Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2([CH3:13])[CH3:12].B([O-])[O-].Br[C:18]1[N:23]2[N:24]=[CH:25][N:26]=[C:22]2[C:21]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][N:37]([CH:40]([CH3:42])[CH3:41])[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)=[N:20][CH:19]=1>>[CH:40]([N:37]1[CH2:36][CH2:35][N:34]([C:31]2[CH:30]=[CH:29][C:28]([NH:27][C:21]3[C:22]4[N:23]([N:24]=[CH:25][N:26]=4)[C:18]([C:2]4[CH:3]=[C:4]5[C:8](=[CH:9][CH:10]=4)[C:7](=[O:11])[NH:6][C:5]5([CH3:13])[CH3:12])=[CH:19][N:20]=3)=[CH:33][CH:32]=2)[CH2:39][CH2:38]1)([CH3:42])[CH3:41]
Reactant: CC(C)N1CCN(c2ccc(Nc3ncc(Br)n4ncnc34)cc2)CC1
Reactant: CC1(C)NC(=O)c2ccc(Br)cc21
Agent: [O-]B[O-]
Product: CC(C)N1CCN(c2ccc(Nc3ncc(-c4ccc5c(c4)C(C)(C)NC5=O)n4ncnc34)cc2)CC1

Procedure:
5-Bromo-3,3-dimethyl-2,3-dihydroisoindol-1-one is converted to the corresponding boronate in a fashion analogous to Intermediate 6, Step 3. This is then used to prepare the title compound from (5-bromo[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-[4-(4-isopropylpiperazin-1-yl)-phenyl]amine using methods as described for Compound 120, Step 4. LCMS: Rt=0.92 (100%), m/z=497 (M+H)+.
Reaction SMILES: C([NH:8][C:9]1([CH3:22])[CH2:17][C:16]2[C:11](=[CH:12][C:13]([CH2:20][CH3:21])=[C:14]([CH2:18][CH3:19])[CH:15]=2)[CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[CH2:18]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[CH2:20][CH3:21])[CH2:10][C:9]([NH2:8])([CH3:22])[CH2:17]2)[CH3:19]
Reactant: CCc1cc2c(cc1CC)CC(C)(NCc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: CCc1cc2c(cc1CC)CC(C)(N)C2

Procedure:
A solution of benzyl-(5,6-diethyl-2-methyl-indan-2-yl)-amine (0.48 g) in methanol (10 ml) is stirred under an atmosphere of hydrogen in the presence of 10% Pd/C at room temperature for 18 hours. The mixture is filtered through celite and the filtrate is concentrated in vacuo to give the title compound. ES+ MS m/e 204 (MH+)
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]#[N:6].[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH4+].C(Cl)(Cl)Cl>CN(C)C=O>[CH3:1][CH:2]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[CH2:3][CH2:4][C:5]1[NH:36][N:35]=[N:34][N:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(CCC#N)Cc1ccc(OCc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(CCc1nnn[nH]1)Cc1ccc(OCc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Temperature: 135 °C

Procedure:
A mixture of 4-methyl-5(4-(4-(2-quinolinylmethyloxy)benzyloxy)phenyl)valeronitrile (1.5 g.), sodium azide (3 g), ammonium chloride (1.9 g) in dimethylformamide (20 ml) is stirred and heated at 135° C. for 18 hours. After cooling, the reaction mixture is poured into ice water and the insoluble material is taken up by chloroform. The residue from the evaporation of chloroform is purified by silica gel dry column (5% methanol chloroform as eluant) to yield 5-(3-methyl-4-(4-(4-(2-quinolinylmethyloxy)benzyloxy)-phenyl)butyl)tetrazole.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(Cl)(=O)=O)=[CH:3][CH:2]=1.O.N1C=C[CH:16]=[CH:15][CH:14]=1>>[CH2:5]1[C:6]2[C:1](=[CH:11][CH:14]=[CH:15][CH:16]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccncc1
Solvent: O
Product: c1ccc2c(c1)CCCC2
Reaction time: 15 h

Procedure:
To a solution of the above compound (11 g; 57.6 mmol) in pyridine (20 ml) at 0° C. was added, dropwise a solution of p-toluenesulfonyl chloride (11 g; 57.7 mmol) in pyridine (20 ml). The mixture was left at ambient temperature for 15 hours, then poured into water and extracted with CH2Cl2. The organic phase was washed with 2N HCl and 0.5N NaHC3, dried over MgSO4 and evaporated to give -methoxy-1-tosyloxyimino-,1,2,3,4-tetrahydronaphthalene as a brown solid (16 g; 100%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)[CH2:4][C:5](OCC)=[O:6]>C1(C)C=CC=CC=1>[Cl:16][C:12]1[CH:11]=[C:10]([CH:3]2[CH2:2][NH:1][C:5](=[O:6])[CH2:4]2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)CC(CN)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Product: O=C1CC(c2cccc(Cl)c2)CN1
Yield: 49.2 %

