Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16](I)=[CH:17][C:9]1=2.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][N:32]=2)[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:34]3[CH:33]=[N:32][C:31]([N:28]4[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]4)=[CH:36][CH:35]=3)=[CH:17][C:9]1=2
Reactant: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(I)cc21
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: CN1CCN(c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)cn2)CC1
Yield: 28 %

Procedure:
1-(5-Chloro-2-trifluoromethylbenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (40 mg) was reacted with 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4A to give the title compound as a pale orange solid (28% yield). M.p. 226-227° C., LCMS: m/z=503.90 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.34 (s, 3H), 2.51 (t, J=5.0 Hz, 4H), 3.47-3.56 (m, 6H), 3.62-3.69 (m, 2H), 4.61 (s, 2H), 4.92 (bs, 1H), 6.49 (d, J=1.0 Hz, 1H), 6.64 (d, J=8.8 Hz, 1H), 7.34 (d, J=8.3 Hz, 1H), 7.52-7.58 (m, 2H), 7.61-7.65 (m, 2H), 8.18 (d, J=2.3 Hz, 1H).
Reaction SMILES: [N:1]12[CH2:26][CH2:25][CH2:24][C@@H:23]1[C:22](=[O:27])[O:21][CH2:20][CH2:19][CH:18]=[CH:17][CH2:16][CH2:15][O:14][C:13](=[O:28])[C@@H:12]1[N:8]([CH2:9][CH2:10][CH2:11]1)[C:7](=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]2=[O:30]>C(OC(=O)C)C.[Pd]>[N:1]12[CH2:26][CH2:25][CH2:24][C@@H:23]1[C:22](=[O:27])[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:13](=[O:28])[C@@H:12]1[N:8]([CH2:9][CH2:10][CH2:11]1)[C:7](=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]2=[O:30]
Reactant: O=C1OCCC=CCCOC(=O)[C@H]2CCCN2C(=O)CCCCC(=O)N2CCC[C@H]12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1OCCCCCCOC(=O)[C@H]2CCCN2C(=O)CCCCC(=O)N2CCC[C@H]12
Yield: 78.9 %

Procedure:
A mixture of 150 mg (0.36 mmol) (12R,23R)-14,21-dioxa-1,8-diaza-tricyclo[21.3.0.0 8,12]hexacos-17-ene-2,7,13,22-tetraone and 20 mg 10%) palladium/carbon in 5 ml ethylacetate was hydrogenated over night. Filtration and removal of the solvent yielded 120 mg (79%) (12R,23R)-14,21-dioxa-1,8-diaza-tricyclo[21.3.0.0 8,12]hexacosane-2,7,13,22-tetraone as a light yellow oil, MS m/e (%): 423 (M+H+, 100).
Reaction SMILES: C(C1C=CC(C(=O)C)=CC=1)(C)(C)C.[C:14]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]([NH:26]C(NC2C=CC=C3C=2C=CN=C3)=O)[CH3:25])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([C:18]1[CH:19]=[CH:20][C:21]([CH:24]([NH2:26])[CH3:25])=[CH:22][CH:23]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(NC(=O)Nc1cccc2cnccc12)c1ccc(C(C)(C)C)cc1
Agent: CC(=O)c1ccc(C(C)(C)C)cc1
Product: CC(N)c1ccc(C(C)(C)C)cc1

Procedure:
The title compound was prepared using 1-(4-tert-butylphenyl)ethanone and the procedures described in Examples 136A and 136B Example 140B N-[1-(4-tert-butylphenyl)ethyl]-N′-5-isoquinolinylurea
Reaction SMILES: [Br:1][C:2](=[CH:9]OCC)[C:3](=O)[C:4]([F:7])([F:6])[F:5].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[NH:22][NH2:23].Br>C(O)C>[Br:1][C:2]1[C:3]([C:4]([F:5])([F:6])[F:7])=[N:23][N:22]([C:15]2[C:16]([Cl:21])=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[Cl:13])[CH:9]=1
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Reactant: CCOC=C(Br)C(=O)C(F)(F)F
Agent: Br
Solvent: CCO
Product: FC(F)(F)c1nn(-c2c(Cl)cc(Cl)cc2Cl)cc1Br
Yield: 30.4 %

