Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:20][CH2:19][C:18]4[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:17]=4[NH:16][C:15]3=[O:27])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:28]([C:30]1[CH:39]=[C:38]([CH3:40])[C:33]2[NH:34][C:35](=[O:37])[O:36][C:32]=2[CH:31]=1)=[O:29].[H][H]>[Pd].CO>[OH:29][CH:28]([C:30]1[CH:39]=[C:38]([CH3:40])[C:33]2[NH:34][C:35](=[O:37])[O:36][C:32]=2[CH:31]=1)[C:3]1[CH:4]=[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:20][CH2:19][C:18]4[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:17]=4[NH:16][C:15]3=[O:27])[CH2:10][CH2:9]2)[N:6]=[N:7][CH:2]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5[nH]c(=O)oc5c4)c(Cl)nn3)CC1)C(=O)N2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(O)c4cc(C)c5[nH]c(=O)oc5c4)cnn3)CC1)C(=O)N2

Procedure:
A mixture of 0.25 g (0.40 mmol) 3-{1-[6-chloro-5-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyridazin-3-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one, 0.10 mL (0.71 mmol) TEA and 50 mg palladium on charcoal (Pd/C 10%) in MeOH was hydrogenated for 3 h at 50° C. in a hydrogen atmosphere of 50 psi. After filtration of the reaction mixture the filtrate was evaporated down to approx. 3 mL and mixed with a little ice water. The precipitate formed was suction filtered and dried. The residue contained the desired product in the mixture and was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@:8]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C@H:12]([CH:13]=[O:14])[C@@H:11]([CH3:15])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[C:26]([F:29])([F:28])[F:27].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:5][C:6](=[O:23])[NH:7][C@:8]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C@H:12]([CH:13]([OH:14])[C:26]([F:29])([F:28])[F:27])[C@@H:11]([CH3:15])[O:10][CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C[C@H]1OC[C@@](NC(=O)OC(C)(C)C)(c2ccccc2F)[C@@H]1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H]1OC[C@@](NC(=O)OC(C)(C)C)(c2ccccc2F)[C@@H]1C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 492 %

Procedure:
[(3S,4S,5R)-3-(2-Fluoro-phenyl)-4-formyl-5-methyl-tetrahydro-furan-3-yl]-carbamic acid tert-butyl ester (Preparation Example 30-(2)) (2.00 g, 0.62 mmol) dissolved in THF (20 mL). Trimethyl(trifluoromethyl) silane (175.89 mg, 1.23 mmol) was added followed by TBAF (0.080 g, 0.30 mmol). The reaction mixture was stirred at RT and monitored by LCMS (Agilent Method A), retention time 5.61 min (MH+ 294). The reaction went to completion after 2 h. The reaction was then concentrated, saturated aqueous ammonium chloride (10 ml) was added and extracted with DCM (2×20 ml). The combined organic phases were combined, dried over MgSO4 concentrated and purified by flash chromatography (Hexane/EtOAc 5-40%). 1.20 g (49% yield) of the title compound was isolated as a mixture of the 2 epimers (85/15).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.CCO.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1>CCO>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:14][CH:15]=1)#[N:20]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: C1CNCCN1
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(CN2CCNCC2)cc1

