Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([OH:17])=O)[CH2:10]1)(OC(C)(C)C)=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[F:51][C:52]([F:62])([F:61])[C:53]1[CH:60]=[CH:59][CH:58]=[CH:57][C:54]=1[CH2:55][NH2:56]>CN(C)C=O>[NH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([NH:56][CH2:55][C:54]2[CH:57]=[CH:58][CH:59]=[CH:60][C:53]=2[C:52]([F:51])([F:61])[F:62])=[O:17])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCCC(C(=O)O)C1
Reactant: NCc1ccccc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC1CCCC(C(=O)NCc2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(Boc-amino)cyclohexanecarboxylic acid (500 mg, 2.055 mmol, 1 equivalent) in dimethylformamide (10 ml) was added O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 781 mg, 2.055 mmol, 1 equivalent) and diisopropylethylamine (0.716 ml, 4.11 mmol, 2 equivalents). 2-trifluoromethyl benzylamine (360 mg, 2.055 mmol, 1 equivalent) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated to give the crude product, which was purified with RP-HPLC. The purified compound was treated with 50% TFA in DCM (20 ml) at room temperature for 2 hours, and then the solvents were removed in vacuo. The product (103 mg, 12% yield) was carried onto the next step without further purification. MS (ES+): m/e 301.06 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[C:6]([CH3:15])=[CH:7][N:8]([CH:11]([CH2:13][CH3:14])[CH3:12])[C:9]=2[CH:10]=1.Cl.[CH3:30][N:31]([CH3:48])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.CCOC(C)=O.O>[CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([CH2:32][N:31]([CH3:48])[CH3:30])[CH:34]=3)[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]3[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])=[O:17])[C:5]=2[C:6]([CH3:15])=[CH:7]1)([CH2:13][CH3:14])[CH3:12]
Reactant: CCC(C)n1cc(C)c2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(Br)cc21
Reactant: CN(C)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCC(C)n1cc(C)c2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(-c3cccc(CN(C)C)c3)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Added sequentially to a reaction vial were 6-bromo-1-(sec-butyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-1H-indole-4-carboxamide (0.15 g, 0.338 mmol), N,N-dimethyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine-hydrochloride (0.131 g, 0.439 mmol) and potassium phosphate (tribasic) (0.287 g, 1.350 mmol), followed by 1,4-Dioxane (4 mL) and water (0.75 mL). The suspension was stirred under N2 degassing for 10 min., and then added PdCl2(dppf)-CH2Cl2 adduct (0.028 g, 0.034 mmol). The reaction vial was sealed, placed into a heat block at 95° C., and stirred for 1.5 h. The contents were removed from heating and allowed to cool to room temperature. The aq layer was removed from bottom of the reaction vial via pipette. The reaction mixture was diluted into EtOAc (20 mL) followed by addition of 0.2 g each of Thiol-3 silicycle resin and silica gel. The volatiles were removed in vacuo and the residue dried on hi-vac for 1 h. The contents were purified by silica gel chromatography (dry loaded, eluent:A:Dichloromethane, B: 10% (2M Ammonia in Methanol) in Chloroform; Gradient B: 8-95%). The obtained solid was concentrated from TBME to afford a foam, and was dried in vacuum oven at 45° C. for 18 h. The product was collected as 116 mg (65%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.73 (t, J=7.33 Hz, 3H), 1.41 (d, J=6.57 Hz, 3H), 1.82 (dq, J=9.85, 7.16 Hz, 2H), 2.08-2.12 (m, 3H), 2.15-2.21 (m, 9H), 2.24 (s, 3H), 3.44-3.49 (m, 2H), 4.35 (d, J=5.05 Hz, 2H), 4.57-4.70 (m, 1H), 5.86 (s, 1H), 7.19-7.26 (m, 2H), 7.30 (s, 1H), 7.36-7.44 (m, 1H), 7.58-7.65 (m, 2H), 7.76 (d, J=1.26 Hz, H), 8.21 (t, J=5.05 Hz, 1H), 11.47 (s, 1H); LCMS M+H=499.3.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=CC=[C:10]([CH2:13][N:14]3[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][C:27]([O:33][CH3:34])=[CH:28][CH:29]=5)[CH:24]=4)(=[O:22])=[O:21])[C:15]3=[O:35])[CH:11]=2)[CH:6]=[CH:5][N:4]=1.C([O:40]C(=O)N[C@H]1CCN(NCC2OC3C=CN=C(N)C=3C=2)C1=O)(C)(C)C>>[ClH:1].[NH2:2][C:3]1[C:12]2[CH:11]=[C:10]([CH2:13][N:14]3[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][C:27]([O:33][CH3:34])=[CH:28][CH:29]=5)[CH:24]=4)(=[O:22])=[O:21])[C:15]3=[O:35])[O:40][C:7]=2[CH:6]=[CH:5][N:4]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(NCc2cc3c(N)nccc3o2)C1=O
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc5ccnc(N)c5c4)C3=O)cc2c1
Agent: Cl
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cc5c(N)nccc5o4)C3=O)cc2c1

Procedure:
Using the procedure described in example 85j 150 mg of [l-((4-amino-furo[3,2-c]pyridin-2-yl)methylamino)-2-oxopyrrolidin-3-(S)yl]carbamic acid tert-butyl ester was transformed into 110 mg of the title compound. MS ESI+: 467 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([CH:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:25]=3)[O:21][N:20]=2)[CH:16]=[C:15]([CH3:37])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([CH:32]4[CH2:33][CH2:34][CH2:35][CH2:36]4)[CH:25]=3)[O:21][N:20]=2)[CH:16]=[C:15]([CH3:37])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: COc1cc(-c2nc(-c3cc(C)c(OCCCC(=O)OC(C)(C)C)c(Cl)c3)no2)cc(C2CCCC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2nc(-c3cc(C)c(OCCCC(=O)O)c(Cl)c3)no2)cc(C2CCCC2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
A solution of tert-butyl 4-(2-chloro-4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-6-methylphenoxy)butanoate (90 mg, 170 μmol) in DCM (5 mL) is cooled to 0° C. before TFA (1 mL) is added. The mixture is stirred at 0° C. for 10 min, then at rt for 30 min. The mixture is again cooled to 0° C. before another portion of TFA (1 mL) is added. Stirring is continued at rt for 2 h. The mixture is concentrated and the crude product is purified by prep. HPLC to give the title compound (59 mg) as white solid; LC-MS: tR=1.14 min, [M+H]+=472.29; 1H NMR (CDCl3): δ 8.13 (s br, 1H), 8.02 (d, J=1.4 Hz, 1H), 7.88 (d, J=0.7 Hz, 1H), 7.47 (s, 1H), 7.25 (s, 1H), 4.05 (t, J=5.9 Hz, 2H), 4.00 (s, 3H), 3.17-3.28 (m, 1H), 2.74 (t, J=7.3 Hz, 2H), 2.39 (s, 3H), 2.21 (quint, J=6.5 Hz, 2H), 2.05-2.15 (m, 2H), 1.81-1.95 (m, 4H), 1.68-1.80 (m, 2H).
