Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][CH:20]=1.CCN(CC)CC>CCO>[C:22]([NH:21][C:17]1[CH:16]=[C:15]([NH:14][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])[CH:20]=[CH:19][CH:18]=1)(=[O:24])[CH3:23]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(=O)Nc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)Nc1cccc(Nc2ccc(C(=O)O)cc2[N+](=O)[O-])c1

Procedure:
A mixture of 4-fluoro-3-nitrobenzoic acid (5) (10.2 g, 54.9 mmol), N-(3-aminophenyl)acetamide (9.21 g, 66.6 mmol) and Et3N (1.4 mL, 10.1 mmol) in anhydrous EtOH (160 mL) was heated at reflux under N2 overnight. The reaction mixture was then cooled and filtered, and the orange solid collected by filtration. It was then washed with 2 M HCl(aq), and dried in vacuo to give 4-{[3-(acetylamino)phenyl]amino}-3-nitrobenzoic acid. 1H NMR (400 MHz, DMSO-d6): δ 2.03 (s, 3H), 7.02 (d, J=7.9 Hz, 1H), 7.13 (d, J=9.0 Hz, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.68 (s, 1H), 7.93 (dd, J=9.0, 1.9 Hz, 1H), 8.62 (s, 1H), 9.76 (s, 1H), 10.08 (s, 1H), 13.02 (br, 1H); MS (ES+): m/z 316 [MH+]
Reaction SMILES: [CH:1]([O:4][C:5]1[C:18]2[CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[C:16]3[C:15](=[O:29])[NH:14][CH:13]=[CH:12][C:11]=3[NH:10][C:9]=2[CH:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].F[B-](F)(F)F.[CH3:35][O+](C)C.C(=O)([O-])O.[K+]>ClCCCl>[CH:1]([O:4][C:5]1[N:6]=[CH:7][CH:8]=[C:9]2[C:18]=1[CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26])[C:16]1[C:15]([O:29][CH3:35])=[N:14][CH:13]=[CH:12][C:11]=1[NH:10]2)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1nccc2c1C(c1ccccc1C(F)(F)F)c1c(cc[nH]c1=O)N2
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCCl
Product: COc1nccc2c1C(c1ccccc1C(F)(F)F)c1c(ccnc1OC(C)C)N2

Procedure:
7.5 g (18.7 mMole) (±)-1,2,5,10-tetrahydro-9-isopropoxy-1-oxo-10-(2-trifluoromethylphenyl)-pyrido[4,3-b][1,6]naphthyridine (see Example 2) and 5.0 g (34 mMole) trimethyloxonium tetrafluoroborate are stirred for 24 hours at ambient temperature in 200 ml 1,2-dichloroethane under an atmosphere of nitrogen. The reaction mixture is then shaken with a saturated aqueous solution of potassium hydrogen carbonate and the organic phase is separated off, washed with water and dried over anhydrous sodium sulphate. The residue obtained after evaporation in a vacuum is chromatographed on silica gel with toluene/ethyl acetate (3:1 v/v). The fraction with the Rf of 0.2 is isolated and recrystallized from n-hexane/diisopropyl ether. There is obtained (±)-5,10-dihydro-1-isopropoxy-9-methoxy-10-(2-trifluoromethylphenyl)-pyrido[4,3-b][1,6]naphthyridine in the form of colorless crystals; mp 183°-185° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.CS(C)=O.[CH2:12](Cl)[C:13]#[CH:14]>O.C(=O)([O-])[O-].[Ag+2]>[C:12]([O:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)#[C:13][CH3:14]
Reactant: C#CCCl
Reactant: Oc1ccncc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: CC#COc1ccncc1
Temperature: 25 °C
Yield: 3.6 %

