Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH3:21])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)=[N:5]1.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27]1[CH:31]=[C:30]([C:32](O)=[O:33])[NH:29][N:28]=1>>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@H:2]([NH:1][C:32]([C:30]3[NH:29][N:28]=[C:27]([C:23]4[O:22][CH:26]=[CH:25][CH:24]=4)[CH:31]=3)=[O:33])[CH3:21])[N:5]=2)=[CH:10][C:11]=1[C:17]([F:20])([F:19])[F:18])#[N:14]
Reactant: O=C(O)c1cc(-c2ccco2)n[nH]1
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(C(F)(F)F)c2)n1
Product: C[C@H](Cn1ccc(-c2ccc(C#N)c(C(F)(F)F)c2)n1)NC(=O)c1cc(-c2ccco2)n[nH]1
Yield: 74.5 %

Procedure:
(The title compound was prepared from (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)benzonitrile (0.080 g, 0.272 mg) and 3-(furan-2-yl)-1H-pyrazole-5-carboxylic acid (0.053 g, 0.299 mmol) using the method of Example 34(d) affording 0.092 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.17 (d, 3H), 4.30-4.39 (m, 2H), 4.42-4.51 (m, 1H), 6.61 (m, 1H), 7.03 (d, 1H), 7.76 (m, 1H), 7.86 (d, 1H), 8.17 (d, 1H), 8.27 (m, 2H), 8.34-8.36 (m, 1H), 13.69 (m, 1H).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[O:22][CH:21]=[N:20][C:19]=2[CH2:23][CH3:24])=[N:16][CH:17]=1.[Cl:25]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.O>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[O:22][C:21]([Cl:25])=[N:20][C:19]=2[CH2:23][CH3:24])=[N:16][CH:17]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CCc1ncoc1-c1ccc(Br)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc(Cl)oc1-c1ccc(Br)cn1
Temperature: 25 °C
Yield: 89 %

Procedure:
LiHMDS (1.0 M in THF, 8.5 mL, 8.5 mmol) was added dropwise to a solution of Example 44A (1.97 g, 7.78 mmol) in THF (26 mL) at −78° C. After 30 min solid hexachloroethane (1.84 g, 7.78 mmol) was added in one portion and the reaction mixture was stirred while warming to ambient temperature overnight. The reaction was diluted with water and extracted with EtOAc. The organic extract was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on silica gel (Analogix® Intelliflash 280™; SF25-120 g column; 100% hexane 0-5 min, then 0% to 25% EtOAc/hexanes eluant, 5-40 min) afforded 1.99 g (89%) of the title compound as a yellow oil that solidified on standing. 1H NMR (300 MHz, CDCl3) δ 8.67 (dd, J=2.4, 0.6, 1H), 7.86 (dd, J=8.5, 2.4, 1H), 7.47 (dd, J=8.5, 0.6, 1H), 3.02 (q, J=7.5, 2H), 1.27 (t, J=7.5, 3H). MS (DCI+) m/z 287/289 (M+H).
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5]OC(=O)C(F)(F)F)=O.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH:21]1C=CC=C[CH:22]=1>O>[CH:17]12[CH2:16][CH:22]([CH:19]([C:20]#[N:15])[CH2:18]1)[CH2:21][CH:2]2[C:3]#[N:5]
Reactant: c1ccccc1
Reactant: c1ccncc1
Reactant: O=C(NOC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: N#CC1CC2CC1CC2C#N
Yield: 73 %

Procedure:
In a 2-l flask equipped with a stirrer, a thermometer and a reflux condenser, 179.0 g (1.2 moles) of 5-cyano-bicyclo[2.2.1]hepta-2-carbaldehyde, 292.6 g (1.3 moles) of N,O-bis(trifluoroacetyl)hydroxylamine, 197.8 g (2.5 moles) of pyridine and 600 ml of benzene were charged. The resulting mixture was gradually heated and refluxed for 3 hours under stirring. Deionized water (500 ml) was thereafter added to the reaction mixture. The water layer so obtained was removed, whereby an oil was obtained. The oil was distilled under reduced pressure, whereby 128.0 g of bicyclo[2.2.1]heptane-2,5-dicarbonitrile were obtained at 131°-136° C./1 mmHg (yield: 73%). The following is the results of an elemental analysis of the target product.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:13]I.[H-].[Na+]>O1CCCC1>[CH3:13][O:12][CH2:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: OCC1CCC2(CC1)OCCO2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1CCC2(CC1)OCCO2
Yield: 780 %