Procedure:
In a 500 ml flask fitted with reflux condenser and magnetic stirrer, 135.7 g (561 mmoles) of ethyl 4-amino-3-(3-chlorophenyl)butanoate 378 are dissolved in 200 ml of toluene, and the mixture is refluxed for 30 min. The solution is concentrated to dryness and the residue purified by PrepLC (1 kg SiO2, CH2Cl2/EtOH, 98:2->95:5) to give 54.4 g of pure 379 (49.2%).
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][NH:9][C:5]=2[C:4]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)=[N:3][CH:2]=1.[CH2:20]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:20]([CH:27]1[CH2:32][CH2:31][N:30]([C:14]([C:13]2[CH:12]=[C:11]([NH:10][C:4]3[C:5]4[NH:9][CH:8]=[CH:7][C:6]=4[N:1]=[CH:2][N:3]=3)[CH:19]=[CH:18][CH:17]=2)=[O:16])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)c1cccc(Nc2ncnc3cc[nH]c23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(c1cccc(Nc2ncnc3cc[nH]c23)c1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
A mixture of 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic acid (153 mg), 4-benzylpiperidine (158 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (173 mg), 1-hydroxybenzotriazole (138 mg) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 hrs. The reaction mixture was concentrated under reduced pressure, water was added and extracted with ethyl acetate containing tetrahydrofuran. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→20:80). The obtained product was dissolved in ethyl acetate containing methanol and tetrahydrofuran, washed with aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The precipitate was collected by filtration to give the title compound (201 mg) as a pale-brown powder.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:18][CH2:19][CH:20]1[CH2:24][CH2:23][CH:22]([CH2:25][OH:26])[CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl.Cl>[Si:11]([O:18][CH2:19][CH:20]1[CH2:24][CH2:23][CH:22]([CH:25]=[O:26])[CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC(CO)C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)OCC1CCC(C=O)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 97.6 %

Procedure:
To a solution of oxalyl chloride (3.44 mL, 39.3 mmol) in dichloromethane (200 mL) at −78° C. was added, dropwise, dry DMSO (4.36 mL, 61.4 mmol). After 10 min at −78° C., a solution of (3-((tert-butyldimethylsilyloxy)methyl)cyclopentyl)methanol (6.0 g, 24.56 mmol) in CH2Cl2 (180 mL) was slowly added and the mixture stirred at −78° C. After 1 h, triethylamine (17.11 mL, 122.8 mmol) was added and stirring continued at −78° C. for 10 min after which the mixture was allowed to warm to 23° C. The reaction mixture was diluted with HCl 1N (pH˜6) and the phases separated. The organic fraction was dried (MgSO4), filtered and concentrated in vacuo to give 5.81 g (97% yield) of the title compound as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 9.62 (1 H, d, J=2.5 Hz), 3.54 (2 H, ddd, J=12.0, 10.0, 6.3 Hz), 2.73-2.82 (1 H, m), 2.14-2.24 (1 H, m), 1.89-2.00 (2 H, m), 1.74-1.85 (2 H, m), 1.57 (1 H, dt, J=13.1, 8.6 Hz), 1.33-1.44 (1 H, m), 0.91 (9 H, s), 0.06 (6 H, s).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][N:37]([CH:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]3)[CH:38]=2)O1>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:34]4[CH:35]=[N:36][N:37]([CH:39]5[CH2:40][CH2:41][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:43][CH2:44]5)[CH:38]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Product: CN1CCN(c2cc(N3CCc4ccc(-c5cnn(C6CCN(C(=O)OC(C)(C)C)CC6)c5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate. LCMS (M+H)+: m/z=574.5.
Reaction SMILES: C(OC([NH:11][C@H:12]([CH2:22][CH3:23])/[CH:13]=[CH:14]/[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O)C1C=CC=CC=1.C(O)(=O)C>CO.[C].[Pd]>[C:15]([OH:17])(=[O:16])[CH3:14].[NH2:11][C@H:12]([CH2:22][CH3:23])[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16]
Reactant: CC[C@H](/C=C/C(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@@H](N)CCC(=O)OC(C)(C)C
Reaction time: 7 h

