Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][C:13]1[C:18]2[O:19][C@@H:20]([CH2:23][OH:24])[CH2:21][O:22][C:17]=2[CH:16]=[CH:15][CH:14]=1.Cl>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:24][CH2:23][C@@H:20]2[O:19][C:18]3[C:13]([Cl:12])=[CH:14][CH:15]=[CH:16][C:17]=3[O:22][CH2:21]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: OC[C@H]1COc2cccc(Cl)c2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COc3cccc(Cl)c3O2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-toluenesulphonyl chloride (3.15 g) in dry pyridine (15 ml) was added to a solution of (S)-8-chloro-1,4-benzodioxan-2-ylmethanol (3.32 g; prepared in a similar manner to that described above) in dry pyridine (40 ml) and the mixture stirred at ambient temperature for 18 hours, then poured onto ice and dilute hydrochloric acid added to give pH4. The mixture was extracted with dichloromethane (2×200 ml) and the combined extracts washed with brine and dried over magnesium sulphate. The solvent was evaporated to give (R)-8-chloro-1,4-benzodioxan-2-ylmethyl 4-toluenesulphonate (5.21 g) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=3)=[C:3]([C:16]([O:18][CH3:19])=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Cc1cccc(N)c1
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)OC)cnc12
Product: CCOC(=O)c1cnn2c(Nc3cccc(C)c3)c(C(=O)OC)cnc12
Yield: 572.6 %

Procedure:
In the same manner as in Example 19, step 5 and using methyl 7-chloro-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylate (3.00 g, 10.6 mmol) obtained in Example 21, step 2 and m-toluidine (1.70 g, 1.73 mmol), the title compound (3.51 g, 94%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[C:21]2[CH2:26][CH2:25][CH:24]([NH:27]C(=O)OC(C)(C)C)[CH2:23][CH:22]=2)[CH3:10])[C:5]([C:35]#[N:36])=[C:4]([CH3:37])[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[C:21]2[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH:22]=2)[CH3:10])[C:5]([C:35]#[N:36])=[C:4]([CH3:37])[N:3]=1
Reactant: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2C2=CCC(NC(=O)OC(C)(C)C)CC2)c1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2C2=CCC(N)CC2)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A round-bottom flask was charged with tert-butyl (4-(5-((S)-1-((2-amino-5-cyano-6-methylpyrimidin-4-yl)amino)ethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)cyclohex-3-en-1-yl)carbamate (0.079 g, 0.157 mmol), DCM (2 mL), and TFA (0.969 mL, 12.57 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The solvent was evaporated using a stream of nitrogen. A portion of the crude material was purified via preparative HPLC (acid mode, 5-25% ACN/water gradient). The product-containing fractions were dried in vacuo to give the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.81 (d, J=6.82 Hz, 3H), 0.97-1.16 (m, 1H), 1.30-1.51 (m, 2H), 1.57 (s, 3H), 1.63-1.94 (m, 3H), 2.66 (d, J=8.84 Hz, 1H), 3.07-3.15 (m, 3H), 4.69-4.88 (m, 1H), 5.02 (br s, 1H), 5.86 (d, J=3.03 Hz, 1H), 7.05 (d, J=3.03 Hz, 1H), 7.45 (d, J=4.04 Hz, 1H); ESI-MS m/z [M+H]+ calc'd for C22H26N8, 403. found 403.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:18]([O:22][C:23]([N:25]([CH2:27][C:28](O)=[O:29])[CH3:26])=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]([CH2:27][C:28]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:29])[CH3:26])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: NC(=O)c1c(N)ncn1Cc1cccc(Cl)c1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Product: CN(CC(=O)Nc1ncn(Cc2cccc(Cl)c2)c1C(N)=O)C(=O)OC(C)(C)C
Yield: 85 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 17, using 1.13 g (4.50 mmol) of 4-amino-1-(3-chlorobenzyl)-5-imidazolecarboxamide prepared in the same manner as in Example 51 and 2-(N-t-butyloxycarbonyl-N-methylamino)acetic acid instead of 3-pyridylacetic acid hydrochloride to obtain 1.61 g of 4-(2-(N-t-butyloxycarbonyl-N-methylamino)acetylamino)-1-(3-chlorobenzyl)-5-imidazolecarboxamide (yield 85%).
Reaction SMILES: C([NH:11][C:12]([CH3:25])([CH3:24])[CH2:13][O:14][CH:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:16]([CH3:19])([CH3:18])[CH3:17])(OCC1C=CC=CC=1)=O>CO.[Pd]>[NH2:11][C:12]([CH3:25])([CH3:24])[CH2:13][O:14][CH:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:16]([CH3:18])([CH3:17])[CH3:19]
Reactant: CC(C)(COC(C(C)(C)C)C(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(N)COC(C(C)(C)C)C(C)(C)C