Procedure:
2.3 g (0.01 mole) of 3-bromo-4-ethoxy-1,1,1-trifluorobut-3-en-2-one are added to a solution of 4.2 g (0.02 mol) of 2,4,6-trichlorophenyl-hydrazine in 100 ml of ethanol which contains 0.01 mole hydrogen bromide. The mixture is refluxed for 5 hours and then concentrated under reduced pressure, and ice water is added to the residue. Extraction with dichloromethane, washing with saturated sodium chloride solution until neutral, clarification over anhydrous sodium sulphate and concentration gives 4.6 g of a crude product, which is chromatographed on 120 g of silica gel using toluene/petroleum ether (ratio 1:1). 1.2 g of 4-bromo-1-(2,4,6-trichloro-phenyl)-3-trifluoromethylpyrazole of melting point 93°-94° C. (from petroleum ether) are obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Br[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=1.[OH-].[Na+]>CN(C=O)C.O>[Br:19][C:17]1[CH:16]=[N:15][CH:14]=[C:13]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH:18]=1
Reactant: Brc1cncc(Br)c1
Reactant: COc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2cncc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.3 %

Procedure:
To a stirred suspension of sodium hydride (3.0 g of 80% in mineral oil, 100 mmol) in DMF (95 mL) in an ice water bath, 4-methoxyphenol (12.2 g, 96 mmol) was added slowly under a nitrogen atmosphere. The resulting mixture was warmed to ambient temperature and stirred for 1 h. 3,5-Dibromopyridine (15.6 g of 98%, 65 mmol) was added and the mixture was then heated at 85° C. (bath temperature) for 32 h. The mixture was cooled, diluted with water (120 mL), poured into 5N sodium hydroxide (15 mL), and extracted with ether (3×150 mL). The combined ether extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation, to give a light-yellow oil (21.9 g). The oil was diluted with ethanol and rotary evaporated (twice) to remove residual DMF and then diluted with ether (50 mL) and suction filtered to remove un-reacted 3,5-dibromopyridine. Rotary evaporation and high vacuum treatment left a lard-like product weighing 12.8 g. The product was 94% pure by GC-MS analysis (66% yield) and was sometimes used, without further purification, in subsequent reactions. When desired, further purification (to 99.4%) was accomplished by column chromatography on silica gel, using 85:5:5:4.5:0.5 hexane/chloroform/ethyl acetate/methanol/aqueous ammonia as eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([N:7](C)[C:8](=O)C)=[CH:5][C:4]=1[CH3:14].[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([NH:7][CH3:8])=[CH:5][C:4]=1[CH3:14]
Reactant: COc1ccc(N(C)C(C)=O)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNc1ccc(OC)c(C)c1

Procedure:
A mixture of 4'-methoxy-3'-methyl-N-methylacetanilide (53 g), sodium hydroxide (22 g), water (75 ml) and industrial methylated spirit (200 ml) was heated under reflux for 36 hours. Solvent was removed by evaporation, water (350 ml) was added to the residue and the mixture extracted with diethyl ether (2×300 ml). The combined extracts were washed with water (250 ml), dried over magnesium sulphate and the solvent was removed by evaporation to give the novel compound 4-methoxy-3-methyl-N-methylaniline in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:12][C:13]2[N:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][C:17]([C:23]#[N:24])=[C:16]3OC(C)C)[C:9](=[O:11])[N:10]=1.C(O[Na])(C)=O.O=C1C(=CC2N=C3C(=CC=2)N=CC(C#N)=C3)SC(NCC2SC=CC=2)=N1>CC(O)=O>[Cl:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:12][C:13]2[N:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][C:17]([C:23]#[N:24])=[CH:16]3)[C:9](=[O:11])[N:10]=1
Reactant: CC(C)Oc1c(C#N)cnc2ccc(C=C3SC(NCc4ccc(F)cc4Cl)=NC3=O)nc12
Agent: CC(=O)O[Na]
Agent: N#Cc1cnc2ccc(C=C3SC(NCc4cccs4)=NC3=O)nc2c1
Solvent: CC(=O)O
Product: N#Cc1cnc2ccc(C=C3SC(NCc4ccc(F)cc4Cl)=NC3=O)nc2c1
Temperature: 120 °C
Yield: 33.3 %

