Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:7]=[C:8]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=2)[C:9]([NH2:11])=O)=[N:2]1.O=P(Cl)(Cl)Cl.CO.ClCCl>CN(C=O)C>[NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:7]=[C:8]([CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=2)[C:9]#[N:11])=[N:2]1
Reactant: NC(=O)c1cc(-c2nc[nH]n2)cc(C(F)(F)F)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1cc(-c2nc[nH]n2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 107.6 %

Procedure:
In 3-neck 50 mL round-bottomed flask, 3-(1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)benzamide (0.5 g, 1 eq.) and POCl3 (2.0 mL, 4 eq.) was dissolved in DMF (15 mL, 15 Vol) and reaction mixture was stirred at 25° C. for 1-2 hr. The progress of the reaction was followed by TLC analysis on silica gel with 10% Methanol:dichloromethane as mobile phase and visualization with UV, SM Rf=0.35 and Product Rf=0.45. Reaction mixture was concentrated under reduced pressure to afford 0.1.2 g of crude compound. The crude reaction mixture was purified by column chromatography using silica 60/120 using Methanol: dichloromethane as mobile phase. The column (5×10 cm) was packed in dichloromethane and started eluting in Methanol in gradient manner starting with fraction collection (25-mL fractions) from 1.5% to 2.0% Methanol in dichloromethane. Compound started eluting with 1.5% Methanol in dichloromethane. Fraction containing such TLC profile was collected together to obtain pure 3-(1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)benzonitrile (500 mg), Yield (60%); Mass: (ES+) 238.1 (M+1).
Reaction SMILES: P(I)(I)P(I)I.[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH:22]3O[CH:23]3[CH2:24][CH2:25][CH3:26])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[CH3:8].N1C=CC=CC=1.Cl>C(Cl)Cl>[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][C@H:19](/[CH:22]=[CH:23]/[CH2:24][CH2:25][CH3:26])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[CH3:8]
Reactant: CCCC1OC1[C@H]1CC[C@H](c2ccc(OCC)cc2)CC1
Agent: Cl
Agent: IP(I)P(I)I
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC/C=C/[C@H]1CC[C@H](c2ccc(OCC)cc2)CC1

Procedure:
A suspension of 404.4 mg of diphosphorus tetraiodide in 5 ml of methylene chloride was treated dropwise while gassing with argon at room temperature within 5 minutes with a solution of 205 mg of 4-ethoxy-1-[trans-4-(1,2-epoxypentyl)cyclohexyl]benzene and 0.703 ml of pyridine in 8 ml of methylene chloride. The suspension was heated to reflux while stirring, a further 404.4 mg of diphosphorus tetraiodide being added after 2 hours. After stirring under reflux for a total of 19 hours, the reaction was interrupted and the mixture was treated with 1N hydrochloric acid and extracted three times with diethyl ether. The organic extracts were washed successively with 1N hydrochloric acid, sodium thiosulphate solution and water, dried over magnesium sulphate, filtered and evaporated. Chromatographic separation of the residue (0.2 g) on silica gel with ethyl acetate/petroleum ether (vol. 3:97) as the eluent gave 120 mg of 4-ethoxy-1-[trans-4-(trans-1-pentenyl)cyclohexyl]benzene. After recrystallization from 10 ml of methanol, the product was obtained as white crystals of melting point (C--N) 32.2° C. and clearing point (N--I) 54.9° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]([F:24])([C:18]2[O:19][C:20]([CH3:23])=[N:21][N:22]=2)[CH:12]2[CH2:16][CH2:15][C:14](=O)[CH2:13]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33]N)=[CH:29][CH:28]=1.ClC1C2C3(CCC=2)C(=CC=1)NC(C(S(C1C=CC=C(Cl)C=1)(=O)=O)(F)C1OC(C)=NN=1)C3>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]2[NH:33][C:14]3[CH2:13][CH:12]([C:11]([S:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)(=[O:10])=[O:9])([F:24])[C:18]4[O:19][C:20]([CH3:23])=[N:21][N:22]=4)[CH2:16][C:15]=3[C:29]=2[CH:28]=1
Reactant: Cc1nnc(C(F)(C2CCC(=O)C2)S(=O)(=O)c2cccc(Cl)c2)o1
Reactant: NNc1ccc(Cl)cc1
Agent: Cc1nnc(C(F)(C2CC34CCC=C3C(Cl)=CC=C4N2)S(=O)(=O)c2cccc(Cl)c2)o1
Agent: Cl
Product: Cc1nnc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2cccc(Cl)c2)o1