Procedure:
To a solution of 20.0 g (0.21 mole) 4-hydroxypyridine and 200 ml dimethyl sulfoxide was added 102 g (0.1 mole) silver carbonate. Propargyl chloride (22.5 g, 0.3 mole) was added to this suspension and the mixture heated at 50° for 6 hrs. After cooling to room temperature, the reaction mixture was diluted with water and extracted two times with ether. The combined ether extract was dried, filtered and concentrated as before to give 1.0 g of 4-(propynyloxy)pyridine. The product was 95% pure by vpc. The nmr and ir were compatible with the structure.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH2:11]([C:13]1[S:17][C:16]2[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:15]=2[C:14]=1[S:23](Cl)(=[O:25])=[O:24])[CH3:12]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:23]([C:14]1[C:15]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:16]=2[S:17][C:13]=1[CH2:11][CH3:12])(=[O:24])=[O:25]
Reactant: Cc1noc(N)c1Br
Reactant: CCc1sc2ccc(C)cc2c1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1sc2ccc(C)cc2c1S(=O)(=O)Nc1onc(C)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-ethyl-5-methylbenzo[b]thiophene-3-sulfonamide was prepared in the same manner as described in Example 41. Reaction of 4-bromo-3-methyl-5-aminoisoxazole (1.0 mmole, 0.18 g), NaH (2.5 mmoles, 0.10 g), and 2-ethyl-5-methylbenzo[b]thiophene-3-sulfonylchloride (1.3 mmoles, 0.36 g) in THF (6 ml) yielded, after recrystallization from chloroform and hexanes, 0.25 g (60%) of a light brown crystalline solid, m.p. 176-178° C.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.C[O:26][C:27](=[O:39])[C@@H:28]([NH2:38])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:38][C@@H:28]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[C:27]([OH:26])=[O:39])=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoic acid was coupled to (S)-2-amino-3-(3,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC: RT=10.98 min. MS (ESI−): mass calcd. for C22H15Cl3N4O5S2, 585.87; m/z found, 583/585 [M−H]−. H NMR (500 MHz, CDCl3): 11.35 (s, 1H), 8.36 (dd, J=7.0, 0.8, 1H), 8.21 (dd, J=8.8, 0.8, 1H), 7.74-7.69 (m, 1H), 7.34 (d, J=8.2, 1H), 7.21 (d, J=2.0, 1H), 7.15 (d, J=8.4, 1H), 6.97 (dd, J=8.2, 2.0, 1H), 6.93 (dd, J=8.4, 2.0, 1H), 6.44 (d, J=7.0, 1H), 4.95-5.00 (m, 1H), 3.32-3.16 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:14])([CH3:13])[NH:9][CH2:10]2)=[CH:5][C:4]=1[O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Cl>CCO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:13])([CH3:14])[N:9]([CH2:31][C:30]3[CH:33]=[CH:34][CH:35]=[C:28]([O:27][CH3:26])[CH:29]=3)[CH2:10]2)=[CH:5][C:4]=1[O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:18])[CH3:19]
Reactant: COc1cccc(CCl)c1
Reactant: COc1cc2c(cc1O[Si](C(C)C)(C(C)C)C(C)C)CC(C)(C)NC2
Solvent: CCO
Product: COc1cccc(CN2Cc3cc(OC)c(O[Si](C(C)C)(C(C)C)C(C)C)cc3CC2(C)C)c1
Temperature: 130 °C
Yield: 61.3 %

Procedure:
A mixture of 225 (300 mg, 0.83 mmol), 3-methoxybenzyl chloride (0.13 ml, 0.91 mmol) and TEA (0.3 ml, 1.65 mmol) in EtOH (3 ml) was heated in the microwave at 130° C. for 1.5 h. The reaction mixture was concentrated in vacuo. The crude residue was dissolved in EtOAc (30 ml), washed with brine (20 ml), dried (MgSO4) and concentrated in vacuo. Purification (flashmaster: 20 g, 100% hex to 50% hex/50% EtOAc and then to 100% EtOAc) afforded the title compound (246 mg, 62%) as colourless oil. 1H NMR (270 MHz; CDCl3) 1.04 (18H, d, J=6.7 Hz, CH3CH), 1.12-1.22 (3H, m, 3×SiCHCH3), 1.17 (6H, s, 2×CH3), 2.65 (2H, s, CH2), 3.47 (2H, s, CH2), 3.64 (2H, s, CH2), 3.74 (3H, s, OCH3), 3.79 (3H, s, OCH3), 6.41 (1H, s, CH), 6.48 (1H, s, CH), 6.77 (1H, ddd, J=8.2, 2.2, 1.2 Hz, CH), 6.95-6.98 (2H, m, 2×CH), 7.22 (1H, t, J=8.2 Hz, CH). 13C NMR (67.5 MHz; CDCl3) 12.38 (CH), 17.49 (CH3), 23.26 (CH3), 42.28 (CH2), 49.64 (CH2), 52.11 (C), 53.22 (CH2), 54.72 (OCH3), 55.04 (OCH3), 111.42 (CH), 111.69 (CH), 113.77 (CH), 117.21 (CH), 120.56 (CH), 125.68 (C), 126.34 (C), 128.69 (CH), 142.09 (C), 142.89 (C), 148.66 (C), 159.15 (C). LC/MS (ES+) tr=4.54 min, m/z 484.83 (M++H). HRMS (ES+) calcd. for C29H46NO3Si (M++H) 484.3241, found 484.3242.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[SH:8].CN(C=O)C.CS(O[CH2:19][CH2:20][CH:21]([C:29]1([CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]1=[O:42])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=O)=O>C1COCC1>[CH3:45][CH:44]([CH3:46])[CH2:43][C:29]1([CH:21]([CH2:20][CH2:19][S:8][C:4]2[S:3][CH:7]=[CH:6][CH:5]=2)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:30]1=[O:42]
Reactant: CC(C)CC1(C(CCOS(C)(=O)=O)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Reactant: Sc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)CC1(C(CCSc2cccs2)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
Sodium hydride (60%, 41 mg, 1.0 mmol) is added to a solution of thiophenethiol (118 mg, 1.02 mmol), THF (25 mL) and DMF (25 mL) at 0° C. The mixture is stirred for 30 minutes at 0° C. and a solution of tert-butyl α-[2-(methanesulfonyloxy)ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (490 mg, 1.02 mmol) in THF (15 mL) is added. The solution is allowed to warm slowly and is stirred at room temperature overnight. Concentration, aqueous workup (EtOAc, MgSO4), and purification by flash chromatography (25% EtOAc/hexane) gives 361 mg (71%) of title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])[O:10][C:8](=[O:9])[C:7]=12.[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:14]([C:7]12[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][CH:6]1[NH:12][C:11](=[O:13])[O:10][C:8]2=[O:9])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCBr
Reactant: Cc1cccc2[nH]c(=O)oc(=O)c12
Product: CCCCCCC12C(=O)OC(=O)NC1C=CC=C2C