Procedure:
To a mixture of 2-(2-chloro-4-fluoro-benzylamino)-thiazol-4-one (41.4 mg, 0.16 mmol) (see Example 8), AcONa (160 mg, 1.95 mmol), and 6-formyl-[1,5]naphthyridine-3-carbonitrile (33.6 mg, 0.18 mmol) (see Example 11) in a sealed tube was added AcOH (0.3 mL). The reaction mixture was heated to 120° C. (oil bath) for 2 hrs. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water, AcOEt and ether to give 6-[2-(2-chloro-4-fluoro-benzylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-[1,5]naphthyridine-3-carbonitrile as a light brown solid (22.6 mg, 33.3%). HR-ES (+) m/e calcd for C20H11FClN5OS (M+Na)+ 446.0249. found 446.0251.
Reaction SMILES: CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:53]([O:57][C:58](=[O:71])[CH2:59][C:60]1[C:65]([C:66]([F:69])([F:68])[F:67])=[CH:64][N:63]=[C:62](Cl)[CH:61]=1)([CH3:56])([CH3:55])[CH3:54].[CH3:72][N:73]1[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]1.[NH4+].[Cl-]>O1CCOCC1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:53]([O:57][C:58](=[O:71])[CH2:59][C:60]1[C:65]([C:66]([F:69])([F:68])[F:67])=[CH:64][N:63]=[C:62]([N:76]2[CH2:77][CH2:78][N:73]([CH3:72])[CH2:74][CH2:75]2)[CH:61]=1)([CH3:56])([CH3:55])[CH3:54]
Reactant: CC(C)(C)OC(=O)Cc1cc(Cl)ncc1C(F)(F)F
Reactant: CN1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN1CCN(c2cc(CC(=O)OC(C)(C)C)c(C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium tert-butoxide (354 mg, 3.68 mmol) is dried under high vacuum at approximately 80° C. After purging with argon and cooling to RT, palladium acetate (60 mg, 0.27 mmol), rac-2,2′-bis-diphenylphosphanyl-[1,1]binaphthalenyl (rac-BINAP, 83 mg, 0.13 mmol) and (2-chloro-5-trifluoromethyl-pyridin-4-yl)-acetic acid tert-butyl ester (990 mg, 3.35 mmol) are added. The mixture is dissolved in dioxane (11 ml, degassed with three freeze-thaw cycles under HV/argon), and 1-methyl-piperazine (369 mg, 3.68 mmol) is added. The round bottom flask containing the reaction mixture is immersed into a pre-heated oil bath (T=85° C.). After 1 h, TLC analysis indicated almost complete conversion of starting materials. The reaction mixture is cooled to RT, diluted with EtOAc and poured into a saturated aqueous NH4Cl solution. The organic layer is separated, washed with brine, dried over Na2SO4, and the solvent is evaporated. The residue is purified by FCC (CH2Cl2/MeOH, slow gradient from 99:1 to 94:6) to afford the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.44 (s, 9H), 2.34 (s, 3H), 2.50 (m, 4H), 3.59 (s, 2H), 3.66 (m, 4H), 6.54 (s, 1H), 8.35 (s, 1H). ES+−MS: 360.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([O:28]C)=[O:27])=[CH:20][CH:19]=1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=1)=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C=Cc1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=CC(=O)O)cc1
Reaction time: 23 h
Yield: 91.5 %

Procedure:
To a stirred solution at room temperature of compound XII (560 mg, 1.41 mmol) in THF (20 ml) was added a solution of LiOH.H2O (148 mg, 3.53 mmol) in water (20 ml). After 23 h, the reaction mixture was concentrated, diluted with water and acidified with 1N HCl until pH 4–5 in order to get a white precipitate. After stirring for 15 min, the suspension was filtered off, rinsed with water, and dried to afford the title compound XIII (495 mg, 1.29 mmol, 92% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ(ppm): 9.92 (s, 1H), 8.72 (bs, 1H), AB system (δA=8.02, δB=7.90, J=7.9 Hz, 4H), 7.69 (d, J=16.3 Hz, 1H), 7.62–7.53 (m, 2H), 7.30–7.13 (m, 2H), 6.72 (d, J=16.3 Hz, 1H), 1.48 (s, 9H)
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5].C[Si](Cl)(C)C.C(N(CC)CC)C.[Cl:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33].[OH-].[Na+].Cl>C(Cl)Cl>[Cl:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([NH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5])=[O:33]
Reactant: Nc1ccccc1C(=O)NCCCC(=O)O
Reactant: O=C(Cl)c1ccccc1Cl
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CCCNC(=O)c1ccccc1NC(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 2.00 g (9.01 mmol) of 4-(2-aminobenzoylamino)butanoic acid in 20 mL of dry methylene chloride, add 8.36 g (77.00 mmol) of trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 1.17 g (11.55 mmol) of triethylamine and a solution of 1.35 g (7.70 mmol) of 2-chlorobenzoyl chloride dissolved in 5 mL of dry methylene chloride. Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 30 ml of 10% NaOH to the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCl and extract several times with ethyl acetate. Dry the organic phase with MgSO4 anhydrous and eliminate at low pressure. Wash the crude product several times with ether and finally, purify by recrystallization (EtOH/H2O). This yields 1.27 g (36%) of 4-[2-(2-chlorobenzoylamino)benzoylamino]butanoic acid as a brown solid.
Reaction SMILES: [O:1]1[C:6]([C:7](=[N:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8]([OH:10])=O)=[CH:5][S:4][CH2:3][CH2:2]1.[NH2:19][CH:20]1[C:30](=[O:31])[N:22]2[C:23]([C:27]([OH:29])=[O:28])=[CH:24][CH2:25][S:26][C@H:21]12.C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(OCC)(=O)C.O>[O:1]1[C:6]([C:7](=[N:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8]([NH:19][CH:20]2[C:30](=[O:31])[N:22]3[C:23]([C:27]([OH:29])=[O:28])=[CH:24][CH2:25][S:26][C@H:21]23)=[O:10])=[CH:5][S:4][CH2:3][CH2:2]1
Reactant: CCCCCCON=C(C(=O)O)C1=CSCCO1
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)C1=CSCCO1
Yield: 72.2 %