Procedure:
N-Cbz-2-amino-2-methyl-1-[di-(t-butyl)methoxy]propane is dissolved in CH3OH and hydrogenated over 5% Pd/C in a Paar hydrogenation apparatus. When the reaction is complete the mixture is filtered through Celite and concentrated to yield 2-amino-2-methyl-1-[di-(t-butyl)methoxy]propane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[CH2:12][CH:11]([CH2:13][CH2:14][O:15]S(C3C=CC(C)=CC=3)(=O)=O)[N:10]([CH3:26])[C:9]2=[O:27])=[CH:5][CH:4]=1.[CH2:30]([O:32][C:33](=[O:45])[C:34]([O:37][C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1)([CH3:36])[CH3:35])[CH3:31].N#N>CN(C=O)C>[CH2:30]([O:32][C:33](=[O:45])[C:34]([O:37][C:38]1[CH:43]=[CH:42][C:41]([O:15][CH2:14][CH2:13][CH:11]2[CH2:12][N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:29][CH:28]=3)[C:9](=[O:27])[N:10]2[CH3:26])=[CH:40][CH:39]=1)([CH3:36])[CH3:35])[CH3:31]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Reactant: COc1ccc(CN2CC(CCOS(=O)(=O)c3ccc(C)cc3)N(C)C2=O)cc1
Agent: N#N
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1
Temperature: 25 °C
Yield: 92.8 %

