Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][N:12]=2)(=[O:10])=[O:9])=[CH:3][CH:2]=1.Br[CH2:22][C:23]([O:25]C(C)(C)C)=[O:24]>>[CH:17]([C:14]1[CH:15]=[CH:16][C:11]([S:8]([N:7]([CH2:22][C:23]([OH:25])=[O:24])[C:4]2[CH:3]=[CH:2][C:1]([CH3:20])=[CH:6][CH:5]=2)(=[O:10])=[O:9])=[N:12][CH:13]=1)([CH3:18])[CH3:19]
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Product: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)C)cn2)cc1

Procedure:
prepared by reaction of 5-isopropyl-pyridine-2-sulfonic acid p-tolylamide with tert-butyl bromoacetate
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([O:11][C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-:22].[Na+]>O1CCOCC1.O>[NH2:3][C:4]1[C:5]([O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([OH:22])=[O:1]
Reactant: [OH-]
Reactant: O=C1Cc2cccc(Oc3ccc4ccccc4c3)c2N1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1c(CC(=O)O)cccc1Oc1ccc2ccccc2c1
Reaction time: 72 h
Yield: 54.4 %

Procedure:
A mixture of 2-oxo-7-(β-naphthoxy)indoline (5 g) and sodium hydroxide (1.6 g) in dioxane (40 ml) and water (80 ml) was refluxed with stirring for 72 hrs. After cooling, the reaction mixture was filtered, and the filtrate was evaporated in vacuo. The residue was dissolved in hot ethanol and filtered. The filtrate was evaporated in vacuo, and ethyl acetate was added to the residue. The resultant ethyl acetate solution was heated. The precipitating crystals were collected by filtration and recrystallized from ethanol to give 2-[2-amino-3-(β-naphthoxy)phenyl]acetic acid (2.9 g). This substance was dissolved in an aqueous sodium bicarbonate, and the solution was filtered and lyophilized to give sodium 2-[2-amino-3-(β-naphtoxy)phenyl]acetate (2.8 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:16][CH:17]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(Oc2ccccc2[N+](=O)[O-])cc1
Temperature: 140 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
A mixture of 2-fluoronitrobenzene (1.1 g, 10 mmols), methyl p-hydroxyphenylacetate (1.7 g, 10 mmols) and potassium carbonate (1.4 g, 10 mmols) was stirred at 140° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, then washed with water, and thereafter dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure to give an oil of methyl 4-(2-nitrophenoxy)phenylacetate (2.78 g, 96.9%).
Reaction SMILES: [N:1]([CH:4]([CH2:12][O:13][CH2:14][O:15][CH3:16])[CH:5]([OH:11])[CH2:6][O:7][CH2:8][O:9][CH3:10])=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:1][CH:4]([CH2:12][O:13][CH2:14][O:15][CH3:16])[C@@H:5]([OH:11])[CH2:6][O:7][CH2:8][O:9][CH3:10]
Reactant: COCOCC(O)C(COCOC)N=[N+]=[N-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCOCC(N)[C@@H](O)COCOC
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a stirred solution of the product from Example 1.3 (392 mg, 1.67 mmol) in tetrahydrofuran (10 ml) was added lithium aluminium hydride (1.0M in ether, 3.33 ml) dropwise. The resulting solution was stirred at ambient temperature for 1 hour. The reaction mixture was partitioned between aqueous sodium bicarbonate and ethyl acetate and the aqueous layer evaporated. The residue was triturated with hot ethyl acetate (4×) and the solution evaporated to give the title compound as a colourless oil (261 mg, 75%). 1H NMR (300 MHz, CDCl3) 3.07 (1H, m), 3.38 (3H, s), 3.38 (3H, s), 3.53 (1H, dd, J 6.8, 9.7 Hz), 3.67 (5H, m), 4.64 (2H, s), 4.66 (2H, s); 13C NMR (75 MHz, CDCl3) 52.7, 55.7, 55.7, 70.7, 70.9, 70.9, 97.1, 97.3.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)[N:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][CH2:6]2.C(Cl)Cl>CO.C(Cl)Cl>[C:18]1([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([OH:2])[CH:4]=3)[CH:9]2[C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc2c(c1)CCN(c1ccccc1)C2c1nccs1
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc2c(c1)CCN(c1ccccc1)C2c1nccs1