Procedure:
N,N-Dimethylformamide (0.579 g.), phosphoryl chloride (1.214 g.) and ethyl acetate (3 ml.) were treated in a conventional manner to give a Vilsmeier reagent and the reagent was added to ethyl acetate (7 ml.). To the solution was added 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-hexyloxyiminoacetic acid (syn isomer, 2.00 g.) under stirring to give an activated acid solution. On the other hand, 7-amino-3-cephem-4-carboxylic acid (1.46 g.), trimethylsilylacetamide (3.84 g.), bis(trimethylsilyl)acetamide (4.40 ml.) and ethyl acetate (24 ml.) were stirred to prepare a solution. To the solution was added all at once the activated acid solution at -10° C., and stirred at the same temperature for 1.5 hours. After adding water (30 ml.) and ethyl acetate (15 ml.) to the resultant solution, the solution was shaken sufficiently and the organic layer was separated. An aqueous solution of sodium bicarbonate (30 ml.) was added to the organic solution, shaken sufficiently and the aqueous layer was separated. The solution was adjusted to pH 2.0 with conc. hydrochloric acid and extracted with ethyl acetate (60 ml.). The extract was washed with water (20 ml.) twice, dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diisopropyl ether (50 ml.) and the precipitates were collected by filtration to give 7-[2-(2,3-dihydro-1,4-oxathiin-6yl)-2-n-hexyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.40 g.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl.[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([C:26]2[C@@H:35]3[C@@H:30]([CH2:31][CH:32]=[CH:33][CH2:34]3)[C:29](=[O:36])[N:28]([C:37]3[CH:42]=[CH:41][C:40]([C:43](N4CCN(C5C=CC=CC=5)CC4)=[O:44])=[CH:39][CH:38]=3)[N:27]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[CH3:15]>C(OCC)C>[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([C:26]2[C@@H:35]3[C@@H:30]([CH2:31][CH:32]=[CH:33][CH2:34]3)[C:29](=[O:36])[N:28]([C:37]3[CH:38]=[CH:39][C:40]([C:43]([N:10]4[CH2:9][CH2:8][N:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[CH2:12][CH2:11]4)=[O:44])=[CH:41][CH:42]=3)[N:27]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[CH3:15]
Reactant: CCOc1ccc(C2=NN(c3ccc(C(=O)N4CCN(c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Reactant: c1ccc(N2CCNCC2)nc1
Agent: Cl
Solvent: CCOCC
Product: CCOc1ccc(C2=NN(c3ccc(C(=O)N4CCN(c5ccccn5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC

Procedure:
Prepared from intermediate product A1 and 1-(2-pyridyl)piperazine as described for compound 1. Cystallised from diethyl ether as the free base. M.p. 183–184° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[C:16]2[NH:24][CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][N:33]=[C:34]=[S:35])[CH2:27][CH2:26]2)=[CH:10][CH:9]=1>O1CCCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[C:16]2[NH:24][CH:25]2[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][NH:33][C:34]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[S:35])[CH2:29][CH2:30]2)=[CH:10][CH:9]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCN=C=S)CC3)nc3ccccc32)cc1
Reactant: C1CCNCC1
Solvent: C1CCOC1
Product: Fc1ccc(Cn2c(NC3CCN(CCNC(=S)N4CCCCC4)CC3)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
A mixture of 0.9 parts of piperidine, 4.1 parts of 1-(4-fluorophenylmethyl)-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-1H-benzimidazol-2-amine and 135 parts of tetrahydrofuran was stirred for 2 hours at room temperature. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 1 part (20.2%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-1-piperidinecarbothioamide; mp. 175.6° C. (compound 29).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].N1C=CC=CC=1.[CH2:16]([S:19](Cl)(=[O:21])=[O:20])[CH2:17][CH3:18].Cl>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:19]([CH2:16][CH2:17][CH3:18])(=[O:21])=[O:20]
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1ccc(F)cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To 2,4-difluoro-phenylamine (1, 11.8 g, 91.4 mmol) in 110 mL of dichloromethane, pyridine (8.13 mL, 100 mmol) and propane-1-sulfonyl chloride (4, 11.3 mL, 100 mmol) were added. The reaction was stirred at room temperature overnight, then poured into 1 M aqueous hydrochloric acid, the aqueous layer separated and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The crude material was purified by silica gel column chromatography to give the desired compound (11, 19.98 g, 92.9%). MS(ESI)=[M−H+]−=234.06.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16](Cl)[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][NH:30][C:31]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]=1>>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([N:32]2[C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[N:35]=[C:31]2[NH:30][CH3:29])[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(CN2CCN(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CNc1nc2ccccc2[nH]1
Product: CNc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)C)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 4-(8-((4-tert-butylpiperazin-1-yl)methyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine and N-methyl-1H-benzo[d]imidazol-2-amine were reacted to give 428. LCMS: M+H+=519.3
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9]N.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1>OS(O)(=O)=O.O1CCOCC1>[Br:1][C:2]1[C:3]2[NH:9][C:15]3[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][C:14]=3[C:4]=2[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1ccc(NN)c(Br)c1
Reactant: CN1CCC(=O)CC1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1cc(Br)c2[nH]c3c(c2c1)CN(C)CC3
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 69.6 %

Procedure:
(2-Bromo-4-methylphenyl)hydrazine (21.5 g, 0.107 mol) and 1-methylpiperidin-4-one (12.5 mL, 0.107 mol) was dissolved in 7% H2SO4 in 1,4-dioxane (150 mL) and stirred at 80° C. for 90 min. The reaction was monitored by TLC. After completion of the reaction, the dioxane was evaporated under reduced pressure, and the residue basified with aq. NaHCO3 solution, and extracted with EtOAc. The organic layer was evaporated under reduced pressure. The crude product was crystallized from hexane and diethyl ether to afford 20.8 g of 6-bromo-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3) d (ppm): 10.9 (s, 1H), 7.20 (s, 1H), 7.10 (s, 1H), 3.50 (s, 2H), 2.90-2.80 (t, 2H), 2.70-2.60 (t, 2H), 2.40 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:21])[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-])=O)=[O:5])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:21])[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(C)c1Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cnn(C)c1Nc1ccccc1N
Yield: 86.4 %

Procedure:
1-Methyl-5-(2-nitro-phenylamino)-1H-pyrazole-4-carboxylic acid ethyl ester (20.8 g, 72 mmol) from Example E11.1 was dissolved in methanol (330 ml) and hydrogenated over 10% Pd/C catalyst for 4 h. The mixture was filtered through Celite® filter agent and the filtrate was concentrated in vacuo to give a white solid identified as the title compound (16.2 g, 87%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[C:5]([CH3:14])([CH3:13])[CH2:4][CH2:3]1.[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([C:9]2[C:8]([CH3:12])=[CH:7][C:6]3[C:5]([CH3:14])([CH3:13])[CH2:4][CH2:3][C:2]([CH3:15])([CH3:1])[C:11]=3[CH:10]=2)=[O:22])=[CH:19][CH:18]=1
Reactant: Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc2c(cc1C(=O)c1ccc(Br)cc1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene (2 g, 9.9 mmol) and 4-bromobenzoyl chloride (2.17 g, 9.9 mol) were dissolved in 20 mL of CH2Cl2 and cooled to 0° C. using an ice-water-NaCl bath. AlCl3 (3.95 g, 29.7 mmol) was added in portions at over 5 min. The dark reaction mixture was allowed to stir at 0° C. for 5 min. The reaction was quenched by slow addition of ice at 0° C. The mixture was diluted with water and 150 mL of EtOAc was added and the layers were separated. The aqueous layer was washed with additional EtOAc (150 mL). The combined organic layers were washed with water (200 mL) and brine (100 mL) and dried over MgSO4. The filtrate was concentrated in vacuo to yield a yellow foamy solid residue that was recrystallized from MeOH (40 mL).