Reaction SMILES: [C:1]1([C:11]2[CH:12]=[C:13]([CH:21]=[CH:22][CH:23]=2)[NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.Br[C:25]1[CH:26]=[C:27]([C:31]2[N:32]([C:36]3[C:41]([CH:42]([CH3:44])[CH3:43])=[CH:40][CH:39]=[CH:38][C:37]=3[CH:45]([CH3:47])[CH3:46])[CH:33]=[CH:34][N:35]=2)[CH:28]=[CH:29][CH:30]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH:45]([C:37]1[CH:38]=[CH:39][CH:40]=[C:41]([CH:42]([CH3:44])[CH3:43])[C:36]=1[N:32]1[CH:33]=[CH:34][N:35]=[C:31]1[C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[N:14]([C:13]1[CH:21]=[CH:22][CH:23]=[C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][N:2]=2)[CH:12]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:47])[CH3:46]
Reactant: CC(C)c1cccc(C(C)C)c1-n1ccnc1-c1cccc(Br)c1
Reactant: c1ccc(Nc2cccc(-c3nccc4ccccc34)c2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1-n1ccnc1-c1cccc(N(c2ccccc2)c2cccc(-c3nccc4ccccc34)c2)c1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
3-(isoquinolin-1-yl)-N-phenylaniline (1.65 g, 5.57 mmol), 2-(3-bromophenyl)-1-(2,6-diisopropylphenyl)-1H-imidazole (2.256 g, 5.89 mmol), sodium tert-butoxide (0.802 g, 8.35 mmol), Pd2dba3 (0.102 g, 0.111 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos) (0.184 g, 0.449 mmol) were charged into the reaction vessel with 150 mL of toluene. This mixture was evacuated and back-filled with nitrogen. The reaction mixture was then heated to reflux for 18 h. The reaction mixture was cooled to room temperature then was diluted with 75 mL of water. This mixture was then filtered through a pad of Celite®. The toluene layer was separated and dried over magnesium sulfate. The organics were filtered and stripped under vacuum. The crude residue was passed through a silica gel column using 2-40% ethyl acetate/DCM yielding 3-(1-(2,6-diisopropylphenyl)-1H-imidazol-2-yl)-N-(3-(isoquinolin-1-yl)phenyl)-N-phenylaniline (2.60 g, 4.34 mmol, 78% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28].[CH3:30][C:31]1([CH3:37])[CH2:35][CH2:34][CH2:33][CH:32]1[NH2:36]>CN(C=O)C>[CH3:30][C:31]1([CH3:37])[CH2:35][CH2:34][CH2:33][CH:32]1[NH:36][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28]
Reactant: CC1(C)CCCC1N
Reactant: O=C(NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(-c2ccc(F)cc2)cc1
Solvent: CN(C)C=O
Product: CC1(C)CCCC1Nc1ccc(S(=O)(=O)NC(=O)c2ccc(-c3ccc(F)cc3)cc2)cc1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
A solution of Example 1D (50 mg, 0.12 mmol) and 2,2-dimethylcyclopentylamine (65 mg, 0.58 mmol) in DMF (2.0 mL) was heated to 120° C. in a sealed vial with shaking for 16 hours. The mixture was concentrated, dissolved in 1:1/DMSO:methanol (1.0 mL) and purified by reverse phase preparative HPLC using 0.1% TFA in H2O/CH3CN to provide the desired product. MS (APCI(+)) m/e 529 (M+NH4)+; 1H NMR (500 MHz, DMSO-d6) δ 12.45 (br s, 1H), 8.69 (d, 1H), 8.49 (d, 1H), 7.99 (dd, 1H), 7.97 (d, 2H), 7.80 (2d, 4H), 7.39 (d, 1H), 7.33 (t, 2H), 3.88 (ddd, 1H), 2.28-2.25 (m, 1H), 1.75-1.55 (m, 5H), 1.07 (s, 3H), 1.02 (s, 3H).