Procedure:
The title compound was prepared by analogy to Example 48 except that 6-methoxy-2-phenyl-1-thiazol-2-yl-1,2,3,4-tetrahydroisoquinoline was used instead of 6-methoxy-1-(4-methoxy-phenyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline, and neat CH2Cl2 to 10% MeOH/CH2Cl2 was used as eluent for flash chromatography purification.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH2:19][CH3:20])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:9][CH:8]=1.II.C(O)(=O)C.C(O)(=O)C.[I:31]C1C=CC=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>>[Br:1][C:2]1[S:3][C:4]([I:31])=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH2:19][CH3:20])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:9][CH:8]=1
Reactant: CCCCC(CC)Cc1ccc(-c2ccsc2Br)cc1
Reactant: Ic1ccccc1
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCC(CC)Cc1ccc(-c2cc(I)sc2Br)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The procedure was adapted from Yokoyama, A. Macromolecules 2004, 37, 1169. A 100-mL round bottom flask was charged with 2-bromo-3-[4-(2-ethylhexyl)-phenyl]-thiophene (2.6 g, 7.4 mmol), purged with N2, and anhydrous dichloromethane (18 mL) was added via a deoxygenated syringe. The reaction flask was cooled down to 0° C., whereupon iodine (I2) (1.04 g, 4.1 mmol) and iodobenzene diacetate (PhI(OAc)2) (1.4 g, 4.4 mmol) were added in one portion, and the mixture was stirred at ambient temperature for 4 hours. An aqueous solution of sodium thiosulfate (NaS2O3) (10%) was added to the reaction mixture; the aqueous layer was separated and extracted with diethyl ether (3×50 mL). The collected organic phase was washed with aqueous NaS2O3 (10%) and dried over anhydrous MgSO4. After filtration, the solvent and iodobenzene were removed by evaporation under reduced pressure. The crude product was purified using column chromatography on silica gel with hexane as the eluent (Rf=0.38). The compound was dried under vacuum to yield 3.35 g (95%) of slightly yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[C:19](=[O:21])[NH2:20])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:19]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:9]=1[OH:8])[C:13]([O:15][CH3:16])=[O:14])(=[O:21])[NH2:20]
Reactant: COC(=O)c1ccc(OCc2ccccc2)c(C(N)=O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(O)c(C(N)=O)c1
Yield: 96.4 %

Procedure:
Hydrogenolysis is effected by dissolving 1.2 gm (4.2 mmol) of methyl 4-benzyloxy-3-carbamoylbenzoate in 60 mL of methanol (warmed to effect solution), adding 1 gm of 10% Pd/C (50% water) catalyst, and stirring under 48 psi of hydrogen overnight at room temperature. The reaction mixture is filtered, and the catalyst is repeatedly washed with 10% MeOH/DCM. The combined filtrates are evaporated to dryness to give 0.79 gm (4.05 mmol, 96% yield) of methyl 3-carbamoyl-4-hydroxybenzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[CH:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[S:8][C:4]=2[CH:3]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:12][O:11][C:9]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([N:1]([CH2:6][C:5]3[CH:13]=[CH:14][CH:2]=[CH:3][CH:4]=3)[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=[CH:13][C:5]=2[CH:6]=1)=[O:10]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc2ccc(N)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(N(Cc3ccccc3)Cc3ccccc3)cc2s1