Procedure:
To a solution of piperazine (5.17 g, 60 mmol, 2 equiv) in EtOH (40 mL) was added 1 M HCl-EtOH (60 mL) dropwise over 1 h and the suspension was heated to 70° C. for 1 h. α-Bromo-p-tolunitrile (5.88 g, 30 mmol, 1 equiv) was added and the reaction was heated to reflux for 16 h. After cooling the solvent was removed by rotary evaporation and the residue was partitioned between CH2Cl2 (70 mL) and 2N aqueous KOH (70 mL) and the combined organic phase was washed with saturated aqueous NaCl (100 mL) and dried (MgSO4). Chromatography (SiO2, 20% CH3OH-5% Et3N-CH2Cl2) afforded the monoalkylated material (2.6 g, 6.0 g theoretical, 43%) as an amber oil.
Reaction SMILES: [C:1]1(O)C2C(=CC=CC=2)C=CC=1.[Br:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[OH:23].BrNC(C)(C)C.C(=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[Br:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[O:23][CH3:1]
Reactant: Oc1cccc2ccccc12
Reactant: Oc1c(Br)ccc2ccccc12
Agent: CC(C)(C)NBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1c(Br)ccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-naphthol was converted into 2-bromo-1-naphthol by reaction with a slurry of N-bromo-t-butylamine at -78° C. according to the procedure described in Pearson, Wysong, Breder, J. Org. Chem., 32, 2358 (1967). To a solution of 1 mole (crude) of the bromonaphthol in 750 mL of acetone was added 175 g of potassium carbonate. Over a 2-hour period, 95 mL of dimethylsulfate was added dropwise to the mechanically stirred reaction mixture. The resulting slurry was stirred at 25° C. overnight. The solids were filtered and the solution was stripped to yield a dark brown oil. Initial purification was accomplished by vacuum distillation (80-120° C., 0.2 Torr) followed by further purification by HPLC with hexane to yield 145 g of 2-bromo-1-methoxynaphthalene as a pale yellow oil. NMR confirmed the structure.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].CC([N-]C(C)C)C.C(C1C=CC=CC=1)C.[C:37]1([S:43]([O:46][C:47]2[CH:48]=[CH:49][C:50]([CH2:53]Br)=[N:51][CH:52]=2)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1COCC1.CCOCC.CCCCCC>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][CH:9]([CH2:53][C:50]2[CH:49]=[CH:48][C:47]([O:46][S:43]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)(=[O:45])=[O:44])=[CH:52][N:51]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Oc1ccc(CBr)nc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOC(=O)C(Cc1ccc(OS(=O)(=O)c2ccccc2)cn1)N=C(c1ccccc1)c1ccccc1
Reaction time: 0.75 h
Yield: 72.8 %

Procedure:
A solution of ethyl N-(diphenylmethylene)glycinate (1.71 g, 6.40 mmol) in dry THF (10 ml) was added to a stirrred solution of LDA (2M in heptane/TNF/ethylbenzene, 320 ml, 6.40 mmol) in dry THF 910 ml) at −70° under nitrogen. After stirring at this temperture for 0.75 h, a solution of 5-benzenesulphonyloxy-2-bromomethylpyridine (2.00 g, 6.01 mmol); [prepared as described by Myers et al, J.O.C. 61, 813 (1996)] in dry THF (10 ml) was added. The reaction mixture was stirred at −70° for 1 h then at room temperature for 18 h. The reaction was quenched with water 910 ml) then partitioned between EtOAc (70 ml) and bring (30 ml). The phases were separated and the aqueous phase re-extracted with EtOAc (2×40 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford the crude product as a dark oil. Chromatography (silica: 60-75% Et2O/Hexane) afforded the title compound as a tan-coloured solid (2.25 g, 72%). δH (CDCl3) 8.02 (1H, d, J 2.8 Hz), 7.72 (2H, d, J 8.0 hz), 7.59 (1H, t, J 8.0 hz), 7.50 (2H, dd, J 8.4 Hz), 7.40-7.27 (8H, m), 7.19 (1H, dd, J 8.5, 2.8 Hz), 7.11 (1H, d, J 8.5 Hz), 6.67 (2H, br d, J 8.0 Hz), 4.50 (1H, dd, J 9.0, 4.6 Hz), 4.25-4.10 (2H, m), 3.50-3.33 (2H, m) and 1.24 (3H, t, J 7.2 Hz), m/z (ES+, 70V) 515 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[N:12]=[C:11]([OH:13])[C:10]([NH:14][C:15](=O)[C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([O:23][CH3:24])=[C:18]([CH3:25])[CH:17]=3)=[C:9]([OH:27])[N:8]=2)=[CH:4][CH:3]=1>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[N:12]=[C:11]([OH:13])[C:10]3[N:14]=[C:15]([C:16]4[CH:21]=[C:20]([CH3:22])[C:19]([O:23][CH3:24])=[C:18]([CH3:25])[CH:17]=4)[O:27][C:9]=3[N:8]=2)=[CH:4][CH:3]=1
Reactant: COc1c(C)cc(C(=O)Nc2c(O)nc(Cc3ccc(Cl)cc3)nc2O)cc1C
Solvent: O=P(Cl)(Cl)Cl
Product: COc1c(C)cc(-c2nc3c(O)nc(Cc4ccc(Cl)cc4)nc3o2)cc1C