Procedure:
1,4-Dioxaspiro[4.5]decane-8-methanol (2 g, 1 mmol) (commercial available or prepared as in Bioorganic & Medicinal Chemistry, 13(23), 6309-6323; 2005) is methylated using MeI (1.81 mL, 29 mmol) and NaH (0.813 g, 20 mmol) in tetrahydrofuran to obtain after 2 hours of stirring at room temperature 1.4 g (7.8 mmol) of the desired compound. MS (m/e): 187.3 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:14][N:15](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:14]([C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6])#[N:15]
Reactant: COC(=O)c1cc(Cl)nc(OC)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(C#N)nc(OC)c1
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
Under N2, methyl 2-chloro-6-methoxyisonicotinate (CAS 42521-10-8) (3.97 g, 19.7 mmol, Eq: 1.00), zinc cyanide (2.77 g, 23.6 mmol, Eq: 1.2) and Tetrakis-triphenylphosphin-palladium (1.14 g, 985 μmol, Eq: 0.05) were mixed in DMF (67.5 ml). The RM was stirred under microwave at 160° C. for 30 minutes. Control with LC-MS: the reaction was finished.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[CH2:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][CH2:36][NH:35]1>>[CH3:1][O:2][C:3](=[O:33])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:25][CH:24]=2)[CH:12]=[C:13]([N:35]2[CH2:36][CH2:37][C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:34]2)[CH:14]=1)[CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: c1ccc2c(c1)CCNC2
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: COC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N2CCc3ccccc3C2)c1
Yield: 85 %

Procedure:
The title compound was prepared in 85% yield from 4-methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid methyl ester and tetrahydroisoquinoline under the conditions described in Example 24, step (a).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.N1(C2CCCCCCCCCC2)CCCN=CCCCCC1.C1CCN2C(=NCCC2)CC1.[CH2:42]([O:49][C:50]1[N:51]=[N:52][C:53]([C:64]#[CH:65])=[CH:54][C:55]=1[O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O1CCCC1.[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>[CH2:42]([O:49][C:50]1[N:51]=[N:52][C:53]([C:64]#[C:65][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:54][C:55]=1[O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: Clc1cccc(I)c1
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Clc1cccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Temperature: 80 °C
Yield: 30 %

Procedure:
To a solution of 1-chloro-3-iodobenzene (0.862 g, 3.62 mmol) in dry tetrahydrofuran (11 ml) was added copper(I) iodide (0.063 g, 0.33 mmol), bis(triphenylphosphine)-palladium(II) chloride (0.115 g, 0.16 mmol) and 1,8-diazabicycloundec-7-ene and (DBU; 2.97 ml, 19.72 mmol). The reaction was then purged and evacuated with nitrogen several times before 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5; 1.04 g, 3.29 mmol) was added. The reaction vessel was sealed and heated to 80° C. for 1 hour. Upon cooling, the resultant mixture was partitioned between ethyl acetate and water. The combined organic portions were washed with water (×2) and brine, dried (MgSO4), filtered and concentrated to give a brown oil. The crude oil was purified by silica chromatography (eluting with 0-20% ethyl acetate in petrol) to yield 3,4-bis(benzyloxy)-6-((3-chlorophenyl)ethynyl)pyridazine as a yellow solid (yield=30%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6](C)[CH:5]=[CH:4][N:3]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:16](=O)([O-])[O-].[K+].[K+].CCCCCCC>C(OCC)(=O)C>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][N:3]1[CH:4]=[C:5]([CH3:16])[CH:6]=[CH:7][C:2]1=[O:1])[CH3:15]
Reactant: CCOC(=O)CBr
Reactant: Cc1ccnc(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1cc(C)ccc1=O
Yield: 76 %

