Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=[N:8][N:9]1[CH:13]2[CH2:14][CH:15]([OH:17])[CH2:16][CH:12]2[N:11]([CH2:18][CH2:19][CH3:20])[C:10]1=[O:21])C1C=CC=CC=1.CO>[Pd].C(O)(=O)C>[NH2:8][N:9]1[CH:13]2[CH2:14][CH:15]([OH:17])[CH2:16][CH:12]2[N:11]([CH2:18][CH2:19][CH3:20])[C:10]1=[O:21]
Reactant: CCCN1C(=O)N(N=Cc2ccccc2)C2CC(O)CC21
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN1C(=O)N(N)C2CC(O)CC21
Temperature: 15 °C
Reaction time: 72 h
Yield: 103 %

Procedure:
The compound of step (f) (7.0 g) was added to a solution of methanol (280 ml) and acetic acid (2.25 ml) containing 10% Pd on carbon (2.5 g) and the resulting mixture stirred at 15° C. under an atmosphere of hydrogen for 3 days. The catalyst was removed by filtration through Celite and concentration of the filtrate in vacuo gave the desired product as an oil (5.0 g).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH3:29])[N:12]2[C:13](=[O:28])[C:14]([NH:17][C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[CH:15][N:16]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30](OC(NC1C(=O)N2[C@H](C(OC(C)(C)C)=O)CCC2=NC=1)=O)[C:31]1C=CC=CC=1.C(I)C=C>>[C:1]([O:5][C:6]([C:8]1([CH2:29][CH:30]=[CH2:31])[N:12]2[C:13](=[O:28])[C:14]([NH:17][C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[CH:15][N:16]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Reactant: CC(C)(C)OC(=O)C1(C)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Agent: C=CCI
Product: C=CCC1(C(=O)OC(C)(C)C)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Yield: 55 %

Procedure:
According to the procedure for the preparation of intermediate 19a, alkylation of intermediate 1g (250 mg, 0.649 mmol) with allyl iodide afforded 153 mg (55%) of intermediate 20a. MS (ESI) 426.4 (M+H+), 448.4 (M+Na+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[Br:16][C:17]1[O:21][C:20]([C:22]2[O:23][CH:24]=[C:25]([CH2:27]Cl)[N:26]=2)=[CH:19][CH:18]=1>>[Br:16][C:17]1[O:21][C:20]([C:22]2[O:23][CH:24]=[C:25]([CH2:27][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:26]=2)=[CH:19][CH:18]=1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(-c2ccc(Br)o2)n1
Product: Brc1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)o1
Yield: 87 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 2-(5-bromo-2-furyl)-4-chloromethyloxazole to give 2-(5-bromo-2-furyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 87%. Recrystallization from ethyl acetate-isopropyl ether gave colorless needles, mp 115-116° C.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[F:37])[CH2:28][CH2:27][C:26]([C:38]([OH:40])=O)=[CH:25][C:24]=3[CH:41]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O>O1CCCC1>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[F:37])[CH2:28][CH2:27][C:26]([C:38]([NH:29][C:23]4[CH:24]=[CH:41][C:20]([CH2:4][N:2]([CH3:1])[CH:3]5[CH2:12][CH2:11][O:10][CH2:6][CH2:7]5)=[CH:21][CH:22]=4)=[O:40])=[CH:25][C:24]=3[CH:41]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CN(C)C=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccc2F)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccccc2F)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(2-fluorobenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (200 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (146 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (30 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (108 mg) and triethylamine (496 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature overnight, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8) to give 7-(4-butoxyethoxyphenyl)-1-(2-fluorobenzyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 66) (139 mg) as yellow amorphous.