Procedure:
A mixture of toluene-4-sulfonic acid 2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethyl ester (3.10 g, 7.41 mmol), 2-(4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester (1.50 g, 6.69 mmol) and CS2CO3 (2.62 g, 8.04 mmol) in DMF (70 mL) was heated at 65° C. for under N2 for 16 h. The reaction mixture was cooled to room temperature, quenched with aqueous 1 N HCl (25 mL), and worked up extractively with EtOAc and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 5:1 hexanes:acetone to afford 2.92 g (93%) 2-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester. MS (ES+) Calc'd for C36H47N2O6 (M+1) 603. Found m/z 603 (100%). 1H NMR.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH:11]=[N:12][C:8]=2[CH:7]=1)=[O:5].[CH3:22][CH2:23][Mg+].[Br-].[NH4+].[Cl-]>C1COCC1>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[N:10]1[C:9]2[CH:19]=[CH:20][C:6]([C:4](=[O:5])[CH2:22][CH3:23])=[CH:7][C:8]=2[N:12]=[CH:11]1
Reactant: CON(C)C(=O)c1ccc2c(c1)ncn2C1CCCCO1
Reactant: CC[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(=O)c1ccc2c(c1)ncn2C1CCCCO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To the solution of 168 (70 mg, 0.24 mmol) and THF cooled to 0° C. under Ar was added EtMgBr (0.72 mL, 1M solution). The mixture was stirred at 0° C. for 2 h then NH4Cl solution was added carefully. The mixture was extracted with EtOAc, washed sequentially with H2O and brine and dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography to afford 45 mg (72%) of 1-[1-(tetrahydro-pyran-2-yl)-1H-benzoimidazol-5-yl]-propan-1-one (170) as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH:11]([OH:16])[C:12]([F:15])([F:14])[F:13])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[C:4]2[CH:21]=[CH:22][CH:23]=[CH:24][C:3]1=2.[CH3:25][C:26]([CH3:41])([C:30]([NH:32][CH2:33][C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])=[O:31])[C:27](O)=[O:28]>>[CH3:25][C:26]([CH3:41])([C:30]([NH:32][CH2:33][C:34]([F:39])([F:40])[C:35]([F:36])([F:38])[F:37])=[O:31])[C:27]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH:11]([OH:16])[C:12]([F:15])([F:13])[F:14])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[C:4]2[CH:21]=[CH:22][CH:23]=[CH:24][C:3]1=2)=[O:28]
Reactant: CC(C)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Reactant: N[C@@H]1C(=O)N(CC(O)C(F)(F)F)c2ccccc2-c2ccccc21
Product: CC(C)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CC(O)C(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(3,3,3-trifluoro-2-hydroxy-propyl)-5H,7H-dibenzo[b,d]azepin-6-one and 2,2-dimethyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid, the title compound was prepared in the same manner as example 1c (87%). White solid. MS: m/e=582(M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27](Cl)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1.[N:38]1([C:44](=[O:52])[CH2:45][N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C@H:11]2[C@@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:9]([C:27]([N:49]3[CH2:50][CH2:51][N:46]([CH2:45][C:44]([N:38]4[CH2:39][CH2:40][O:41][CH2:42][CH2:43]4)=[O:52])[CH2:47][CH2:48]3)=[O:28])[C:8]([C:6]3[C:5]([O:30][CH2:31][CH3:32])=[CH:4][C:3]([C:33]([CH3:34])([CH3:35])[C:36]#[N:37])=[C:2]([Cl:1])[CH:7]=3)=[N:12]2)=[CH:18][CH:17]=1
Reactant: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Product: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-2-chloro-5-ethoxy-phenyl)-2-methyl-propionitrile was prepared from (4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12k) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 751.3 [(M+H)+]
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]([CH3:20])[CH3:19])[C:11]3=[O:21])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:30][N:31]1[CH:35]=[C:34]([S:36](Cl)(=[O:38])=[O:37])[N:33]=[CH:32]1>ClCCl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]([CH3:20])[CH3:19])[C:11]3=[O:21])[S:36]([C:34]2[N:33]=[CH:32][N:31]([CH3:30])[CH:35]=2)(=[O:38])=[O:37])=[CH:4][CH:3]=1
Reactant: CC(C)N1C(=O)c2ccc(NCc3ccc(Cl)cc3)cc2C1=O
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)N1C(=O)c2ccc(N(Cc3ccc(Cl)cc3)S(=O)(=O)c3cn(C)cn3)cc2C1=O
Yield: 7 %

Procedure:
To a stirred solution of 5-(4-chloro-benzylamino)-2-isopropyl-isoindole-1,3-dione (50 mg, 0.15 mmol) and pyridine (36 μl, 0.45 mmol) in anhydrous dichloromethane (2 ml) was added 1-methyl-1H-imidazole-4-sulphonyl chloride (60 mg, 0.27 mmol) and the reaction heated at reflux for 15 hrs. The reaction was cooled and the solvent evaporated in vacuo. The crude residue was purified by preparative HPLC (Method D) to afford the title compound as a colourless solid (5 mg, 7%). HPLC retention time 8.14 min. Mass spectrum (ES+) m/z 473 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C)C=O.[Cl:18]N1C(=O)CCC1=O>O>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([Cl:18])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cccc(C(=O)O)c1N
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cl)cc(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 10 h
Yield: 61.1 %