Procedure:
40 g of N-[2-(4-chlorobenzyl)-4,6-dihydroxypyrimidin-5-yl]-4-methoxy-3,5-dimethylbenzamide and 150 ml of phosphorus oxychloride were heated at 70° C. for 1.5 h. The mixture was then allowed to cool. The solid formed was filtered off with suction, washed with diethyl ether and dried. This gave 21.1 g (55%) of the title compound.
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:11]=1[NH2:17])([CH3:4])([CH3:3])[CH3:2].CO[C:22](=N)[C:23]([Cl:26])([Cl:25])[Cl:24]>>[C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][CH2:8][O:9][C:10]1[C:11]2[N:17]=[C:22]([C:23]([Cl:26])([Cl:25])[Cl:24])[NH:16][C:12]=2[CH:13]=[CH:14][CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1cccc(N)c1N
Reactant: COC(=N)C(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OCCOc1cccc2[nH]c(C(Cl)(Cl)Cl)nc12

Procedure:
4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-2-trichloromethyl-1H-benzoimidazole was prepared by a procedure according to example 108 (iii) starting from 503 mg (1.78 mmol) 3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzene-1,2-diamine and 0.31 mL (2.49 mmol) 2,2,2-trichloro-acetimidic acid methyl ester. Yield: 680 mg MS (ES+): m/e=409, chloro pattern.
Reaction SMILES: COC1N=C(C2C=CC=C(OC(F)(F)F)C=2)N(C)C=1C=O.C[O:23][C:24]([C:26]1[N:27]([CH3:44])[C:28]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]([F:43])([F:42])[F:41])[CH:34]=2)=[N:29][C:30]=1[O:31][CH3:32])=[O:25].[Li+].[OH-].Cl>C1COCC1.CO>[CH3:32][O:31][C:30]1[N:29]=[C:28]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]([F:41])([F:42])[F:43])[CH:34]=2)[N:27]([CH3:44])[C:26]=1[C:24]([OH:25])=[O:23]
Reactant: COC(=O)c1c(OC)nc(-c2cccc(OC(F)(F)F)c2)n1C
Agent: COc1nc(-c2cccc(OC(F)(F)F)c2)n(C)c1C=O
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc(-c2cccc(OC(F)(F)F)c2)n(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 816 h

Procedure:
A stirred solution of 0.27 g of a mixture of 5-methoxy-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazole-4-carbaldehyde and 5-methoxy-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazole-4-carboxylic acid methyl ester (ca. 1:1) in 10 ml of THF/MeOH 1:1 was treated with 0.49 ml (0.5 mmol) of a LiOH solution (1.0 molar in H2O) and the mixture was stirred for 34 days at RT. It was then poured into crashed ice, acidified with HCl (1.0 N) and extracted twice with MeCl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 4:1) to give 0.056 g (ca. 22% over two steps) of the title compound, which has been used without further characterization.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:24](=[CH:25][CH:26]=1)[C:17]1[CH:18]([O:22][CH3:23])[O:19][C:20](=[O:21])[C:16]=1[CH:15]=[CH:14]2)=[O:10])C1C=CC=CC=1>CCO.C1COCC1.[Pd]>[OH:10][C:9]([C:11]1[CH:12]=[C:13]2[C:24](=[CH:25][CH:26]=1)[C:17]1[CH:18]([O:22][CH3:23])[O:19][C:20](=[O:21])[C:16]=1[CH:15]=[CH:14]2)=[O:8]
Reactant: COC1OC(=O)c2ccc3cc(C(=O)OCc4ccccc4)ccc3c21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC1OC(=O)c2ccc3cc(C(=O)O)ccc3c21