Reaction SMILES: C([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH2:20][CH3:21])[C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12](C(=O)C)=[CH:11][CH:10]=3)(=O)C.ClC1C=CC=[C:25]([C:29]([O:31]O)=[O:30])C=1>C(Cl)(Cl)Cl>[C:29]([O:31][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH2:20][CH3:21])[C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([O:31][C:29](=[O:30])[CH3:25])=[CH:11][CH:10]=3)(=[O:30])[CH3:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCn1c2ccc(C(C)=O)cc2c2cc(C(C)=O)ccc21
Solvent: ClC(Cl)Cl
Product: CCn1c2ccc(OC(C)=O)cc2c2cc(OC(C)=O)ccc21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 104 g (0.37 mole) of 3,6-diacetyl-N-ethylcarbazole in 1700 ml of chloroform (hydrocarbon stabilized) previously cooled to 15°C was added 138 g (0.8 mole) of m-chloroperbenzoic acid. The reaction was stirred at room temperature for 4 days, then filtered. The filtrate was washed with saturated sodium bicarbonate solution and with water, then dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo leaving a solid which was recrystallized from acetone-water and then from acetone methanol to give the desired product. M.P. 138°-139°C, λmaxEtOH 237, E1cm1% 1330.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[NH:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[O:28][CH2:29][CH3:30])=[N:17][CH:16]2[CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:11][CH:10]=1.ClC1C=CC([CH:43]2[N:47]([C:48](N3CCN(C)CC3)=[O:49])C(C3C=CC(OC)=CC=3OCC)=[N:45][CH:44]2CC2CCCC2)=CC=1>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[N:19]([C:48]([N:47]3[CH2:43][CH2:44][NH:45][C:3](=[O:5])[CH2:2]3)=[O:49])[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[O:28][CH2:29][CH3:30])=[N:17][CH:16]2[CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:13][CH:14]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(C2CCCC2)C(c2ccc(Cl)cc2)N1
Reactant: O=C(O)C(F)(F)F
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Product: CCOc1cc(OC)ccc1C1=NC(C2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
4-[5-(4-Chloro-phenyl)-4-cyclopentyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one was prepared from 5-(4-chloro-phenyl)-4-cyclopentyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole, trifluoroacetate salt (Example 19) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 525.2271, calculated for C28H34N4O4Cl [(M+H)+]525.2263.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[CH:16]([C:17]([O:19]CC)=[O:18])[CH2:15][C:14]2([CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH2:13]1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O.CO>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[CH:16]([C:17]([OH:19])=[O:18])[CH2:15][C:14]2([CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH2:13]1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4]
Reactant: CCOC(=O)C1CC2(CCOCC2)CN1C(=O)[C@@H](NC(=O)OC)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1CC2(CCOCC2)CC1C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
To a solution of ethyl 2-{N-[(methyloxy)carbonyl]-L-valyl}-8-oxa-2-azaspiro[4.5]decane-3-carboxylate (102) (310 mg, 0.84 mmol) in a 2:1:1 mixture of THF/water/methanol (6 mL) was added lithium hydroxide monohydrate (70 mg, 1.67 mmol) and the reaction stirred at room temperature for 2 h. Treated with 1 N HCl (1.6 mL), partitioned between EtOAc and water (30 mL each), organic layer extracted with EtOAc (30 mL), dried (MgSO4) and concentrated to give a white foam (211 mg, 74% yield). This material was used in subsequent steps without additional purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.43 (br. s., 1H) 7.19-7.41 (m, 1H) 4.05-4.28 (m, 1H) 3.91-4.05 (m, 2H) 3.40-3.71 (m, 6H) 3.20-3.28 (m, 1H) 1.81-1.98 (m, 2H) 1.70-1.80 (m, 1H) 1.46-1.69 (m, 2H) 1.32-1.46 (m, 1H) 0.65-1.03 (m, 10H).
Reaction SMILES: [Na+].[Br-:2].CS(O[CH2:8][C@@H:9]1[CH2:13][C:12]([F:15])([F:14])[CH2:11][N:10]1[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([C:25]([F:28])([F:27])[F:26])[CH:17]=1)(=O)=O>C(#N)C.C(OCC)(=O)C.O>[Br:2][CH2:8][C@@H:9]1[CH2:13][C:12]([F:15])([F:14])[CH2:11][N:10]1[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([C:25]([F:28])([F:27])[F:26])[CH:17]=1