Reaction SMILES: [H][H].[F:3][C:4]([F:34])([F:33])[C@H:5]([O:12][C:13]([CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25]CC3C=CC=CC=3)[CH:21]=2)[CH2:16]1)=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>[Pd].O1CCCC1>[F:3][C:4]([F:33])([F:34])[C@H:5]([O:12][C:13]([CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([OH:25])[CH:21]=2)[CH2:16]1)=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC[C@@H](OC(=O)C1CCc2cc(OCc3ccccc3)ccc2C1)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCC[C@@H](OC(=O)C1CCc2cc(O)ccc2C1)C(F)(F)F
Reaction time: 24 h
Yield: 100 %

Procedure:
Hydrogen gas was blown into a mixture of 8.19 g (18.3 mmol) of the 1,2,3,4-tetrahydro-6-benzyloxynaphthalene-2-carboxylic acid (R)-1-trifluoromethylheptyl ester obtained in the fourth stage, 3.6 g of 5% palladium/carbon as a catalyst and 50 ml of tetrahydrofuran with stirring at room temperature and ordinary pressure for 24 hours. The reaction mixture was filtered using Celite as a filter aid, and the filtrate obtained was concentrated to obtain 6.78 g (18.3 mmol) of 1,2,3,4-tetrahydro-6-hydroxynaphthalene-2-carboxylic acid (R)-1-trifluoromethylheptyl ester as a brown liquid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH2:59])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1>C1COCC1.CS(C)=O>[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH:59][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: O=C(O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
From 4-fluoro-benzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+13.3° (c=0.32, DMSO), ES-MS m/e (%): 389 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[F:12].CN(C=O)C.CCN(CC)CC.[CH3:25][O:26][CH2:27][C:28]#[CH:29]>C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[C:29]#[C:28][CH2:27][O:26][CH3:25])[C:6]([O:8][CH3:9])=[O:7]
Reactant: C#CCOC
Reactant: COC(=O)c1ccc(Br)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCC#Cc1ccc(C(=O)OC)cc1F
Temperature: 60 °C
Reaction time: 1.17 h

Procedure:
To methyl 4-bromo-3-fluoro-benzoate (2.50 g, 10.7 mmol), copper (I) iodide (204 mg, 1.07 mmol) and Pd(PPh3)2Cl2 (753 mg, 1.07 mmol) in a flask under Argon was added DMF (degassed for 30 min) and reaction cooled to 0 C. Et3N (1.95 mL, 14.0 mmol) was added followed by 3-methoxyprop-1-yne (997 μL, 11.8 mmol) and the mixture was allowed to stir at 60° C. for 70 min. The mixture was cooled, diluted with ethyl acetate and filtered. The filtrate was washed sequentially with 1 M HCl, 10% NH4OH and brine solutions. The organic layer was separated, dried and purified with silica gel using ethyl acetate-hexanes to give methyl 3-fluoro-4-(3-methoxyprop-1-ynyl)benzoate. ESI-MS m/z calc. 222.2, found 223.2 (M+1)+; Retention time: 1.53 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.75 (ddd, J=11.2, 8.8, 1.5 Hz, 2H), 7.50 (dd, J=7.9, 7.0 Hz, 1H), 4.37 (s, 2H), 3.92 (s, 3H), 3.47 (s, 3H).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:22]3[CH:23]=[C:24]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=[CH:26][C:21]=3[O:20][CH2:19][C:18]2=[O:31])[CH2:11][CH2:10]1)=O)(C)(C)C.NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:22]3[CH:23]=[C:24]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=[CH:26][C:21]=3[O:20][CH2:19][C:18]2=[O:31])[CH2:11][CH2:10]1
Reactant: COC(=O)c1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)CO2
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: COC(=O)c1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2

Procedure:
Methyl 4-(2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (Intermediate 85) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:12][CH:11]2[CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N+](=[CH2:19])=[N-]>C1COCC1>[CH3:19][O:15][C:14](=[O:16])[CH2:13][CH:11]1[CH2:12][CH:10]1[C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=1
Reactant: COc1ccc(C2CC2CC(=O)O)cc1F
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Product: COC(=O)CC1CC1c1ccc(OC)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
After [2-(3-fluoro-4-methoxy-phenyl)-cyclopropyl]-acetic acid (0.075 g, 0.33 mmol) obtained in Step D was dissolved in THF (1 mL), diazomethane (2.7 ml, 0.66 mmol, 0.25M ether) was added thereto, and the mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure and purified by column chromatography (eluent, EtOAc/Hex=1/2) to obtain the title compound (0.063 g, 79%).