Procedure:
In analogy to example 74.6, from (RS,SR)-3-[(3-chloro-benzenesulfonyl)-fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)-methyl]-cyclopentanone and (4-chloro-phenyl)-hydrazine hydrochloride was prepared (RS,SR)-7-chloro-2-[(3-chloro-benzenesulfonyl)-fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)-methyl]-1,2,3,4-tetrahydro-cyclopenta[D]indole as a light brown solid, MS: 480 (MH+).
Reaction SMILES: [Br:1][C:2]1[N:11]2[C:5]([CH2:6][NH:7][CH2:8][C:9]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:10]=32)=[N:4][N:3]=1.C=O.[C:19]([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[N:11]2[C:5]([CH2:6][N:7]([CH3:19])[CH2:8][C:9]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:10]=32)=[N:4][N:3]=1
Reactant: Clc1ccc2c(c1)CNCc1nnc(Br)n1-2
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1Cc2cc(Cl)ccc2-n2c(Br)nnc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.4 %

Procedure:
A mixture of 1-bromo-8-chloro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (1.9 g, 6.4 mmol) and paraformaldehyde (1.5 g, 51 mmol) in methanol (64 ml) was heated at reflux for 16 h. After cooling to 0° C. sodium cyanoborohydride (0.8 g, 13 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. After quenching with 1 M aqueous sodium hydroxide solution (200 ml) the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Flash chromatography over aminopropyl-modified silica gel with n-heptane/ethyl acetate as eluent gave the title compound (0.61 g) as white solid with a purity of ca. 85% as assessed by 1H-NMR. MS m/e: 313 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[K+].[K+].Cl>O1CCOCC1.O.ClCCl.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]>[ClH:1].[Cl:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:3]=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[CH2:22][CH2:21][CH2:20][C@@H:19]4[CH3:23])[N:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: C[C@H]1CCCN1c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: C[C@H]1CCCN1c1cccc(Nc2cc(-c3cccc(Cl)c3)nn3ccnc23)n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 5.6 %

Procedure:
A mixture of (S)-6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (200 mg, 0.61 mmol), 3-chlorophenylboronic acid (79 mg, 0.67 mmol), Pd2 dba3 (26 mg, 0.061 mmol), X-phos (87 mg, 0.24 mmol) and K2CO3 (190 mg, 1.83 mmol) were dissolved in dioxane/water (30 mL/3 mL), the reaction mixture degassed with bubbling nitrogen for 5 minutes, then heated at 100° C. with stirring for 3 h. The solvent was removed in vacuo then purified by chromatography (silica gel, dichloromethane/methanol 80:1) to give a residue which was further purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% TFA, v/v) in a linear fashion over 9 min) to afford a product which was dissolved in dichloromethane (10 mL) then concentrated HCl (2 mL) added slowly and stirred at room temperature for 10 min. The solvent was removed in vacuo to afford (S)-6-(3-chlorophenyl)-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-aminehydrochloride (15 mg, 6%) as an orange solid. 1H NMR (300 MHz, DMSO): δ 9.78 (s, 1H), 8.88 (s, 1H), 8.33-8.31 (m, 1H), 7.96-7.81 (m, 3H), 7.65-7.46 (m, 3H), 6.73-6.69 (m, 1H), 6.13 (d, 1H, J=8.1 Hz), 4.28-4.24 (m, 1H), 3.63-3.58 (m, 1H), 3.47-3.41 (m, 1H), 2.12-2.02 (m, 3H), 1.74-1.73 (m, 1H), 1.16 (d, 3H, J=6.3 Hz). LC-MS: [M+H]+, 405, tR=2.26 min, HPLC: 99.61% at 214 nm, 95.33% at 254 nm, tR=5.36 min.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C1COCC1.C1COCC1.[N:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[CH3:26].[C:27](=O)([O:30]C)[O:28][CH3:29]>O>[CH3:26][C:20]1[CH:21]=[C:22]([CH2:25][C:27]([O:28][CH3:29])=[O:30])[CH:23]=[CH:24][N:19]=1
Reactant: COC(=O)OC
Reactant: Cc1ccnc(C)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)Cc1ccnc(C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 16.3 %