Reactant: CS(=O)(=O)OC[C@@H]1CC(F)(F)CN1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CC(F)(F)C[C@H]2CBr)cc1C(F)(F)F
Temperature: 80 °C
Yield: 72.1 %

Procedure:
NaBr (420 mg, 131 μL, 4.08 mmol) was added to a solution of (S)-(4,4-difluoro-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidin-2-yl)methyl methanesulfonate (330 mg, 0.82 mmol) in acetonitrile (2.0 mL) and heated at 80° C. for 16 h. The reaction mixture was diluted with ethyl acetate (10 mL) and water (5 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (15-50% ethyl acetate/hexane) to obtain (S)-2-(bromomethyl)-4,4-difluoro-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine (230 mg, 72%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J=8.7 Hz, 1H), 7.09-7.07 (m, 2H), 4.76-4.71 (m, 1H), 4.16-3.99 (m, 2H), 3.74 (dd, J=10.6, 3.0 Hz, 1H), 3.60 (t, J=9.7 Hz, 1H), 2.94-2.80 (m, 1H), 2.66-2.55 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([F:27])[CH:21]=1>C(O)(C)C>[ClH:1].[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[C:22]([F:27])[CH:21]=1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1ccc(Br)cc1F
Solvent: CC(C)O
Product: COCCOc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OC
Product: Cl
Temperature: 25 °C
Yield: 82.3 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (1 07 mg, 0.4 mmol) and 4-bromo-2-fluoroaniline (76 mg, 0.4 mmol) in isopropanol (7 ml) was heated at reflux for 2 hours. The mixture was allowed to cool to ambient temperature, the precipitated solid was collected by filtration, washed with isopropanol and ether and dried to give 4-(4-bromo-2-fluoroanilino)6-methoxy-7-(2-methoxyethoxy)quinazoline hydrochloride (151 mg, 82%) as an off-white solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)O1.[NH2:23][C:24]1[C:29]([C:30]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[O:31])=[CH:28][C:27](Br)=[CH:26][N:25]=1.[C:40](=[O:43])([O-])[O-:41].[Na+].[Na+]>>[C:40]([OH:41])([C:18]([F:21])([F:20])[F:19])=[O:43].[NH2:23][C:24]1[C:29]([C:30]([N:32]2[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]2)=[O:31])=[CH:28][C:27]([C:9]2[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)=[CH:26][N:25]=1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OB(c2cc(C(F)(F)F)cc3[nH]ncc23)OC1(C)C
Reactant: CN1CCN(C(=O)c2cc(Br)cnc2N)CC1
Agent: [Na+]
Product: CN1CCN(C(=O)c2cc(-c3cc(C(F)(F)F)cc4[nH]ncc34)cnc2N)CC1
Product: O=C(O)C(F)(F)F
Temperature: 135 °C
Yield: 75.2 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1H-indazole (20 mg, 0.064 mmol), (2-amino-5-bromopyridin-3-yl)(4-methylpiperazin-1-yl)methanone (PREPARATION x56, 1 mL, 0.096 mmol), sodium carbonate (27.2 mg, 0.256 mmol), and PdCl2(dppf)CH2Cl2 (5.23 mg, 6.41 μmol) were sealed in a vial, which was heated to 135° C. for 30 minutes in a microwave reactor. The reaction mixture was purified by preparative HPLC, eluting with ACN/H2O (containing 0.05% TFA). The product-containing fractions were dried to give a TFA salt of the title compound as a tan solid (9.73 mg). ESI-MS m/z [M+H]+ calc'd for C19H19F3N6O, 405.2. found 405.3.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([Cl:19])[C:16]=1[O:17][CH3:18])[C:10]([NH2:13])([CH3:12])[CH3:11].C(N(CC)CC)C.O>CN(C)C(=O)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([Cl:19])[C:16]=1[O:17][CH3:18])[C:10]([NH:13][CH2:2][C:3](=[O:5])[CH3:4])([CH3:11])[CH3:12]
Reactant: COc1c(Cl)cc(C(C)(C)N)cc1Cl
Reactant: CC(=O)CCl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: COc1c(Cl)cc(C(C)(C)NCC(C)=O)cc1Cl
Temperature: 80 °C
Yield: 54.6 %

Procedure:
10.0 g (0.1 mol) of chloroacetone, 14.1 g (0.06 mol) of 3,5-dichloro-4-methoxy-α,α-dimethylbenzylamine and 7.2 g (0.07 mol) of triethylamine were dissolved in 100 ml of N,N-dimethylacetamide, and the mixture was heated at 80° C. for about three hours under stirring under a nitrogen atmosphere. The reaction solution was cooled, then poured into a large amount of water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magensium sulfate. The solvent was distilled off under reduced pressure to obtain 9.5 g (yield: 89%) of the desired compound.