Procedure:
To a mixture of 1.67 g of 2-amino-3-methoxybenzoic acid and 100 ml of N,N-dimethylformamide was added 1.3 g of N-chlorosuccinimide at room temperature, and the resulting mixture was stirred at room temperature for 10 hours. Water was poured into the reaction mixture, and a deposited precipitate was collected by filtration to obtain 1.2 g of 2-amino-5-chloro-3-methoxybenzoic acid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].C1(N=C=NC2CCCCC2)CCCCC1.[C:24]([NH:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1C=CC=CC=1>[C:24]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([O:7][C:6](=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][Br:1])=[CH:35][CH:34]=1)(=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Nc1ccc(O)cc1)c1ccccc1
Reactant: O=C(O)CCCCBr
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccccc1
Product: O=C(CCCCBr)Oc1ccc(NC(=O)c2ccccc2)cc1

Procedure:
A mixture of 9 g. of 5-bromopentanoic acid, 10.2 g. of dicyclohexyl carbodiimide and 10.75 g. of p-benzoylaminophenol was boiled for 2 hours in benzene. After cooling, the solution was filtered and the solvent distilled off. As a residue 5-bromopentanoic acid p-benzoylaminophenyl ester was obtained.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([F:16])[CH:8]=1.Cl.[CH:19]1([C:22]2[C:23]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[N:24][CH:25]=[C:26]([CH:28]3[CH2:30][CH2:29]3)[CH:27]=2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[C:23]([N:31]3[CH2:32][CH2:33][N:34]([C:11]([C:10]4[CH:14]=[CH:15][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:17])=[CH:8][C:9]=4[F:16])=[O:13])[CH2:35][CH2:36]3)=[N:24][CH:25]=[C:26]([CH:28]3[CH2:30][CH2:29]3)[CH:27]=2)[CH2:20][CH2:21]1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1F
Agent: Cl
Product: O=C(c1ccc(N2CCCS2(=O)=O)cc1F)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 66.7 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-fluorobenzoic acid (259 mg) described in Preparation Example 23 and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine hydrochloride (280 mg) described in Preparation Example 87 and to by the reaction and treatment in the same manner as in Example 86, the title compound (323 mg) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH:34][C:33]([C@@H:35]5[CH:39]=[C:38]([CH2:40]C)[CH2:37][N:36]5C(OC(C)(C)C)=O)=[N:32][CH:31]=4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.Cl.C(C1CN[C@H](C2NC(C3C=CC(C4C=CC(C5NC([C@@H]6CCCN6)=NC=5)=CC=4)=CC=3)=CN=2)C=1)C>O1CCOCC1>[CH3:40][C:38]1[CH2:37][NH:36][C@H:35]([C:33]2[NH:34][C:30]([C:27]3[CH:28]=[CH:29][C:24]([C:21]4[CH:20]=[CH:19][C:18]([C:15]5[NH:14][C:13]([C@@H:9]6[CH2:10][CH2:11][CH2:12][NH:8]6)=[N:17][CH:16]=5)=[CH:23][CH:22]=4)=[CH:25][CH:26]=3)=[CH:31][N:32]=2)[CH:39]=1
Reactant: CCC1=C[C@@H](c2ncc(-c3ccc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)cc3)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: CCC1=C[C@@H](c2ncc(-c3ccc(-c4ccc(-c5cnc([C@@H]6CCCN6)[nH]5)cc4)cc3)[nH]2)NC1
Agent: Cl
Solvent: C1COCCO1
Product: CC1=C[C@@H](c2ncc(-c3ccc(-c4ccc(-c5cnc([C@@H]6CCCN6)[nH]5)cc4)cc3)[nH]2)NC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 111.8 %