Procedure:
A mixture of 7-benzyloxycarbonyl-1-methoxynaphtho[1,2-c]furan-3(1H)-one (33 mg, 0.095 mmol) and a catalytic amount of 10% Pd/C in 2 mL of EtOH was stirred at rt under an atmosphere of H2 (balloon) for 2 h. The mixture was then diluted with THF and filtered through a pad of Celite. The filtrate was then concentrated in vacuo. The crude material was dissolved in saturated aqueous NaHCO3 and washed with EtOAc. The aqueous layer was then acidified with 1 M aqueous HCl and extracted with EtOAc. The extract was dried over MgSO4 and concentrated in vacuo affording 19 mg (79%).
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:38]=[CH:39][C:40]([C:43]#[C:44][C:45]3[CH:46]=[CH:47][C:48]([O:54][CH2:55][CH2:56][N:57]4[CH2:61][CH2:60][CH2:59][CH2:58]4)=[C:49]([CH:53]=3)[C:50]([OH:52])=O)=[N:41][CH:42]=2)=[CH:33][CH:32]=1.CN>CN(C=O)C>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]2[CH:38]=[CH:39][C:40]([C:43]#[C:44][C:45]3[CH:46]=[CH:47][C:48]([O:54][CH2:55][CH2:56][N:57]4[CH2:58][CH2:59][CH2:60][CH2:61]4)=[C:49]([CH:53]=3)[C:50]([NH:2][CH3:1])=[O:52])=[N:41][CH:42]=2)=[CH:35][CH:36]=1
Reactant: O=C(O)c1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
80 mg (0.25 mmol) TBTU and 69 μL triethylamine are added to a solution of 112 mg (0.25 mmol) 5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzoic acid (Example 22) in 5 mL DMF and the reaction mixture is stirred for 2 h at RT. Then 31 mg (1.0 mmol) methylamine are added and stirring is continued for a further 2 h at RT. The mixture is evaporated down i. vac., the residue is combined with dilute Na2CO3 solution, extracted exhaustively with DCM and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, DCM to DCM/MeOH/NH3 7:3:0.3).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:9]=2[C:10]([NH:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][C:19](=[O:27])[N:20]3[CH2:23][C:24](O)=[O:25])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][NH2:37].C1COCC1.Cl>CO>[CH:1]1([NH:7][C:8]2[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:9]=2[C:10]([NH:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][C:19](=[O:27])[N:20]3[CH2:23][C:24]([NH:37][CH3:36])=[O:25])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CN1C(=O)CCc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3NC3CCCCC3)cc21
Reactant: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)CN1C(=O)CCc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3NC3CCCCC3)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of [7-{[2-(cyclohexylamino)-4-(trifluoromethyl)benzoyl]amino}-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetic acid (70 mg), N,N′-carbonyldiimidazole (70 mg), methylamine aqueous solution (1 mL) and THF was stirred at room temperature for 3 hours, mixed with methanol and stirred for 20 minutes. A 0.5 M hydrochloric acid was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol, 20:1 to 10:1) to obtain 2-(cyclohexylamino)-N-{1-[2-(methylamino)-2-oxoethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl}-4-(trifluoromethyl)benzamide (12 mg) as a solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([NH:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: O=C1CCCCC1
Product: CC(C)(C)OC(=O)N1CC[C@H](NC2CCCCC2)C1

Procedure:
tert-butyl (3S)-3-(cyclohexylamino)pyrrolidine-1-carboxylate was prepared by a method similar to that described in preparation 1 using tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate and cyclohexanone to yield the desired product, 5.9 g (82%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].[CH:13]([Mg]Cl)([CH3:15])[CH3:14]>C1COCC1>[OH:5][CH:4]([C:3]1[CH:6]=[C:7]([CH3:12])[C:8]([O:10][CH3:11])=[CH:9][C:2]=1[OH:1])[CH:13]([CH3:15])[CH3:14]
Reactant: COc1cc(O)c(C=O)cc1C
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1cc(O)c(C(O)C(C)C)cc1C
Reaction time: 0.5 h