Reaction SMILES: [P:1]([O:23][C@@:24]([C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=1[F:47])([C@H:31]([C:33]1[C:38]([F:39])=[CH:37][N:36]=[CH:35][N:34]=1)[CH3:32])[CH2:25][N:26]1[CH:30]=[N:29][CH:28]=[N:27]1)([O:13]CC1C(F)=CC=CC=1Cl)([O:3]CC1C(F)=CC=CC=1Cl)=[O:2].[OH-].[Na+].S(=O)(=O)(O)O>[Pd].C1(C)C=CC=CC=1.O>[P:1]([OH:13])([OH:3])([O:23][C@@:24]([C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=1[F:47])([C@H:31]([C:33]1[C:38]([F:39])=[CH:37][N:36]=[CH:35][N:34]=1)[CH3:32])[CH2:25][N:26]1[CH:30]=[N:29][CH:28]=[N:27]1)=[O:2]
Reactant: C[C@@H](c1ncncc1F)[C@@](Cn1cncn1)(OP(=O)(OCc1c(F)cccc1Cl)OCc1c(F)cccc1Cl)c1ccc(F)cc1F
Agent: [Pd]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H](c1ncncc1F)[C@@](Cn1cncn1)(OP(=O)(O)O)c1ccc(F)cc1F
Reaction time: 24 h
Yield: 68.2 %

Procedure:
A mixture of the compound of step (a) (50 g, 70 mmol), sodium hydroxide (8.40 g, 210 mmol) and 5% palladium on carbon catalyst (10 g) in toluene (450 ml) and water (150 ml) was hydrogenated at room temperature and 414 kPa (60 p.s.i.) for 24 hours. The reaction mixture was filtered through celite (trade mark) and the toluene layer separated and discarded. The aqueous layer was then washed with methylene chloride (2×75 ml) and toluene (2×75 ml) and then cooled to 0° C. whereupon sulphuric acid (10.3 g, 105 mmol) was added. After granulating at 0° C. for 1 hour the product was filtered, washed with water (60 ml) and dried under vacuum at 50° C. for 16 hours to give the title compound (20.5 g, 68%). The proton NMR data was identical to that obtained in Example 3(b).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:15][CH3:16])=[C:4]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]>CO.C1COCC1.[Pd]>[Cl:1][C:2]1[C:3]([O:15][CH3:16])=[C:4]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1Cl
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CCC(=O)O)c(OC)c1Cl
Yield: 99 %

Procedure:
A suspension of 3a (12.57 g, 51.88 mmol) in a mixture of MeOH (50 ml) and THF (200 ml) was hydrogenated at 50 psi in the presence of 10% Pd/C (0.3 g) for 4 h. The catalyst was removed by filtration through Celite and the filtrate was concentrated to afford 12.6 g (51.5 mmol, 99% yield) of analytically pure (HPLC, 1H NMR) 4a as a white solid. 1H NMR (DMSO-d6): δ 7.15 (d, J=8.6 Hz, 1H), 6.86 (d, J=8.6 Hz, 1H), 3.81 (s, 3H), 3.75 (s, 3H), 2.78 (t, J=7.5 Hz, 2H), 2.49 (t, J=7.5 Hz, 2H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[C:28]([O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]1[CH:34]=[CH:35][C:36]([C:37]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:8]4[C:7]5[CH2:6][CH2:5][O:4][C:12]=5[CH:11]=[CH:10][N:9]=4)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:38])=[CH:40][CH:41]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)Oc1ccc(C(=O)O)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CC(C)(C)Oc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4CCO5)CC3)CC2)cc1

Procedure:
The title compound, white solid (82 mg, 65%), MS (ISP) m/z=507.3 [(M+H)+], mp 200° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 4-tert-butoxy-benzoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[S:24][CH:25]=[CH:26][C:27]=2[CH3:28])[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20]([C:23]4[S:24][CH:25]=[CH:26][C:27]=4[CH3:28])[O:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: Cc1ccsc1-c1nc(CCl)co1