Procedure:
To a solution of (S)-tert-butyl 2-(5-(4′-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-ethyl-2H-pyrrole-1(5H)-carboxylate (intermediate 26) (0.171 g, 0.248 mmol) in dioxane (4 mL) was added a solution of 5.5N HCl in dioxane (2.5 mL) at 0° C. The mixture was stirred at room temperature for 20 hours. The resulting mixture was concentrated to give 2-((S)-4-methyl-2,5-dihydro-1H-pyrrol-2-yl)-5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazole (Intermediate 29) (0.121 g, yield: 83%) as a brown solid. ES LC-MS m/z=451 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=[N:14]O)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: ON=C1CCN(CC2CCCCC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: NC1CCN(CC2CCCCC2)CC1
Yield: 87.7 %

Procedure:
A solution of 1-cyclohexylmethylpiperid-4-one oxime (37.8 g; 0.18 moles) dissolved in anhydrous diethyl ether (250 ml) was added little by little to a suspension of lithium aluminium hydride (14.04 g; 0.36 moles) in anhydrous diethyl ether (200 ml). On completion of the addition, the resultant mixture was heated to the boiling point and maintained there under reflux for 12 hours, and then thoroughly cooled whilst water (14 ml), 15% (w/v) aqueous sodium hydroxide solution (14 ml) and water (42 ml) were added successively. The mixture was filtered and the ethereal solution was dried (Na2SO4) and the solvent removed in vacuo. The product 1-cyclohexylmethyl-4-aminopiperidine (31 g) was isolated as a viscous liquid, b.p. 105°-110° C./0.3 mm Hg.
Reaction SMILES: [C:1]1([N:7]=[C:8]2[C:13](Cl)([Cl:14])[CH2:12][CH2:11][CH2:10][C:9]2(Cl)[Cl:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>ClC1C=CC=CC=1>[C:1]1([NH:7][C:8]2[C:9]([Cl:16])=[CH:10][CH:11]=[CH:12][C:13]=2[Cl:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC1(Cl)CCCC(Cl)(Cl)C1=Nc1ccccc1
Solvent: Clc1ccccc1
Product: Clc1cccc(Cl)c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.9 %

Procedure:
A 1 l glass reactor was charged with 100 g (0.32 mole) of N-phenyl-2,2,6,6-tetrachlorocyclohexaneimine obtained in Example 1 and 500 g of chlorobenzene, and the mixture was heated in an oil bath with stirring. While keeping the reaction temperature at 100° C., the reaction was continued for 5 hours. After the reaction was completed, the reaction mixture was cooled to 25° C., and washed with 300 g of a 10% aqueous solution of sodium hydroxide. Then, the organic layer was dried with sodium sulfuric anhydride, from which chlorobenzene was distilled away under reduced pressure to give 64.7 g of N-phenyl-2,6-dichloroaniline in the state of a black solid (yield: 85%, mp: 49.5° to 50.7° C.). The obtained N-phenyl-2,6-dichloroaniline had a purity of 92.1% measured by means of gas chromatography.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:19][C:20](=[O:22])[CH3:21])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9](N2CCOCC2)[N:8]=1.Cl.[CH:24]1(C(N)=N)[CH2:26][CH2:25]1>>[CH:24]1([C:9]2[N:8]=[C:7]([C:6]3[S:5][C:4]([NH:19][C:20](=[O:22])[CH3:21])=[N:3][C:2]=3[CH3:1])[CH:12]=[CH:11][N:10]=2)[CH2:26][CH2:25]1
Reactant: CC(=O)Nc1nc(C)c(-c2ccnc(N3CCOCC3)n2)s1
Reactant: N=C(N)C1CC1
Agent: Cl
Product: CC(=O)Nc1nc(C)c(-c2ccnc(C3CC3)n2)s1