Reaction SMILES: [F:1][CH:2]([F:19])[CH:3]1[CH2:8][CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[CH2:5][CH2:4]1.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C.[H][H]>[Pd].CCO>[F:1][CH:2]([F:19])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1
Reactant: O=C(OCc1ccccc1)N1CCC(C(F)F)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: CCO
Product: FC(F)C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
A 250 flask charged with benzyl 4-(difluoromethyl)piperidine-1-carboxylate (1.16 g, 4.31 mmol), palladium, 10 wt. % (dry basis) on activated carbon, wet, degussa type e101 ne/w (0.563 g, 0.265 mmol) and EtOH (25 mL) was evacuated/backfilled with hydrogen (1 atm, 3×). After stirring overnight at room temperature, more palladium, 10 wt. % (dry basis) on activated carbon, wet, degussa type e101 ne/w (1.09 g) was added and the reaction was evacuated/backfilled with hydrogen (1 atm, 3×). After stirring overnight the reaction was filtered through a pad of Celite and the pad was washed with EtOH. Concentration of the filtrate in vacuo gave 4-(difluoromethyl)piperidine as a light-yellow oil (90 mg, 15% yield).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4](O)=[O:5].[CH2:10]([NH:17][C:18]([NH2:20])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[CH2:10]([N:17]1[C:4](=[O:5])[CH:3]([C:2]([F:9])([F:8])[F:1])[CH2:7][NH:20][C:18]1=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=C(C(=O)O)C(F)(F)F
Reactant: NC(=O)NCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C1NCC(C(F)(F)F)C(=O)N1Cc1ccccc1
Temperature: 90 °C
Reaction time: 5 h
Yield: 71.9 %

Procedure:
A mixture of α-trifluoromethylacrylic acid (700 mg; 5.0 mmoles) and benzylurea (796 mg; 5.3 mmoles) in DMF (5 ml) was heated at 90° C. with stirring for 5 hours. After the reaction mixture was cooled to 0° C., a solution of DCC (1.13 g; 5.5 mmoles) in DMF (3 ml) was added dropwise. The mixture was stirred for 1 hour, and the precipitated solid was filtered off and washed with ethyl acetate. The solvents were evaporated under reduced pressure from the combined filtrates. The residue was purified by a column chromatography on silica gel (ethyl acetate:chloroform=1:1) to give 979 mg (yield: 72%) of 3-benzyl-5-trifluoromethyl-5,6-dihydrouracil. m.p.: 129.2°-129.7° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1)#[N:2].[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:11]2[NH:10][C:5]3[C:4]([C:3]=2[C:1]#[N:2])=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:13]=1
Reactant: N#CCc1ccccc1NC(=O)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1c(-c2cccnc2)[nH]c2ccccc12
Temperature: 130 °C
Reaction time: 18 h

Procedure:
N-(2-cyanomethyl-phenyl)-nicotinamide (0.095 g, 0.384 mmol) is dissolved in DMF (3 mL). NaH (60%, 0.015 g, 0.384 mmol) is added and the mixture is heated to 130° C. After 18 h, the mixture is cooled down, diluted with ethyl acetate, and washed with 1M aqueous sodium hydroxide. The combined washings are back-extracted with ethyl acetate. The combined organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by silica gel flash chromatography (dichloromethane-methanol, 99:1 to 19:1) to give 2-pyridin-3-yl-1H-indole-3-carbonitrile as a brown solid. 1H NMR (400 MHz, MeOD) δ ppm 7.29-7.32 (m, 1H), 7.34-7.39 (m, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.66 (dd, J=8.0, 4.9 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 8.39-8.44 (m, 1H), 8.68 (dd, J=4.8, 1.5 Hz, 1H), 9.15 (d, J=1.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=3)[N:12]=[C:11]([C:21]([OH:23])=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH3:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][C:17]([NH2:24])=[CH:18][CH:19]=3)[N:12]=[C:11]([C:21]([OH:23])=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: N
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(Cl)nc2)n1
Product: Nc1ccc(-n2nc(C(=O)O)cc2-c2cc(F)cc(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
70 mg (80%, 0.16 mmol) of the compound of Example 23A is mixed with ammonia solution (14 N, 1.5 ml) and kept in the microwave in a sealed tube for 13 hours at 150° C., whereby a pressure of 20 bar develops. After cooling to room temperature, the ammonia solution is removed i. vac., and the residue is purified via preparative HPLC (mobile solvent: acetonitrile/water gradient). 20 mg (38% of theory) of the title compound is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][C:7](=S)[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[NH:3]1.[C:15]([NH:18][NH2:19])(=O)[CH3:16]>C(O)CCC>[CH3:16][C:15]1[N:6]2[C:5]3[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=3[NH:3][C:2]([CH3:14])([CH3:1])[CH2:8][C:7]2=[N:19][N:18]=1
Reactant: CC1(C)CC(=S)Nc2ccccc2N1
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2n1-c1ccccc1NC(C)(C)C2
Temperature: 130 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
A disposable tube was charged with 4,4-dimethyl-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-thione (600 mg, 2.91 mmol) and a stirbar. nBuOH (30 mL) was added, followed by acetohydrazide (431 mg, 5.82 mmol), and the solution was stirred at 130° C. overnight. The solution was concentrated with celite and purified by silica gel chromatography (eluting with methylene chloride/methanol/ammonium hydroxide) to yield 1,5,5-trimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine as an off-white amorphous solid (0.153 g, 0.67 mmol, 23%).