Procedure:
An LDA-THF solution (2.00 mol/L, 65.0 mL, 130 mmol) was cooled to −78° C., then a THF solution (50.0 mL) of 2,4-lutidine (10.7 g) was added thereto, followed by stirring for 2 hours. Then, the temperature was raised to 0° C., and a THF solution (50.0 mL) of dimethyl carbonate (11.7 g) was added dropwise to the mixture, followed by stirring for 30 minutes. Water was added to the reaction mixture, and the resulting mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give methyl 2-methylpyridin-4-ylacetate (2.69 g, yield 16%).
Reaction SMILES: C(N(CC)CC)C.[OH:8][NH:9][CH2:10][CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:25][C:26]1[NH:27][C:28]([CH3:51])=[C:29]([C:45]([O:47][CH2:48][CH2:49]Br)=[O:46])[CH:30]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([N+:42]([O-:44])=[O:43])[CH:37]=2)[C:31]=1[C:32]([O:34][CH3:35])=[O:33].Cl>CN(C)C=O.CC(C)=O.C(OCC)C.O>[CH3:25][C:26]1[NH:27][C:28]([CH3:51])=[C:29]([C:45]([O:47][CH2:48][CH2:49][N:9]([CH2:10][CH2:11][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[OH:8])=[O:46])[CH:30]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([N+:42]([O-:44])=[O:43])[CH:37]=2)[C:31]=1[C:32]([O:34][CH3:35])=[O:33]
Reactant: ONCCC(c1ccccc1)c1ccccc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCBr)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(O)CCC(c2ccccc2)c2ccccc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 105 °C
Reaction time: 1 h

Procedure:
3 ml of triethylamine were added to a solution of 2.40 g of N-hydroxy-3,3-diphenylpropylamine in 17 ml of dimethylformamide. 4.39 g of methyl 2-bromoethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate were added to the mixture. The mixture was then maintained in a nitrogen atmosphere and heated for 160 minutes at 105° C. After cooling, the mixture was poured into water and extracted with a diethyl ether:ethyl acetate mixture. The organic layer was washed many times with water and then dried. The solvent was evaporated off in vacuo. The oily residue obtained was purified first by chromatography on a silica gel column with ethyl acetate gradient in toluene and then on a silica gel column containing ammonia at 5.5% by weight with about 6N methanolic ammonia gradient in chloroform. The solid thus obtained was dissolved in a 2:1 by volume acetone:diethyl ether mixture and hydrogen chloride in diethyl ether was added. The hydrochloride hemihydrate of the title compound was filtered off, washed with isopropanol and dried at 100° C. and 0.5 mmHg for 1 hour. Yield 1.51 g, m.p. 100°-105° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:12](=[O:18])[C:13]([C:15]([OH:17])=[O:16])=[CH:14][N:9]3[C:10]=2[C:5]([CH2:6][CH2:7][N:8]3[CH3:19])=[C:4](F)[C:3]=1[F:21].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C(#N)C>[NH2:1][C:2]1[C:11]2[C:12](=[O:18])[C:13]([C:15]([OH:17])=[O:16])=[CH:14][N:9]3[C:10]=2[C:5]([CH2:6][CH2:7][N:8]3[CH3:19])=[C:4]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:3]=1[F:21]
Reactant: C1CCNC1
Reactant: CN1CCc2c(F)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Solvent: CC#N
Product: CN1CCc2c(N3CCCC3)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Temperature: 80 °C