Procedure:
To a solution of tert-butyl (2E, 4R)-4-{[(benzyloxy)carbonyl]amino}-2-hexenoate (9.73 g, 30.5 mmol) in methanol (200 ml) were added acetic acid (3.5 ml, 61 mmol) and 10% Palladium carbon (3.2 g). The mixture was stirred under a hydrogen atmosphere for 7 hours. Catalyst was filtered off under a nitrogen gas and the filtrate was condensed with an evaporator to give tert-butyl (4R)-4-aminohexanoate acetic acid salt (7.5 g, quantitatively).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].[CH:48]1([NH2:54])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:54][CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc(Br)cc2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC(c2ccc(NC3CCCCC3)cc2)C1
Temperature: 90 °C
Yield: 80 %

Procedure:
To a suspension of 3-(4-bromophenyl)-piperidine-1-carboxylic acid tert-butyl ester (8.0 g, 23.5 mmol), palladium acetate (210 mg, 0.94 mmol), 2-(di-t-butyl phosphino)biphenyl (560 mg, 1.88 mmol), and sodium t-butoxide (3.2 g, 33.3 mmol) in toluene (80 mL) was added cyclohexylamine (2.8 g, 28.2 mmol) at room temperature. After heating at 90° C. for 5 h, the resulting suspension was passed through a Celite column. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting 5-25% of ethyl acetate in hexane to afford 3-(4-cyclohexylaminophenyl)-piperidine-1-carboxylic acid tert-butyl ester (6.74 g, 18.8 mmol, 80%) as white crystals.
Reaction SMILES: CC([O-])=O.CC([O-])=O.[Cu+2:9].[CH:10]1[CH:29]=[CH:28][C:26](=[O:27])/[C:12](=[CH:13]/[NH:14][CH2:15][CH2:16][NH:17]/[CH:18]=[C:19]2/[CH:20]=[CH:21][CH:22]=[CH:23][C:24]/2=[O:25])/[CH:11]=1>C(O)C>[CH:21]1[CH:20]=[C:19]([CH:18]=[N:17][CH2:16][CH2:15][N:14]=[CH:13][C:12]2[C:26]([O-:27])=[CH:28][CH:29]=[CH:10][CH:11]=2)[C:24]([O-:25])=[CH:23][CH:22]=1.[Cu+2:9]
Reactant: O=C1C=CC=C/C1=C/NCCN/C=C1\C=CC=CC1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCO
Product: [O-]c1ccccc1C=NCCN=Cc1ccccc1[O-]
Temperature: 80 °C
Reaction time: 24 h

Procedure:
The Cu(OAc)2 (0.5 mmol) and Salen (N′N′-bis(3-tert-butyl-5-bromo-salicylidene)-1,2-diaminocyclohexane, 0.5 mmol) and were dissolved in dried ethanol (20 mL). The mixture was stirred at 80° C. for 24 hours. After that the compound Salen-Cu was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[C:18]([F:21])([F:20])[F:19])[N:3]=1.[CH3:22][NH:23][C:24]([CH:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)=[O:25].N12CCCN=C1CCCCC2>C1COCC1>[C:8]([C:7]1[C:2]([NH:32][C@@H:29]2[CH2:28][CH2:27][C@H:26]([C:24]([NH:23][CH3:22])=[O:25])[CH2:31][CH2:30]2)=[N:3][C:4]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[C:18]([F:21])([F:20])[F:19])=[N:5][CH:6]=1)#[N:9]
Reactant: N#Cc1cnc(NCc2cnccc2C(F)(F)F)nc1Cl
Reactant: CNC(=O)C1CCC(N)CC1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CNC(=O)[C@H]1CC[C@@H](Nc2nc(NCc3cnccc3C(F)(F)F)ncc2C#N)CC1
Temperature: 60 °C