Reaction SMILES: [C:1]([O-])(=[O:3])[CH3:2].[Na+].[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([NH:24][C:25]([CH:27]=[CH:28][C:29](O)=[O:30])=[O:26])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1>C(OC(=O)C)(=O)C>[Br:6][C:7]1[CH:8]=[C:9]([N:13]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N:24]4[C:29](=[O:30])[CH:28]=[CH:27][C:25]4=[O:26])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[C:1](=[O:3])[CH3:2])[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)C=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N(c1cccc(Br)c1)c1ncnc2ccc(N3C(=O)C=CC3=O)cc12
Temperature: 25 °C
Yield: 39 %

Procedure:
Sodium acetate (0.10 g, 1.2 mmol) was added to a suspension of 3-[4-(3-bromo-phenylamino)-quinazolin-6-ylcarbamoyl]-acrylic acid (Z) (0.25 g, 0.61 mmol) in 5 mL of acetic anhydride, and the mixture was heated under reflux for 30 minutes. After cooling to room temperature, the reaction was filterd and the filtrate concentrated to dryness in vacuo. The residue was taken up in EtOAc and washed sequentially with saturated sodium bicarbonate, water, and brine. The EtOAc portion was dried over magnesium sulfate, filtered and concentrated to afford a faintly pink solid. The solid was recrystallized twice from EtOAc to afford N-(3-bromo-phenyl)-N-[6-[2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-quinazolin-4-yl]-acetamide (0.104 g, 39%) as an off-white powder, mp 174-175° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Cl-].[NH4+].[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1>>[CH2:1]([N:8]1[C:12]([CH2:20][C:19]2[CH:20]=[CH:19][C:18]([C:22]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)=[CH:22][CH:18]=2)([OH:13])[CH2:11][CH2:10][C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cc1ccccc1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: O=C1CCC(O)(Cc2ccc(-c3ccccc3)cc2)N1Cc1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
9.5 g N-Benzylsuccinimide is added to 120 ml THF and the mixture is then cooled to −78° C. A solution of 4-methylbiphenylmagnesium chloride in THF (1.3 eq) is then added. The subsequent mixture is then stirred for 2 h at −78° C. The mixture is then warmed to 10° C. and 100 ml saturated ammonium chloride solution is added. The phases are separated and the aqueous phase is extracted with toluene. The combined organic phases are washed with water then brine and then concentrated in vacuo. The crude material is crystallized from toluene to give 1-Benzyl-5-biphenyl-4-ylmethyl-5-hydroxy-pyrrolidin-2-one. 1H NMR (DMSO): 1.72 (1H), 1.91 (1H), 2.27 (2H), 2.72 (1H), 2.97 (2H), 4.40 (1H), 4.55 (1H), 7.21-7.66 (14H).
Reaction SMILES: C([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([NH2:17])[C:11]=2[N:10]=[C:9]1[NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.[CH2:35]([N:37]=C=O)[CH3:36].O1CCOCC1.Cl>C(#N)C>[Cl:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[Cl:33])[CH2:26][N:23]1[CH2:24][CH2:25][CH:20]([CH2:19][NH:18][C:9]2[NH:17][C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([NH:8][C:6]([NH:37][CH2:35][CH3:36])=[O:5])[C:11]=3[N:10]=2)[CH2:21][CH2:22]1
Reactant: CCN=C=O
Reactant: CC(C)(C)OC(=O)n1c(NCC2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)nc2c(N)cccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: CCNC(=O)Nc1cccc2[nH]c(NCC3CCN(Cc4ccc(Cl)c(Cl)c4)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 4-amino-2-{[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-amino}-benzimidazole-1-carboxylic acid tert-butyl ester (10 mg, 0.02 mmol) in acetonitrile (1 ml), ethyl isocyanate (0.08 mmol) was added and the mixture was stirred at room temperature overnight. After adding a 4N hydrogen chloride-1,4-dioxane solution (1 ml) to the reaction mixture, it was stirred at 50° C. for 1 hour and then the reaction mixture was passed through SCX (Bond Elute SCX500MG). The SCX was washed with methanol and elution was performed with a 2N ammonia-methanol solution. The solvent was distilled off under reduced pressure to obtain 1-(2-{[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazol-4-yl)-3-ethyl-urea. The compound was identified by LC-MS.