Procedure:
Methyl 6-aminobenzothiophene-2-carboxylate (29 mg, 0.140 mmol) was dissolved in 1 mL of anhydrous DMF and reacted with benzyl bromide (40 μL, 0.38 mmol) in the presence of potassium carbonate (41 mg, 0.30 mmol) at 80° C. under a nitrogen atmosphere for 16 h. The reaction mixture was used in the next step without further purification. MS (EI): cal'd 388 (MH+), exp 388 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:33])[C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)[C:19]=4[CH3:34])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl.C1COCC1>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]([NH:24][C:20]2[C:19]([CH3:34])=[C:18]([C:7]3[C:6]4[C:5]5[C:13](=[CH:14][C:2]([NH:1][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:3][CH:4]=5)[NH:12][C:11]=4[C:10]([C:15]([NH2:17])=[O:16])=[CH:9][CH:8]=3)[CH:23]=[CH:22][CH:21]=2)=[O:33])=[CH:31][CH:30]=1
Reactant: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(N)ccc3c12
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(NS(C)(=O)=O)ccc3c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 7-amino-4-(3-(4-fluorobenzamido)-2-methylphenyl)-9H-carbazole-1-carboxamide (Example 54-5, 30 mg, 0.066 mmol) and TEA (0.018 mL, 0.133 mmol) in DCM-THF (2:1, 3 mL) was treated with methanesulfonyl chloride (10 μL, 0.133 mmol). The mixture was stirred at rt for 1.5 h, and was concentrated and purified by preparative HPLC to provide 4-(3-(4-fluorobenzamido)-2-methylphenyl)-7-(methylsulfonamido)-9H-carbazole-1-carboxamide as a white solid (Example 59-1, 3.5 mg, 9%). 1H NMR (500 MHz, methanol-d4) δ 7.91-8.01 (2 H, m), 7.83 (1 H, d, J=7.8 Hz), 7.45 (1 H, d, J=1.7 Hz), 7.42 (1 H, d, J=7.8 Hz), 7.34 (1 H, t, J=7.8 Hz), 7.12-7.20 (3 H, m), 6.95 (1 H, d, J=7.8 Hz), 6.88 (1 H, d, J=8.6 Hz), 6.73 (1 H, dd, J=8.5, 2.1 Hz), 2.85 (3 H, s), 1.90 (3 H, s). Mass spectrum m/z 531.0 (M+H)+. Also obtained was 4-(3-(4-fluorobenzamido)-2-methylphenyl)-7-(N-(methylsulfonyl)methylsulfonamido)-9H-carbazole-1-carboxamide as a white solid (Example 59-2, 14 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ 11.67 (1 H, s), 10.08 (1 H, s), 8.21 (1 H, br. s.), 7.97-8.08 (3 H, m), 7.79 (1 H, d, J=1.8 Hz), 7.53 (1 H, br. s.), 7.48 (1 H, d, J=7.3 Hz), 7.26-7.39 (3 H, m), 7.15 (1 H, d, J=6.5 Hz), 6.93-7.03 (2 H, m), 6.86 (1 H, d, J=8.3 Hz), 3.46 (6 H, d, J=9.0 Hz), 1.86 (3 H, s). Mass spectrum m/z 607.2 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:32]#[N:33])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38][OH:39]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:39][CH2:38][CH2:37][CH2:36][N:35]([CH3:40])[CH3:34])=[C:23]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:32]#[N:33])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: CN(C)CCCO
Reactant: COCCOc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Product: COCCOc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1OCCCN(C)C

Procedure:
Following the procedure of Example 19, 4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-fluoro-6-(2-methoxyethoxy)-3-quinolinecarbonitrile (300 mg, 0.62 mmol) and 2 mL of 3-dimethylamino-1-propanol provides 115 mg of 4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[3-(dimethylamino)propoxy]-6-(2-methoxyethoxy)-3-quinolinecarbonitrile, mp 194-203° C.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][Cl:6].[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1>>[Cl:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH3:8])=[CH:10][CH:11]=1
Reactant: OC(CCl)CCCl
Reactant: Cc1ccc(O)cc1
Product: Cc1ccc(OCC(O)CCCl)cc1
Yield: 42 %

Procedure:
Utilizing the procedure of Preparation 16, 1,4-dichloro-2-butanol was reacted with 4-methylphenol to give white title compound, m.p. 62°-64° C. in 42% yield.
Reaction SMILES: Cl.NC[CH:4]1[CH2:33][CH2:32][N:7]2[C:8]3[C:13]([C:14]([C:15]4[C:16](=[O:31])[NH:17][C:18](=[O:30])[C:19]=4[C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]([CH3:29])[CH:21]=4)=[C:6]2[CH2:5]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.C1N=C[N:36]([C:39](N2C=NC=C2)=[S:40])C=1>CN(C)C=O.O1CCCC1>[N:36]([CH:4]1[CH2:33][CH2:32][N:7]2[C:8]3[C:13]([C:14]([C:15]4[C:16](=[O:31])[NH:17][C:18](=[O:30])[C:19]=4[C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]([CH3:29])[CH:21]=4)=[C:6]2[CH2:5]1)=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:39]=[S:40]
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(CN)C4)C(=O)NC2=O)c2ccccc21
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(N=C=S)C4)C(=O)NC2=O)c2ccccc21
Yield: 59.9 %