Procedure:
As described for example 320a, 2-hydroxy-4-methyl-pyridine was reacted with ethyl bromoacetate and potassium carbonate. Extractive workup followed by chromatography (SiO2, heptane:ethyl acetate=100:0 to 0:100) afforded the title compound as a colorless liquid (yield: 76%). MS: m/e=196.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:34]=[CH:33][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)\[CH2:23][C:24]([OH:26])=O)=[CH:17][CH:16]=1.Cl.C([N:38]=C=NCCCN(C)C)C.CN(C)C=O>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)\[CH2:23][C:24]([NH2:38])=[O:26])=[CH:33][CH:34]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CC(=O)O)c2ccccc2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CC(N)=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.5 %

Procedure:
A mixture of E-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-3-phenylpropionic acid (600 mg), 1-hydroxybenzotriazole ammonia complex (260 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (328 mg) and N,N-dimethylformamide (5 ml) was stirred at room temperature for 15 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed successively with an aqueous solution of potassium carbonate and an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from tetrahydrofuran-hexane to obtain E-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-3-phenylpropanamide (512 mg, yield 86%) as colorless crystals. m.p. 164-165° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:49])[C:32]([C:47]#[N:48])=[CH:33][C:34]([N:37]([CH2:45][CH3:46])C(=O)OC(C)(C)C)([CH3:36])[CH3:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:33][C:34]([NH:37][CH2:45][CH3:46])([CH3:35])[CH3:36])[C:47]#[N:48])=[O:49])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CCN(C(=O)OC(C)(C)C)C(C)(C)C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(C)(C)C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.7 %

Procedure:
To a solution of tert-butyl 5-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl(ethyl)carbamate (60 mg, 0.089 mmol) in DCM (8 mL) was added 2 mL of CF3COOH. The mixture was stirred for 2 h at room temperature, then concentrated and purified by Prep-HPLC. Conditions: (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (40% CH3CN up to 100% in 20 min); Detector, 254 nm. This resulted in 12 mg (16%) of the title compound as a white solid and bis TFA salt. LC-MS: m/z 569 (M+H+). H1-NMR (400 MHz, CDCl3+D2O, ppm): 8.31 (s, 1H), 7.51-7.44 (m, 3H), 7.37 (s, 1H), 7.28-7.25 (m, 1H), 7.13 (d, J=7.6 Hz, 2H), 6.95 (dd, J=8.4, 2.0 Hz, 1H), 6.85 (q, J=11.6 Hz, 2.0 Hz, 1H), 4.89-4.65 (m, 3H), 3.76-3.57 (m, 4H), 2.14-1.83 (m, 4H), 1.50-1.49 (d, 6H), 1.31 (t, q=6.8 Hz, 3H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([CH2:14][N:15]2[CH:23]=[N:22][C:21]3[C:20](=[O:24])[NH:19][C:18]([NH2:25])=[N:17][C:16]2=3)[S:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C.O>[Br:1][C:23]1[N:15]([CH2:14][C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)[C:16]2[N:17]=[C:18]([NH2:25])[NH:19][C:20](=[O:24])[C:21]=2[N:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc2c(ncn2Cc2cccs2)c(=O)[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc2c(nc(Br)n2Cc2cccs2)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-Bromosuccinimide (2.82 g; 15.7 mmol) was added to a cold (0° C. suspension of 9-(2-thenyl)guanine (3.5 g; 14.1 mmol) in DMF (100 ml) and the mixture was stirred for 30 minutes at 0° C. and then at room temperature for 24 hours. The reaction mixture was then diluted with 75 ml of water and filtered. Recrystallization of the product from DMF gave the analytical sample, yield 3.1 g; mp 294°-295° C. (dec).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[N:28]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[C:37]([O:36][C:34]([N:28]1[CH2:33][CH2:32][N:31]([CH2:12][C:9]2[C:10](=[O:11])[N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[N:6]=[C:7]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=3)[CH:8]=2)[CH2:30][CH2:29]1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)Cn1nc(-c2ccc(C(F)(F)F)cc2)cc(COS(C)(=O)=O)c1=O
Product: CC(C)Cn1nc(-c2ccc(C(F)(F)F)cc2)cc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1=O
Yield: 83.5 %