Procedure:
4-Chloro-2-(((4-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrimidine-5-carbonitrile (1.0 equiv.) was placed in a sealable flask with (1s,4s)-4-amino-N-methylcyclohexanecarboxamide (1.0 equiv.), 1,8-diazabicyclo[5.4.0]undec-7-ene (1.2 equiv.), and THF (0.1 M). The flask was purged with nitrogen and sealed. The reaction mixture was heated to 60° C. for 18 h. Standard work-up afforded cis-4-((5-cyano-2-(((4-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrimidin-4-yl)amino)-N-methylcyclohexanecarboxamide (48.2% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.73 (d, J=5.08 Hz, 1H), 8.64-8.69 (m, 1H), 8.29 (t, J=5.66 Hz, 1H), 8.21 (s, 1H), 7.72 (d, J=5.08 Hz, 1H), 7.53-7.66 (m, 1H), 7.00-7.12 (m, 1H), 4.62-4.73 (m, 2H), 3.69 (br. s., 1H), 2.53-2.61 (m, 3H), 2.15-2.30 (m, 1H), 1.70-1.97 (m, 2H), 1.42-1.62 (m, 3H), 1.15-1.27 (m, 3H). MS (ESI) m/z 434.3 [M+1]+
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]2[CH:30]=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[ClH:38].C(O)C.C(=O)([O-])[O-].[NH4+:46].[NH4+]>ClCCl.C(O)C>[ClH:38].[CH3:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]2[CH:30]=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:46])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1cccc(C)c1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1cccc(C)c1
Yield: 79 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-methylphenyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 79% of theory, C29H32N6O3 (512.6) Rf value: 0.10 (silica gel; dichloromethane/ethanol=4:1) ##EQU59##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](C=C[CH:9]=[C:10]2[CH2:13][O:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[NH2:19]O>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](=[CH:5][CH:4]=1)[NH:19][CH:9]=[C:10]2[CH2:13][O:14][NH:15][C:16](=[O:18])[CH3:17]
Reactant: COc1ccc2cccc(CONC(C)=O)c2c1
Reactant: NO
Product: COc1ccc2[nH]cc(CONC(C)=O)c2c1

Procedure:
By carrying out the procedure in the same manner as for the synthesis of the compound of Example 1, but replacing 0-[(7-methoxynaphth-1-yl)methyl]hydroxylamine with O-[5-methoxyindol-3-yl)methyl]hydroxylamine (preparation 10), the title compound is obtained.
Reaction SMILES: C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.[Br:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26])=O.[OH-].[Na+]>C([O-])(O)=O.[Na+]>[Br:15][CH2:16][CH2:17][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26]
Reactant: COc1ccccc1C(=O)CBr
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1CCBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
A mixture of triethylsilane (34.9 g, 0.3 mol), TFA (96 mL) and 2-bromo-1-(2-methoxy-phenyl)-ethanone (6.9 g, 30 mmol) is stirred at rt for 30 min before it is poured onto an ice/water mixture (600 mL). The mixture is neutralised by adding 2 N aq. NaOH and sat. aq. NaHCO3 (200 mL), and is extracted with DCM (2×200 mL). The combined organic extracts are dried over Na2SO4, filtered and evaporated. The obtained residue is purified by chromatography on silica gel (TBME:EA 40:1) to give 1-(2-bromo-ethyl)-2-methoxy-benzene (4.50 g) as a colourless liquid. LC: tR=1.00 min.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][N:6]=1)(=[O:4])=[O:3].[Br:12]CC1C=CC(S(C)=O)=NC=1.C1C(=O)N(Br)C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6][CH:7]=1
Reactant: Cc1ccc(S(C)(=O)=O)nc1
Reactant: CS(=O)c1ccc(CBr)cn1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(CBr)cn1
Temperature: 25 °C

Procedure:
To a solution of 0.25 g of 2-methanesulfonyl-5-methyl-pyridine (from the preparation of 5-bromomethyl-2-methanesulfinyl-pyridine, step b)) in 20 mL carbon tetrachloride was added 0.27 g NBS and 4 mg benzoyl peroxide. This mixture was refluxed for 4 hours. The reaction mixture was cooled to room temperature, washed with aqueous sodium hydrogen carbonate solution, dried over sodium sulphate, and concentrated to dryness. Purification by flash chromatography (silica, heptane/ethyl acetate) provided 0.11 g of 5-bromomethyl-2-methanesulfonyl-pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:17]([C:18]([O:20]CC[Si](C)(C)C)=[O:19])=[C:16]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:15]=[C:14]([CH3:33])[CH:13]=2)[N:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.Cl>O1CCCC1>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:17]([C:18]([OH:20])=[O:19])=[C:16]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:15]=[C:14]([CH3:33])[CH:13]=2)[N:6]=1
Reactant: COc1cc(OC)nc(Oc2cc(C)nc(-c3ccccc3)c2C(=O)OCC[Si](C)(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)nc(Oc2cc(C)nc(-c3ccccc3)c2C(=O)O)n1
Yield: 61.2 %