Procedure:
A solution of 505 mg of the pyrroledione product of Example 2 in 20 ml of dimethylformamide was treated with a solution of 222 mg of 1,1-thiocarbonyldiimidazole in 5 ml of tetrahydrofuran. After 17 hours the solvent was evaporated and the residue was purified by chromatography on silica gel with methanol/dichloromethane (1:99). Trituration with n-hexane gave 297 mg of 3-[6,7,8,9-tetrahydro-8-isothiocyanato-pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione in the form of a red solid of melting point 285°-287° C.
Reaction SMILES: [CH3:1][C:2]([C:6]([OH:8])=[O:7])([CH2:4][OH:5])[NH2:3].O=S(Cl)Cl.[CH3:13]O>>[CH3:13][O:7][C:6](=[O:8])[C:2]([NH2:3])([CH3:1])[CH2:4][OH:5]
Reactant: CC(N)(CO)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(C)(N)CO
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A strring solution of α-methyl-DL-Serine (1 g, 8.39 mmol) in MeOH (40 mL) in a flame dried round bottom flask under an inert atmosphere was cooled to 0° C. and SOCl2 (1.84 mL, 25.19 mmol) was slowly added. After addition of the SOCl2 was complete, the reaction mixture was stirred 12 h at rt and then concentrated in vacuo to a white solid that was used directly in the next reaction.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].Cl[C:15]1[C:20]([Cl:21])=[CH:19][C:18]([NH2:22])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1.O>CN(C=O)C>[Cl:21][C:20]1[C:15]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][C:17]([N+:23]([O-:25])=[O:24])=[C:18]([NH2:22])[CH:19]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: Oc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Cl)c(Oc2ccccc2)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 64.2 %

Procedure:
To a solution of phenol (0.500 g, 5.31 mmol) in dry DMF (20 mL) was added solid sodium t-butoxide (0.510 g, 5.31 mmol). The mixture was heated to 100° C. for 60 min, then 4,5-dichloro-2-nitro-phenylamine (1.00 g, 4.83 mmol) was added and the reaction mixture was heated at 100° C. for 19 h. The reaction mixture was allowed to cool to ambient temperature. The reaction mixture was added to water and extracted with EtOAc. The combined organic layers were washed with 1M Na2CO3, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (hexanes:EtOAc, 5% to 30% over 20 minutes) to yield the titled compound as an orange solid (0.821 g, 64%). 1H NMR (400 MHz, CDCl3): 8.27 (s, 1H), 7.50-7.34 (m, 2H), 7.27 (d, J=8.9 Hz, 2H), 7.10 (dd, J=8.6, 1.1 Hz, 2H), 6.02 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[CH:17][C:18]=3[O:20][CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][NH:23]3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:29][N:30]([CH3:35])[CH2:31][C:32](O)=[O:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[CH:17][C:18]=3[O:20][CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:32](=[O:33])[CH2:31][N:30]([CH3:35])[CH3:29])[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)CC(=O)O
Reactant: COc1cc(OC[C@@H]2CCCN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Product: COc1cc(OC[C@@H]2CCCN2C(=O)CN(C)C)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Yield: 73 %

Procedure:
The procedure described in Example 1 was repeated using N-(3-chloro-4-fluoro-phenyl)-7-methoxy-5-[(2S)-pyrrolidin-2-ylmethoxy]-quinazolin-4-amine (96 mg) and N,N-dimethylglycine (27 mg) to give the title compound as a white solid in 73% yield; NMR Spectrum (DMSO-d6) 9.90 (s, 1H), 8.40 (s, 1H), 8.15 (dd, 1H), 7.72-7.62 (m, 1H), 7.40 (t, 1H), 6.88 (d, 1H), 6.78 (d, 1H), 4.66-4.58 (m, 1H), 4.40 (dd, 1H), 4.19 (dd, 1H), 3.90 (s, 3H), 3.66-3.40 (m, 2H), 3.20-3.06 (m, 2H), 2.40 (s, 6H), 2.10-1.82 (m, 4H); MH+ 488.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>C1COCC1.CO>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][C:5]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C1(Cc2ccc(-c3ccccc3)cc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(-c3ccccc3)cc2)(C(=O)O)CC1

Procedure:
To a solution of 4-biphenyl-4-ylmethyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (11.4 mmol; 4.65 g) in THF (30 mL) and methanol (20 mL) was added a 1M solution of sodium hydroxide (28.4 mmol; 28.4 mL) and the resulting mixture was heated to reflux for 48 hours. The resulting mixture was then evaporated and a 1N hydrochloric acid solution (200 mL) was added to the residue. A white precipitate formed that was separated via filtration to yield 4-biphenyl-4-ylmethyl-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester. MS (ESI) m/z 395.76 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][N:3]=1.[CH2:10]([NH2:13])[CH2:11][NH2:12]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:12][CH2:11][CH2:10][NH2:13])=[CH:4][N:3]=1
Reactant: NCCN
Reactant: BrCc1ccc(Br)nc1
Solvent: CC#N
Product: NCCNCc1ccc(Br)nc1
Temperature: 25 °C
Yield: 96 %