Procedure:
Following the procedure of Example 1(10), 2-isobutyl-4-methanesulfonyloxymethyl-6-(4-trifluoromethyl phenyl)-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 83.5%).
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([NH2:8])([CH3:7])[CH3:6])=[O:3].C(O)(C(O)=O)=O.O=[CH:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>CO>[CH3:6][C:5]1([CH3:7])[NH:8][CH:16]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:1][C:2](=[O:3])[CH2:4]1
Reactant: CC(=O)CC(C)(C)N
Reactant: COC(=O)CCC=O
Agent: O=C(O)C(=O)O
Solvent: CO
Product: COC(=O)CCC1CC(=O)CC(C)(C)N1
Temperature: 100 °C
Reaction time: 3 h
Yield: 36.7 %

Procedure:
Diacetoneamine hydrogen oxalate (4.25 g) and methyl 4-oxobutanoate (2 g) were suspended in methanol (20 ml). The reaction mixture were stirred at 100° C. for three hours and then at room temperature overnight. It was then evaporated and the residue was purified by Combiflash chromatography (2.0 M ammonia methanol in dichloromethane=0-30%) to give methyl 3-(6,6-dimethyl-4-oxopiperidin-2-yl)propanoate (1.35 g, 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22]([NH:24][NH2:25])=O)=[C:9]1[C:26]([O:28][CH2:29][CH3:30])=[O:27].S(O)(O)(=O)=O.CS[C:38](=[NH:40])[NH2:39].N12CCCC1=NCCC2>C(O)CCC>[NH2:40][C:38]1[N:39]=[C:22]([CH2:21][O:20][CH2:19][C:10]2[NH:11][C:12]([CH3:18])=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])[NH:24][N:25]=1
Reactant: CCOC(=O)C1=C(COCC(=O)NN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: CSC(=N)N
Agent: C1CN=C2CCCN2C1
Agent: O=S(=O)(O)O
Solvent: CCCCO
Product: CCOC(=O)C1=C(COCc2nc(N)n[nH]2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Yield: 15.3 %

Procedure:
A solution of 2-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}-acetylhydrazine (0.87 g), 2-methylisothiourea sulphate (0.68 g) and 1,5-diazabicyclo[4.3.0]non-5-ene (0.74 g) in n-butanol (30 ml) was heated under reflux for 16 hours and then evaporated. The residue was partitioned between dichloromethane and water and the organic layer dried (Na2SO4) and evaporated. The residual oil was purified by chromatography on silica (t.l.c. grade, 10 g) using dichloromethane plus 0-100% v/v ethyl acetate as eluant. Appropriate fractions were combined and evaporated and the residual oil triturated with ethyl acetate. The resulting solid was collected, washed with ethyl acetate and dried to give the title compound (0.14 g), m.p. 199°-202° C. decomp.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11](O)[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:18][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCC(O)c1ccc(CC(C)C)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCC(Br)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-(4-isobutylphenyl)pentanol and carbon tetrabromide in tetrahydrofuran was added triphenylphosphine, and the mixture was stirred at room temperature for 30 minutes. Insoluble materials were removed by filtration and the filtrate was concentrated. Hexane was added to the residue and the mixture was filtered again. Concentration of the filtrate gave crude 1-bromo-1-(4-isobutylphenyl)pentane. Sodium was added portionwise to ethylene glycol at 80° C. while stirring. To the resultant solution was added the obtained crude 1-bromo-1-(4-isobutylphenyl)pentane, and the mixture was stirred at 120° C. for 1 hour. After the mixture was cooled, diluted hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated. Silica gel column chromatography of the concentrate afforded the object compound.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[C:15]1([CH2:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:24][CH2:23][CH2:22][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NCCCc1ccccc1
Solvent: CO
Product: N#CNC(=NCCCc1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 78.1 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.60 g, 3.2 mmol) was dissolved in methanol (10 ml), and 3-phenylpropylamine (0.47 g, 3.5 mmol) was added. The mixture was stirred at room temperature for 50 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure and crystallized from methanol-diethyl ether to give the title compound (0.67 g, 2.5 mmol, yield: 80%) as colorless needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](O)=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:14][CH2:13][CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][CH:7]=1)=[O:24]
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Reactant: O=C(O)c1cccc(Cc2cccc(F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CCNC(=O)c3cccc(Cc4cccc(F)c4)c3)c2c1
Yield: 51.3 %