Procedure:
2.0 g (0.004 mol) of 2-trimethylsilylethyl 4-(4,6-dimethoxypyrimidin-2-yloxy)-2-phenyl-6-methylnicotinate was dissolved in 30 ml of tetrahydrofuran, and 12 ml of 1 mol aqueous solution of tetrabutylammonium fluoride was added thereto. The resultant mixture was stirred at room temperature for one night. The reaction mixture was then poured into 200 ml of water, and 1.5 ml of concentrated hydrochloric acid was added thereto. The resultant reaction mixture was extracted with ethyl acetate, and was washed with water. The resultant reaction mixture was then dried with magnesium sulfate, and the solvent was distilled off to obtain 0.9 g of the aimed product.
Reaction SMILES: [I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[NH2:9][C:10]1[C:11]2[N:12]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1.[CH3:21][O:22][C:23]([NH:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:27]=1[CH2:28]Cl)=[O:24]>CC(C)=O.O>[CH3:21][O:22][C:23]([NH:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:27]=1[CH2:28][NH:9][C:10]1[C:11]2[N:12]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1)=[O:24]
Reactant: COC(=O)Nc1cccc(C)c1CCl
Reactant: Cc1nc2c(N)cccn2c1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)Nc1cccc(C)c1CNc1cccn2c(C)c(C)nc12
Temperature: 25 °C
Yield: 55.7 %

Procedure:
4.5 g of sodium iodide and 6.63 g of dry sodium carbonate are added to a solution of 4.03 g of 8-amino-2,3-dimethylimidazo[1,2-a]pyridine and 6.41 g of 2-methoxycarbonylamino-6-methyl-benzyl chloride in 400 ml of dry acetone, and the mixture is heated under reflux for 6 h. After cooling to RT, 400 ml of water are added and the acetone is distilled off in a water jet vacuum. The aqueous residue is then extracted three times with each time 200 ml of ethyl acetate. The combined organic extracts are washed with 300 ml of water, dried over magnesium sulfate and then concentrated. The residue is purified by chromatography on silica gel (toluene/dioxan=9:1 as eluent). The fractions with Rf =0.2 are concentrated and then recrystallized from diisopropyl ether. 4.71 g (56%) of the title compound of m.p. 136°-138° C. are isolated.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9]([Cl:16])=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1Cl)=[O:5])[CH3:2].C(O)C.[CH2:21]([NH2:23])[CH3:22]>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9]([Cl:16])=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[NH:23][CH2:21][CH3:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Reactant: CCN
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCNc1c(C(=O)OCC)c(C)nc(Cl)c1[N+](=O)[O-]
Yield: 69 %

Procedure:
27.9 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.1 mol.) are dissolved in 100 ml. of ethyl alcohol and 12 g. of triethylamine. At reflux temperature a solution of 4.5 g. of ethylamine in 50 ml. of alcohol is slowly added dropwise with continual stirring. After the addition is completed, the reaction mixture is refluxed for an additional 30 minutes. The solvent is then removed in vacuo and the residue is dissolved in 300 ml. of petroleum ether. The triethylamine hydrochloride is filtered off and the filtrate cooled to 0°; 6-chloro-4-ethylamino-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester crystallizes, yield: 69%, m.p. 36°-37° (methanol).
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][C@H:4]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1.NN>O1CCCC1>[CH2:8]([O:7][C:5](=[O:6])[C@@H:4]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3][C:2](=[S:33])[NH2:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)OCc1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: NN
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC(N)=S)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A 1-L round bottom flask was charged with (S)-benzyl 4-amino-2-(tert-butoxycarbonylamino)-4-oxobutanoate (10.0 g, 31.0 mmol), Lawesson's reagent (6.58 g, 16.3 mmol), and tetrahydrofuran (155 mL). Hydrazine (7.8 mL, 0.248 mol) was added and the resulting mixture was stirred at room temperature for 72 h. The resulting mixture was then concentrated in vacuo and the residue purified via flash silica gel chromatography (Analogix IF-280, SF40-400 g column, gradient 90:10-60:40 Heptane:EtOAc) to yield-(S)-tert-butoxycarbonylamino-3-thiocarbamoyl-propionic acid benzyl ester. MS (ES+) 339 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.C(Cl)(=O)C([Cl:24])=O.CN(C=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([Cl:24])=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reaction time: 12 h
Yield: 98.9 %

Procedure:
The product from Example 34b (4.0 g, 13.6 mmol) in 40 mL of CH2Cl2 was treated with oxalyl chloride (3.5 g, 27.2 mmol) and DMF (catalytic amount). Mixture was stirred for 12 hours. Mixture was concentrated under vacuum giving the title compound as a yellow oil (4.2 g, 100%).