Procedure:
Following the procedure of Step (2) of Preparation A, 6-methyl-isatoic anhydride was reacted with hexyl bromide to yield 1-hexyl-6-methyl-isatoic anhydride.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:5]2[NH:6][C:7]3[N:14]=[CH:13][CH:12]=[CH:11][C:8]=3[C:9](=[O:10])[N:4]2[N:3]=1.[OH-].[K+].[CH3:18]O>>[CH3:1][C:2]1[CH:15]=[C:5]2[N:6]([CH3:18])[C:7]3[N:14]=[CH:13][CH:12]=[CH:11][C:8]=3[C:9](=[O:10])[N:4]2[N:3]=1
Reactant: Cc1cc2[nH]c3ncccc3c(=O)n2n1
Reactant: CO
Agent: [K+]
Agent: [OH-]
Product: Cc1cc2n(C)c3ncccc3c(=O)n2n1
Reaction time: 1 h

Procedure:
3.8 g. of 2-methylpyrazolo[ 1,5-a]pyrido[2,3-d]pyrimidin-9(4H)-one are added to a solution of 1 g. of potassium hydroxide in 50 ml. of methanol and the mixture is stirred at room temperature for 2 hours. The potassium salt of 2-methylpyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-9(4H)-one is filtered off and suspended in 25 ml. of diethyleneglycol dimethyl ether. 5 g. of methyl iodide are added and the mixture is stirred for 1 hour and then filtered off, and the precipitated 2,4-dimethylpyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-9(4H)-one is recrystallized with methanol containing 10% water, yield: 2.1 g. (50%); m.p. 241.9°.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:13][C:9]1[CH:8]=[N:7][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C=NCCCl
Reactant: Nc1cccnc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(NCCCl)Nc1cccnc1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
1-Chloro-2-isocyanato-ethane (560 mg, 5.31 mmol) was added dropwise to a stirred solution of pyridin-3-ylamine (500 mg, 5.31 mmol) in toluene (10 mL) over a period of 30 minutes at 0° C. The reaction temperature was maintained at room temperature for 5 hours. The reaction was monitored by TLC (100% ethyl acetate). The reaction mixture was filtered, washed with toluene and dried under reduced pressure to afford 1.0 g (98% yield) of 1-(2-Chloro-ethyl)-3-pyridin-3-yl-urea.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:21](=[O:37])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][O:14][C:12]1[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]2[NH:20][C:21](=[O:37])[CH2:22][C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccncc3)c1)=N2

Procedure:
The title compound was prepared from {5-methoxy-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M31) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (183 mg).
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].C([Li])CCC.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[O:23])=[CH:17][CH:16]=1.C(O)(=O)C>O1CCCC1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[O:23][CH:2]=[N:1][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:17][CH:16]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: [C-]#[N+]CC(=O)OCC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)c1ncoc1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.5 %