Procedure:
The titled compound is prepared by an analogous procedure to N-[4-Methyl-5-(2-morpholin-4-yl-pyrimidin-4-yl)-thiazol-2-yl]-acetamide (25e) by replacing morpholinoformamidine hydrobromide (part 25c) with cyclopropanecarboxamidine hydrochloride.
Reaction SMILES: B.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:14][CH2:13][C:12](=O)[N:11]([CH:16]([CH3:18])[CH3:17])[CH2:10]2)=[CH:5][C:4]=1[C:19]#[N:20].CO.[ClH:23]>O1CCCC1>[ClH:23].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:14][CH2:13][CH2:12][N:11]([CH:16]([CH3:18])[CH3:17])[CH2:10]2)=[CH:5][C:4]=1[C:19]#[N:20]
Reactant: CC(C)N1CC(c2ccc(N)c(C#N)c2)OCC1=O
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)N1CCOC(c2ccc(N)c(C#N)c2)C1
Reaction time: 3 h

Procedure:
Borane in tetrahydrofuran (1.0M solution; 7.5 ml) was added dropwise, at ambient temperature, to a stirred solution of 2-[4-amino-3-cyanophenyl]-4-[1-methylethyl]-5-oxomorpholine (0.83 g) in dry tetrahydrofuran (60 ml) under nitrogen. The mixture was then heated under reflux with stirring, under nitrogen, for three hours, cooled and methanol (4 ml) in tetrahydrofuran (10 ml) added carefully. The mixture was heated under reflux for one hour, cooled, hydrogen chloride gas passed and the mixture heated under reflux for one hour. After cooling and evaporation to dryness, the residue was dissolved in dilute hydrochloric acid, washed with diethyl ether, the aqueous phase made alkaline by addition of dilute aqueous sodium hydroxide and extracted with dichloromethane. The dichloromethane extracts were washed with brine, dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated to dryness. The residual oil was purified by chromatography on silica gel using 2-3% methanol in dichloromethane as eluant. Conversion to its hydrochloride salt by addition of ethereal hydrogen chloride and recrystallisation from acetone-diethyl ether gave the title compound, m.p. 200°-2° C., as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6][C:5]2=[O:18].Br[CH2:20][CH2:21][CH2:22][CH2:23][Cl:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:24][CH2:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:6][C:5](=[O:18])[C:4]=2[CH:3]=1
Reactant: ClCCCCBr
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1cc(-c2ccccc2)oc2ccc(OCCCCCl)cc12
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A mixture of 6-hydroxyflavone (5.0 g, 21 mmol), 1-bromo-4-chlorobutane (4.86 mL, 42 mmol), and potassium carbonate (12 g, 84 mmol) was refluxed in acetone for 24 hours. The solution was cooled to room temperature, filtered, and the solvent removed in vacuo. The residue was boiled with ether and filtered. Cooling gave 6.1 g (89%) of 6-(4-chlorobutoxy)-2-phenyl-4H-1-benzopyran-4-one as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:13]([C:15]([C:21]#[N:22])=[C:16](SC)[NH:17][CH3:18])#[N:14]>C(#N)C>[C:13]([C:15]([C:21]#[N:22])=[C:16]([NH:17][CH3:18])[NH:12][CH2:11][CH2:10][CH2:9][CH2:8][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:14]
Reactant: CNC(SC)=C(C#N)C#N
Reactant: NCCCCc1ncccc1Cl
Solvent: CC#N
Product: CNC(NCCCCc1ncccc1Cl)=C(C#N)C#N

Procedure:
Reaction of 3-chloro-2-(4-aminobutyl)pyridine with 1,1-dicyano-2-methylthio-2-methylaminoethylene in acetonitrile at room temperature for one hour yields the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18](=[N:26][C:27]#[N:28])[O:19][C:20]4C=CC=C[CH:21]=4)[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>CCO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18](=[N:26][C:27]#[N:28])[O:19][CH2:20][CH3:21])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#CN=C(Oc1ccccc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=NC#N)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-[4-(cyanimino(phenoxy)methyl)piperazin-1-yl]quinoline (196 mg, 0.5 mmol) and potassium tert-butoxide (62 mg, 0.55 mmol) in EtOH (5 mL) are stirred at room temp. for 4 h. The reaction mixture is concentrated, and the residue purified by column chromatography delivering the title product.