Procedure:
3-(3-Fluorobenzyl)-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)benzamide was prepared according to method A with 2-(5-methoxy-1H-indol-3-yl)ethanamine (0.060 g; 0.315 mmol), 3-(3-fluorobenzyl)benzoic acid (0.073 g; 0.316 mmol), HATU (0.120 g; 0.316 mmol) and N,N-diisopropylethylamine (0.135 mL; 0.788 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent 1 to 20% ethyl acetate in dichloromethane) furnished 0.065 g (51%) of the title compound as a white solid.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][C:42](O)=[O:43]>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:42](=[O:43])[CH2:41][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=2)[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1ccccn1
Reactant: Fc1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: O=C(Cc1ccccn1)N1CC[C@H](OCc2cc(F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (28.8 mg) obtained in Example 26 and 2-pyridineacetic acid hydrochloride (20.8 mg) were reacted and treated in the same manner as in the method described in Example 32 to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:53]=[C:54]([F:56])[CH:55]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[N:10]=[C:9]2[NH:34][C:35](=[O:52])[C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]2)=[CH:38][C:37]=1[N+:49]([O-:51])=[O:50].[ClH:57]>O1CCOCC1>[ClH:57].[F:56][C:54]1[CH:53]=[C:4]([CH:3]=[C:2]([F:1])[CH:55]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:34][C:35](=[O:52])[C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:43][CH2:44][N:45]([CH3:48])[CH2:46][CH2:47]2)=[CH:38][C:37]=1[N+:49]([O-:51])=[O:50].[ClH:57]
Reactant: CN1CCN(c2ccc(C(=O)Nc3nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c4ccc(Cc5cc(F)cc(F)c5)cc34)c([N+](=O)[O-])c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-[5-(3,5-difluoro-benzyl)-1-trityl-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide (28.5 mg, 0.04 mmol) in dioxane (1 mL), 4 M HCl in dioxane (0.1 mL) was added and the mixture was stirred at room temperature for 1 hour. After concentration the residue was suspended in diethyl ether/MeOH 1:1, stirred for 20 min., filtered, washed with the same solvent mixture and dried. The desired product was obtained as hydrochloride derivative (19 mg, 87%).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]([C:6]1[CH:31]=[CH:30][C:9]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][CH:7]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:42]([O:49][C:50]1[C:55]([CH:56]=O)=[CH:54][CH:53]=[CH:52][N:51]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C1COCC1>[CH2:42]([O:49][C:50]1[C:55]([CH:56]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH3:2])=[O:5])=[CH:31][CH:30]=2)=[CH:54][CH:53]=[CH:52][N:51]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: O=Cc1cccnc1OCc1ccccc1
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C=Cc2cccnc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
(4-Methoxycarbonylbenzyl)triphenylphosphonium bromide (16.6 g, 33.8 mmol) was suspended in THF (70 ml) under Argon. Lithium bis(trimethylsilyl)amide (1M in THF, 40.5 ml) was added. The reaction mixture was stirred for 1 hour at ambient temperature; the colour changed to orange. 2-Benzyloxy-3-pyridinecarbaldehyde (7.2 g, 33.8 mmol) was added as a solution in THF (50 ml) and the reaction mixture was stirred at amibent temperature overnight (shielded from light). The reaction mixture was partitioned between EtOAc/water, the organic phase was dried (MgSO4) and evaporated. Purification by chromatography (SiO2, eluting with CH2Cl2 /hexane) gave methyl 4-[2-(2-benzyloxy-3-pyridyl)ethenyl]benzoate (9.2 g, 79%).