Procedure:
4 mg of the compound (202) obtained in Example 73 and 10 μl of pyrrolidine were added to 1 ml of acetonitrile, and the solution was heated at 80° C. for 3 hours. After air-cooling, the solvent was removed by distillation, and the residue was filtered off and washed with ethanol and ether in this order to obtain 2 mg of the subject compound (203).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[N+]=[N-]>CCOC(C)=O.[Pd]>[NH:7]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[C:5]([CH2:4][NH2:1])=[CH:6]1
Reactant: [N-]=[N+]=NCc1c[nH]c2ncccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NCc1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
To a mixture of 3-(azidomethyl)-1H-pyrrolo[2,3-b]pyridine (A-4) (1.50 g, 8.63 mmol) in EtOAc (150 mL) was added 10% Pd/C (1.10 g). The resulting reaction mixture was stirred under one atmosphere of H2 at room temperature for 3 h. The mixture was filtered, and the filtrate was concentrated to afford the title compound (1.15 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:22][CH3:23])[C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24](=O)[CH3:25].C([BH3-])#N.[Na+].O>CO.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:22][CH3:23])[C:15]2[C:20]([NH:21][CH2:24][CH3:25])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC=O
Reactant: CCN(c1ncccc1N)C1CCN(Cc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CCNc1cccnc1N(CC)C1CCN(Cc2ccccc2)CC1
Reaction time: 18 h

Procedure:
1-Benzyl-4-[N-ethyl-N-(3-(amino)-2-pyridinyl)amino]piperidine (EXAMPLE 204 Part B, 1.0 g, 3.22 mmol) is dissolved in methanol (8 ml) and cooled to 0°. The acetaldehyde (0.20 ml, 3.54 mmol) and sodium cyanoborohydride (0.31 g, 3.54 mmol) are added and the reaction is slowly warmed to 20°-25° and stirred for 18 hr. Then a further sodium cyanoborohydride (2 eq.) and 1.6 eq. of acetaldehyde are added and the reaction is stirred a further 20 hr. Then it is diluted with ethyl acetate and poured into water, washed with saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography (silica gel; methanol/methylene chloride (2.5/97.5)), gives the title compound, NMR (300 MHz, CDCl3) 7.65, 7.40-7.17, 6.83, 6.71, 4.63, 3.42, 3.10-3.00, 2.93, 2.81, 1.92, 1.72-1.51, 1.17 and 079δ.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]2[S:17][CH:18]=[CH:19][C:20]=2[S:21]([CH3:24])(=[O:23])=[O:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>C(OCC)(=O)C>[ClH:25].[CH3:24][S:21]([C:20]1[CH:19]=[CH:18][S:17][C:16]=1[CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)(=[O:22])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(CCc2sccc2S(C)(=O)=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccsc1CCC1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11.1 g of 1-tert-butoxycarbonyl-4-[2-(3-methylsulfonyl-2-thienyl)ethyl]piperidine was dissolved in 100 ml of ethyl acetate, 100 ml of an ethyl acetate solution of 4N hydrochloric acid was added thereto, and the mixture was further stirred at room temperature for 2 hours. The resulting crystals were collected by filtration, washed with ethyl acetate, and air-dried, to give 7.92 g of the title compound as colorless crystals.
Reaction SMILES: C([Mg]Br)C.[NH:5]1[C:13]2[CH:12]=[CH:11][N:10]=[C:9]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([CH:31]=[O:32])[CH:29]=5)[NH:24][CH:23]=4)[CH2:16][CH2:15]3)[C:8]=2[CH:7]=[CH:6]1.I[C:34]1[N:35]=[CH:36][N:37]([C:39]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:38]=1.[NH4+].[Cl-]>ClCCl>[NH:5]1[C:13]2[CH:12]=[CH:11][N:10]=[C:9]([N:14]3[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([CH:31]([C:34]6[N:35]=[CH:36][N:37]([C:39]([C:40]7[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=7)([C:52]7[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=7)[C:46]7[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=7)[CH:38]=6)[OH:32])[CH:29]=5)[NH:24][CH:23]=4)[CH2:18][CH2:19]3)[C:8]=2[CH:7]=[CH:6]1
Reactant: O=Cc1ccc2[nH]cc(CCN3CCN(c4nccc5[nH]ccc45)CC3)c2c1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: OC(c1ccc2[nH]cc(CCN3CCN(c4nccc5[nH]ccc45)CC3)c2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 18 h