Product: Cc1ccsc1-c1nc(COc2ccc(CCCn3ccnc3)cc2)co1
Yield: 78 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(3-methyl-2-thienyl)oxazole to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(3-methyl-2-thienyl)oxazole. The yield was 78%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 72-73° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:9]=[C:10]([C@@H:15]2[CH2:17][C@H:16]2[NH:18][C:19]2[C:20]3[N:31]=[N:30][N:29]([C@H:32]4[C@@H:36]5[O:37][C:38]([CH3:41])([CH3:40])[O:39][C@@H:35]5[C@@H:34]([O:42][CH2:43][C:44](O)=[O:45])[CH2:33]4)[C:21]=3[N:22]=[C:23]([S:25][CH2:26][CH2:27][CH3:28])[N:24]=2)[CH:11]=[CH:12][C:13]=1[F:14]>C1COCC1>[F:7][C:8]1[CH:9]=[C:10]([C@@H:15]2[CH2:17][C@H:16]2[NH:18][C:19]2[C:20]3[N:31]=[N:30][N:29]([C@H:32]4[C@@H:36]5[O:37][C:38]([CH3:40])([CH3:41])[O:39][C@@H:35]5[C@@H:34]([O:42][CH2:43][CH2:44][OH:45])[CH2:33]4)[C:21]=3[N:22]=[C:23]([S:25][CH2:26][CH2:27][CH3:28])[N:24]=2)[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: CCCSc1nc(N[C@@H]2C[C@H]2c2ccc(F)c(F)c2)c2nnn([C@@H]3C[C@H](OCC(=O)O)[C@H]4OC(C)(C)O[C@H]43)c2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCSc1nc(N[C@@H]2C[C@H]2c2ccc(F)c(F)c2)c2nnn([C@@H]3C[C@H](OCCO)[C@H]4OC(C)(C)O[C@H]43)c2n1
Temperature: -5 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
LiAlH4 (0.151 g) was added to THF (35 mL) slowly at −10° C. To this mixture was added a solution of compound 11a (1.5 g) in THF (15 mL) slowly over 30 min at 0 to −10° C. The reaction mixture was stirred at 0 to −10° C. for 2 hrs. The reaction was monitored by TLC. When the reaction was complete, it was quenched by addition of aqueous saturated ammonium chloride (10 mL), followed by addition of ethyl acetate (20 mL). The phases were separated and the organic phase was concentrated. The residue was purified by column chromatography (eluting with 40% ethyl acetate in hexane). The fractions containing the product were concentrated under reduced pressure to provide compound 12 as an oily mass (0.7 g, 70-75% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH:23]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[C:14]=2[CH3:23])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ccc(-n2c(C)nc(C#Cc3ccnc(Cl)c3)c2C)cc1
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
This compound was prepared according to the general procedure 3 as described hereinabove. 2-Chloro-4-(2-methyl-1-p-tolyl-1H-imidazol-4-ylethynyl)-pyridine (220 mg, 0.71 mmol) was dissolved in 5 mL THF and cooled to −75° C. Lithiumdiisopropylamide (0.61 ml, 1.22 mmol) was added, and the mixture stirred for 15 min at −75° C. Iodomethane (0.08 ml, 1.14 mmol) was added and stirring was continued at −75° C. for 2 hrs. The reaction mixture was quenched with sat. NaHCO3− solution and extracted with water and ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethylacetate 90:10→0:100 gradient) and by recrystallization from dichloromethane and diisopropylether. The desired compound was obtained as a light yellow solid (30 mg, 13%), MS: m/e=322.3 (M+H+).