Procedure:
2-bromo-5-pyridylmethyl bromide (25 g) in a solution of acetonitrile was added dropwise to a solution of ethylenediamine (30 g) in acetonitrile (80 ml) at 0° C. After the reaction was stirred at room temperature for some time, the produced insoluble salts were filtrated off and then the filtrate was concentrated on a water bath at 40° C. to give N-(2-bromo-5-pyridylmethyl)ethylenediamine (22 g).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([NH2:13])=[O:12]>>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([NH2:13])=[O:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc(I)cc1
Reactant: NC(=O)C(Br)c1ccccc1
Product: NC(=O)C(Nc1ccc(I)cc1)c1ccccc1

Procedure:
In accordance with the procedure of example 4 p-iodoaniline and α-bromophenylacetamide were reacted to yield α-(p-iodoanilino)phenylacetamide, Rf =0.65.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][NH:15][N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1N2CCN(CC2)C1.I/[CH:29]=[CH:30]\[C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32]>CN(C=O)C>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:29]=[CH:30]\[C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: FC(F)(F)c1cc(-c2nc[nH]n2)cc(C(F)(F)F)c1
Reactant: CC(C)OC(=O)/C=C\I
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: CC(C)OC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
A 2-L, 3-necked, round-bottomed flask was charged with a solution of 3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazole (160 g) in DMF (960 mL). The solution was treated with DABCO (127.74 g, 2 eq.) and stirred for 30 min before adding (Z)-isopropyl 3-iodoacrylate (150.32 g, 1.1 eq.) dropwise. After ca. 1 hour, the reaction mixture was poured into an ice-water slurry (5 L) and extracted with EtOAc (3×1 L). The combined organic layers were washed with aqueous saturated brine (3×100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure (35° C., 20 mmHg) to afford 250 g of crude compound that was purified by column chromatography (60/120 silica gel) using a ethyl acetate/n-hexane gradient (the column was packed in hexane and the desired compound started eluting from 2% EtOAC/n-hexane). Fractions containing the desired compounds were combined to afford 138 g the pure desired compound (yield: 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11](=[O:16])[CH2:10][NH:9]2)[CH:5]=[C:4]([Cl:17])[C:3]=1[CH:18]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:19]#[N:20].[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>N1C=CC=CC=1>[C:28]([N:9]1[CH2:10][C:11](=[O:16])[N:12]([CH3:15])[C:13](=[O:14])[N:8]1[C:6]1[CH:5]=[C:4]([Cl:17])[C:3]([CH:18]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[C:19]#[N:20])=[C:2]([Cl:1])[CH:7]=1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CN1C(=O)CNN(c2cc(Cl)c(C(C#N)c3ccc(Cl)cc3)c(Cl)c2)C1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CN1C(=O)CN(C(=O)c2ccccc2)N(c2cc(Cl)c(C(C#N)c3ccc(Cl)cc3)c(Cl)c2)C1=O
Reaction time: 8 h
Yield: 20.2 %

Procedure:
To a stirred mixture of 3 parts of 2,6-dichloro-α-(4-chlorophenyl)-4-(3,4,5,6-tetrahydro-4-methyl-3,5-dioxo-1,2,4-triazin-2(1H)-yl)-benzeneacetonitrile and 20 parts of pyridine was added dropwise 1.7 parts of benzoyl chloride during a period of 5 minutes at room temperature and under nitrogen atmosphere. Upon complete addition, stirring was continued overnight at room temperature. The reaction mixture was evaporated in vacuo and the residue was stirred in water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified twice the column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated in vacuo. The residue was crystallized from 8 parts of acetonitrile. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 0.8 parts (20.2%) of 1-benzoyl-2-[3,5-dichloro-4-[(4-chlorophenyl)cyanomethyl]phenyl]-1,6-dihydro-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione; mp. 148.4° C. (compound 79).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9][CH2:10][N:11]([CH3:15])[CH2:12][CH2:13][NH2:14])=[CH:4][CH:3]=1.[C:22]([NH:24][C:25](=[N:33][CH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)[CH:39]=1)OC1C=CC=CC=1)#[N:23]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][NH:14][C:25]([NH:24][C:22]#[N:23])=[N:33][CH2:34][CH2:35][CH2:36][O:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][N:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)[CH:39]=2)[CH3:15])=[CH:4][CH:3]=1
Reactant: CN(CCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Solvent: CCOC(C)=O
Product: CN(CCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.7 g (2.3 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,2-ethanediamine and 0.85 g (2.2 mmol) of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography (eluant: ethyl acetate) analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB-method): m/z (rel. int.[%])=602 ([M+H]+, 5), 230 (100); IR (KBr): 2165 cm-1 (C≡N). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: from 85° C. with decomposition.