Procedure:
At ambient temperature, a 3M solution of 2.2 mmol of ethylmagnesium bromide and then, after 30 minutes, 2.2 mmol of the compound obtained in Step 4 of Example 39, are added to a solution of 2.0 mmol of 4-iodo-1-tritylimidazole in dichloromethane (0.25M). After stirring for 18 hours, the mixture is treated with a saturated solution of NH4Cl and then extracted with dichloromethane, and the organic phase is treated in conventional manner. Chromatography on silica gel enables the expected product to be isolated.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@H:13]([NH:29][CH3:30])[CH2:14][O:15][C:16](=[O:28])[NH:17][C:18]1[N:19]=[CH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:31][C:32]1[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:33]=1[CH2:34][NH:35][C:36](=[O:47])OC1C=CC([N+]([O-])=O)=CC=1.CCN(C(C)C)C(C)C>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C@H:13]([N:29]([CH3:30])[C:36]([NH:35][CH2:34][C:33]1[CH:48]=[CH:49][CH:50]=[C:51]([F:52])[C:32]=1[Cl:31])=[O:47])[CH2:14][O:15][C:16](=[O:28])[NH:17][C:18]1[N:19]=[CH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1cccc(F)c1Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN[C@@H](CNC(=O)OCc1ccccc1)COC(=O)Nc1cc2ccccc2cn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CNC(=O)OCc1ccccc1)COC(=O)Nc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
To a solution of the crude isoquinolin-3-yl-carbamic acid (S)-3-benzyloxycarbonylamino-2-methylamino-propyl ester (9.0 mmol) in THF (35 mL) were added 4-nitrophenyl 2-chloro-3-fluorobenzylcarbamate (2.85 g, 8.79 mmol) and DIEA (2.3 mL, 13.2 mmol) at RT. The reaction mixture was stirred at RT for 30 min. The solvent was removed and the residue was dissolved in EtOAc (400 mL). The organic mixture was washed with NaOH (1 N, 50 mL×3), HCl (0.5 N, 50 mL), saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of EtOAC and hexanes to give Isoquinolin-3-yl-carbamic acid (S)-3-benzyloxycarbonylamino-2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-propyl ester (3.8 g, 71% for two steps) as white foam. LRMS (M+H+) m/z 594.2.
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:7]=2[N:6]=[C:5]1[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19]1[N:24]=[C:23]([F:25])[CH:22]=[CH:21][CH:20]=1)[CH2:2][CH3:3].[C:26](O)(=O)[C:27](C)=[O:28].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>[N+]([O-])([O-])=O.[Ag+].C(Cl)Cl.O>[F:25][C:23]1[N:24]=[C:19]([C:15]2[N:14]([CH2:13][C:5]3[N:4]([CH2:1][CH2:2][CH3:3])[C:8]4[CH:9]=[CH:10][N:11]=[C:12]([CH2:26][CH:27]=[O:28])[C:7]=4[N:6]=3)[CH:18]=[CH:17][N:16]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)C(=O)O
Reactant: CCCn1c(Cn2ccnc2-c2cccc(F)n2)nc2cnccc21
Agent: [Ag+]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CCCn1c(Cn2ccnc2-c2cccc(F)n2)nc2c(CC=O)nccc21
Temperature: 40 °C