Procedure:
To a solution of Ethyl isocyanoacetate (1.00 mL, 9.15 mmol) in Tetrahydrofuran (43 mL) at −78° C. was added 2.5 M n-Butyllithium (9.15 mmol, 9.15 mmol) in hexanes under argon. The mixture was stirred for 20 min. 4-Chlorophenylacetyl chloride (0.753 g, 3.98 mmol) in Tetrahydrofuran (11 mL, 130 mmol) was added at the same temperature. After 1 h, the temperature was raised to rt and then quenched by acetic acid (0.38 g, 6.3 mmol). The mixture was washed with saturated sodium bicarbonate and brine. The organic layer was collected and dried over sodium sulfate. After evaporation, the mixture was purified by chromatography to afford ethyl 5-(4-chlorobenzyl)-1,3-oxazole-4-carboxylate (0.83 g, 78%). LCMS: (FA) ES+ 266.3.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10](O)[C:5]=2[NH:4][N:3]=1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[C:5]2[NH:4][N:3]=[C:2]([CH3:1])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c2c(O)ncnc12
Solvent: CCN(CC)c1ccccc1
Product: Cc1n[nH]c2c(Cl)ncnc12
Reaction time: 0.25 h

Procedure:
A mixture of 3-methyl-7-hydroxypyrazolo[4,3-d]pyrimidine (1.0 g, 6.6 mmol), N,N-diethylaniline (2.0 g) and phosphorous oxychloride (16.5 g) was heated with magnetic stirring in an oil bath. The temperature was raised from 55° to 78° over the course of 40 min. At this point, all of the starting material had dissolved and the solution had turned red. The excess POCl3 was distilled off in vacuo (this procedure took 15 min.) and ice-water (50 ml) was added to the residue. The resulting red solution was saturated with sodium chloride (12 g) whereupon it turned yellow. The solution was extracted with ethyl acetate (4×40 ml) and the combined extract was filtered through alumina (5 g; 80-325 mesh), washed with brine (40 ml), dried (Na2SO4) and evaporated, yielding 0.83 g (74%) of eggshell colored crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([F:26])[C:24]=1F)[C:20]#[N:21].C(N(C(C)C)CC)(C)C>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH:15][C:24]1[C:17]([F:16])=[CH:18][C:19]([C:20]#[N:21])=[CH:22][C:23]=1[F:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Reactant: N#Cc1cc(F)c(F)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CNc1c(F)cc(C#N)cc1F
Yield: 7.2 %

Procedure:
(S)-2-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.36 g) and 3,4,5-trifluorobenzonitrile (1.00 g) were heated under argon in xylene (10 ml) containing diisopropylethylamine (3.3 ml) for 16 h. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried and evaporated to give a solid which was triturated with pentane-ether to afford the title product (0.16 g) as an off white powder. Chromatography of the mother liquors on silica gel eluting with ethyl acetate-pentane mixtures afforded further title product (0.92 g). Mass Spectrum (API+): Found 252 (MH+-tBoc). C18H23F2N3O2 requires 351.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].Cl>C(O)C>[C:1]([NH:4][C:5]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCCCCCCCCCCCCCBr
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Yield: 61.3 %

Procedure:
Diethyl 2-acetamidomalonate (3.0 g) was dissolved in 50 ml of dry ethanol and 1.13 g of sodium ethoxide was added thereto. A solution of 4.7 g of tetradecyl bromide in 20 ml of ethanol was added to the mixed solution while stirring at room temperature. The inside of the reaction vessel was displaced with nitrogen and the mixture was refluxed for about 15 hours. Then, the mixture was neutralized with a 1N aqueous hydrochloric acid solution and concentrated. The concentrate was purified by silica gel column chromatography to give 3.5 g of diethyl 2-acetamido-2-tetradecylmalonate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[C:18]([C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1)#[N:19]>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([O:26][C:22]3[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=3)[C:18]#[N:19])[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: N#Cc1cccc(O)c1
Product: N#Cc1cccc(Oc2nc(Nc3cc[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-cyano-phenol to give 3-[3-(1H-pyrazol-3-ylamino)-isoquinolin-1-yloxy]-benzonitrile. LC-MS m/e 328(MH+).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([CH3:28])[O:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([OH:27])[CH:26]=1)[C:15]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=1)=[O:16])(C(C)(C)C)(C)C.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([F:36])[CH:35]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:29][C:30]1[CH:31]=[C:32]([O:27][C:25]2[CH:24]=[C:14]([CH:13]=[C:12]([O:11][C@@H:10]([CH3:28])[CH2:9][OH:8])[CH:26]=2)[C:15]([NH:17][C:18]2[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=2)=[O:16])[CH:33]=[C:34]([F:36])[CH:35]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](CO)Oc1cc(Oc2cc(F)cc(F)c2)cc(C(=O)Nc2ccn(C)n2)c1
Yield: 22.3 %