Procedure:
The above prepared 2-hydroxy-4-methoxy-5-methyl-benzaldehyde (1.97 g, 11.86 mmol) was dissolved in 30 mL of abs. THF and treated at −15° C. with iPrMgCl (14.8 mL of 2M [THF], 2.5 eq.) and the mixture kept at this temperature for 0.5 h. Careful pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents left 2.45 g of the title compound as white crystals, almost perfectly pure according to TLC and NMR.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:37](OC(=O)C)(=[O:39])[CH3:38]>C(O)(=O)C>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][N:11]([C:37](=[O:39])[CH3:38])[CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:34])[CH3:35])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(CCNCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOP(=O)(CCN(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)C(C)=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
To a solution of (2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonic acid diethyl ester (32 mg, 0.059 mmol) in acetic acid (0.5 mL) was added acetic anhydride (0.5 mL). The solution was stirred at room temperature for 90 minutes when it was quenched by addition of 2 drops of water. The solution was dried in vacuo and the residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 28 mg of the product (81%) as a clear gel. The NMR data of this compound shows two rotamers in a ratio of 70:30. 1H NMR (300 MHz, CDCl3) δ 0.05 (s, 9H), 1.17-1.27 (m, 2H), 1.30 and 1.31 (t, 6H, J=7 Hz), 1.70-1.79 (m, 2H), 1.76 (s, 3H), 2.00 (s, 3H), 2.18 (s, 3H), 3.40-3.52 (m, 2H), 3.46 (d, 2H, J=7 Hz), 3.77 (s, 3H), 3.79 and 3.93 (s, 3H), 4.07 (pent, 4H, J=7 Hz), 4.27-4.35 (m, 2H), 5.13 (s, 2H), 5.22-5.30 (m, 1H) ppm; 31P (121.4 MHz, CDCl3) δ 27.5 and 28.9 ppm; MS (m/z) 584.1 [M+H]+, 606.2 [M+Na]+.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]([CH2:13][C:14]([F:17])([F:16])[F:15])([C:9]([F:12])([F:11])[F:10])[O:8][C:4]=2[CH:3]=1.[Cu][C:21]#[N:22].NCCN>CN(C)C=O>[C:21]([C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]([CH2:13][C:14]([F:17])([F:16])[F:15])([C:9]([F:12])([F:11])[F:10])[O:8][C:4]=2[CH:3]=1)#[N:22]
Reactant: N#C[Cu]
Reactant: FC(F)(F)CC1(C(F)(F)F)Oc2ccc(Br)cc2O1
Solvent: NCCN
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)OC(CC(F)(F)F)(C(F)(F)F)O2
Temperature: 160 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
35 g of the product of Example 24 were dissolved in 75 ml of dimethylformamide, and 10.5 g of copper(I) cyanide were added. The mixture was stirred for 8 hours at 160° C. The hot mixture was then discharged into 100 ml of ice-water, and 30 g of 1,2-diaminoethane were added. After stirring for 30 minutes, the organic phase was separated off and the aqueous phase was extracted with methylene chloride. The combined organic phases were washed with a solution of 30 g of 1,2-diaminoethane in 75 ml of water, dried over magnesium sulphate and distilled under high vacuum to give 20.5 g of product (=69% of theory). The. boiling point was 110° C. at 0.02 mbar. =19F NMR: -58.1 and -84.6 ppm. 1H NMR: 3.08 ppm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH3:14])[C:6]([C:15]#[N:16])=[C:5]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl[CH2:24][C:25]([NH2:27])=[O:26].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:15]([C:6]1[C:7]([CH2:12][CH2:13][CH3:14])=[N:8][C:9]2[C:4]([C:5]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:3][C:2]([O:1][CH2:24][C:25]([NH2:27])=[O:26])=[CH:11][CH:10]=2)#[N:16]
Reactant: NC(=O)CCl
Reactant: CCCc1nc2ccc(O)cc2c(-c2ccccc2)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1nc2ccc(OCC(N)=O)cc2c(-c2ccccc2)c1C#N
Temperature: 60 °C
Reaction time: 18 h
Yield: 85.2 %

Procedure:
A suspension of 6-hydroxy-4-phenyl-2-propylquinoline-3-carbonitrile (0.98 g, 3.4 mmol), chloroacetamide (0.36 g, 3.8 mmol) and potassium carbonate (0.55 g, 4.0 mmol) in N,N-dimethylformamide (10 ml) was stirred at 60° C. for 18 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give 2-[(3-cyano-4-phenyl-2-propylquinolin-6-yl)oxy]acetamide (1.0 g, yield 88%) as pale-yellow crystals.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][CH2:15][CH:16]=O)=[CH:12][C:11]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:10]2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][N:34]([CH2:16][CH2:15][CH2:14][C:13]2[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:23])([F:22])[F:1])=[CH:4][CH:5]=3)[N:10]=[C:11]([CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=2)[CH2:33][CH2:32]1
Reactant: CCCCc1cc(CCC=O)n(-c2ccc(C(F)(F)F)cc2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccc(C(F)(F)F)cc2)n1

Procedure:
258.6 mg (84.7%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(4-trifluoromethylphenyl)-3-butyl-1H-pyrazol-5-yl)propanal (202.6 mg, 0.625 mmol), 1-(2-fluorophenyl)piperazine (148 mL, 0.937 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH:7]2[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1.[N:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[C:23]=[O:24]>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:23]([NH:22][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])[CH:7]2[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=1
Reactant: CC(C)(C)N=C=O
Reactant: FC(F)(F)c1ccc(C2NCCc3c(Br)cccc32)cc1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N1CCc2c(Br)cccc2C1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 50 mL round-bottomed flask was added 5-bromo-1-(4-(trifluoromethyl)-phenyl)-1,2,3,4-tetrahydroisoquinoline (44 mg, 124 μmol, from step 3), CH2Cl2 (2 mL), 2-isocyanato-2-methylpropane (12 mg, 124 μmol, Aldrich). The reaction mixture was stirred at RT for 2 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 50% EtOAc/hexanes to give 5-bromo-N-tert-butyl-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide. MS (ESI pos. ion) m/z: 455 (M+1).