Procedure:
To the mixture of H2O (5 mL) and CH2Cl2 (5 mL) is added 1-Propyl-2-{[2-(2-fluoropyrid-6-yl)-1H-imidazol-1-yl]methyl}-5-aza-1H-benzimidazole (168 mg, 0.5 mmol), pyruvic acid (132 mg, 1.5 mmol), silver nitrate (7 mg, 0.04 mmol), (NH4)2S2O8 (342 mg, 1.5 mmol), and sulfuric acid (98%, 100 mg, 1.0 mmol). The mixture is heated to 40° C. for 2 hr, then cooled to room temperature. The aqueous solution is neutralized to pH 8 with saturated sodium bicarbonate solution and extracted with CH2Cl2. The combined organic layers are dried over Na2SO4 and solvent is removed to give a brown solid. Purification by preparative TLC provides 1 1-(2-({[2-(6-fluoropyridin-2-yl)-1H-imidazol-1-yl]methyl}-1-propyl-1H-imidazo[4,5-c]pyridin-4-yl)ethanone as white solid. 1H NMR (CDCl3) δ 8.48 (d, 1H), 8.12 (dd, 1H), 7.88 (q, 1H), 7.44 (d, 1H), 7.23 (d, 1H), 7.11 (d, 1H), 6.88 (dd, 1H), 6.40 (s, 2H), 4.22 (q, 2H), 2.84 (s, 3H), 1.58 (m, 2H), 0.74 (t, 3H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([NH:22]C(=O)OC(C)(C)C)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:30]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([NH2:22])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:30]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(NC(=O)OC(C)(C)C)cc1OCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N)cc1OCC2
Yield: 25.8 %

Procedure:
tert-butyl 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-ylcarbamate (170 mg, 0.40 mmol) was dissolved in DCM (3.0 mL) and treated with trifluoroacetic acid. After 10 min the solvent was removed in vacuo. The crude residue was re-dissolved in DCM and the solvent removed once again to provide a golden solid. The crude material was purified via HPLC to afford 480 as an off-white solid (32 mg, 32%). LC/MS (ESI+): m/z 311 (M+H). 1H NMR (400 MHz, DMSO) δ 8.05 (d, J=8.6 Hz, 1H), 7.87 (s, 1H), 7.75 (s, 1H), 6.38 (d, J=6.4 Hz, 1H), 6.17 (s, 1H), 5.97-5.84 (m, 1H), 5.52 (s, 2H), 4.39 (s, 4H), 1.46 (d, J=6.4 Hz, 6H)
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[C:3]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[CH2:20]([O:22][C:23]([C:25]([C:30](OCC)=O)=[CH:26][O:27]CC)=[O:24])[CH3:21]>C(O)(=O)C>[CH2:20]([O:22][C:23]([C:25]1[C:26](=[O:27])[N:6]2[N:5]=[C:4]([C:7]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=3)[C:3]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:2]2[NH:1][CH:30]=1)=[O:24])[CH3:21]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]c2c(-c3ccncc3)c(-c3ccc(F)cc3)nn2c1=O
Yield: 81.4 %

Procedure:
A mixture of 5-amino-3-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole (1.02 g) and 1,1-bis(ethoxycarbonyl)-2-ethoxyethylene (864 mg) in acetic acid (10 ml) was refluxed for 3 hours. After cooling, the crude crystalline was obtained and washed with ethanol to give 4,7-dihydro-6-ethoxycarbonyl-2-(4-fluorophenyl)-3-(pyridin-4-yl)-7-oxopyrazolo[1,5-a]pyrimidine (1.23 g).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[F:25][C:26]([F:37])([F:36])[O:27][C:28]1[CH:29]=[C:30]([NH:34]N)[CH:31]=[CH:32][CH:33]=1>>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:34]([C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([O:27][C:26]([F:25])([F:36])[F:37])[CH:29]=4)[N:20]=[CH:19][CH:18]=3)=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Reactant: NNc1cccc(OC(F)(F)F)c1
Product: O=c1ccn(-c2cccc(OC(F)F)c2)nc1-c1ccnn1-c1cccc(OC(F)(F)F)c1

Procedure:
The product was obtained starting from 1-(3-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-10) and 3-trifluoromethoxy-phenylhydrazine according to the method described for example 91. MS: M=465.1 (M+H)+