Procedure:
A solution of 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (202 mg, 0.5 mmol), 3,5-difluorophenylboronic acid (156 mg, 1.0 mmol), copper (II) acetate (182 mg, 1.0 mmol), triethylamine (252 mg, 2.5 mmol) and freshly activated 4 Å molecular sieves (1.5 g) in DCM (10 mL) was stirred at ambient temperature and under ambient atmosphere for 64 hours. The reaction mixture was filtered, washed with DCM (2×10 mL), evaporated in vacuo and the residual oil partitioned between ethyl acetate (25 mL) and 1M hydrochloric acid (10 mL). The ethyl acetate layer was separated, washed sequentially with aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), and evaporated to a residue which was chromatographed by preparative HPLC on C18 reversed phase using 5-95% acetonitrile (+0.2% TFA) in water (+0.2% TFA) as eluant to give the title compound (45 mg).
Reaction SMILES: [NH:1]=[N+:2]=[N-:3].[F:4][C:5]1[CH:6]=[C:7]([C:12](O)([CH3:14])[CH3:13])[CH:8]=[C:9]([F:11])[CH:10]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[N:1]([C:12]([C:7]1[CH:8]=[C:9]([F:11])[CH:10]=[C:5]([F:4])[CH:6]=1)([CH3:14])[CH3:13])=[N+:2]=[N-:3]
Reactant: CC(C)(O)c1cc(F)cc(F)c1
Reactant: [N-]=[N+]=N
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(C)(N=[N+]=[N-])c1cc(F)cc(F)c1
Temperature: -5 °C
Reaction time: 20 h

Procedure:
Hydrogen azide (2M in toluene, 1.5 mol) was added to the solution of 2-(3,5-difluoro-phenyl)-propan-2-ol (Preparation 50, 145 g, 0.84 mol, 1 eq) in chloroform (1 L) and the content of the flask was cooled to −5° C. The mixture of TFA (2.5 mol, 2.98 eq) with chloroform (1:1) was added dropwise at such a rate to keep the internal temperature below −5° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirring was continued for 20 h. The reaction was poured into 2M sodium hydroxide and layers were separated. The aqueous phase was extracted two times with chloroform and combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. After removal of the solvent, the title compound was used in the next step without further purification (171 g, 0.87 mol, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[C:18]1([C:24]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN1C(=O)CCC1>[N+:15]([C:5]1[CH:4]=[CH:3][C:2]([N:29]2[CH2:30][CH2:31][N:26]([C:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:25])[CH2:27][CH2:28]2)=[CH:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(Br)cc1Nc1ccccc1
Reactant: O=C(c1ccccc1)N1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(c1ccccc1)N1CCN(c2ccc([N+](=O)[O-])c(Nc3ccccc3)c2)CC1
Temperature: 25 °C
Yield: 67.6 %

Procedure:
A solution of N-(5-bromo-2-nitrophenyl)benzenamine (200 mg, 0.68 mmol) and phenyl(piperazin-1-yl)methanone (257 mg, 1.36 mmol) in NMP (1.5 mL) was heated to 110° C. for 16 h. The solution was cooled to room temperature to which was slowly added H2O (5 mL). The resulting yellow precipitate was filtered, washed with 2 mL of water, dried (high vacuum, 14 h) to furnish (4-(4-nitro-3-(phenylamino)phenyl)piperazin-1-yl)(phenyl)methanone (187 mg, 0.46 mmol), 68% yield. 1H NMR (500 MHz, CDCl3) d (ppm) 3.10-3.61 (m, 8H), 6.34 (dd, J=2.6, 9.7 Hz, 1H), 6.41 (d, J=2.6 Hz, 1H), 7.24-7.48 (m, 10H), 8.19 (d, J=9.7 Hz, 1H), 9.86 (s, 1H). 13C NMR (125 MHz, CDCl3): d (ppm) 171.0, 155.7, 145.8, 139.3, 135.5, 130.6, 130.2, 129.4, 129.1, 127.6, 126.1, 125.0, 106.2, 96.9, 46.7, 29.9.