ccc3o2)n1
Reactant: COc1ccc2[nH]nc(C(=O)O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)c(C(=O)O)nn2Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
Sodium hydride (60% in mineral oil, 7.79 g) was added into a solution of 5-methoxy-1H-indazole-3-carboxylic acid (17.0 g) in N,N-dimethylformamide (400 ml) at room temperature under nitrogen atmosphere. After 30 minutes, 4-tert-butyl-2-[5-(chloromethyl)benzofuran-2-yl]thiazole (29.76 g) was added to the solution over 5 minutes. After being stirred continuously for 3 hours at 45° C., the reaction mixture was poured into water (2 l) and the reaction vessel was washed with water (200 ml). After combining the washing mixture to the aqueous mixture, the resulting mixture was made acidic with 10% hydrochloric acid aqueous solution (500 ml) and stirred vigorously for one hour. The precipitate was collected by filtration, washed with water and air-dried for one day. The crude product was washed with a mixture of isopropyl alcohol and isopropylethyl ether (7:3) and dried in vacuo to give 5-methoxy-1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}indazole-3-carboxylic acid (36.5 g).