Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:3]=1[C:4]#[N:5].Cl[C:13]1[CH:14]=[C:15]2[N:22]([CH3:23])[C:21]([CH3:25])([CH3:24])[CH2:20][N:16]2[C:17](=[O:19])[N:18]=1>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:13]2[CH:14]=[C:15]3[N:22]([CH3:23])[C:21]([CH3:25])([CH3:24])[CH2:20][N:16]3[C:17](=[O:19])[N:18]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: N#Cc1cc(CO)ccc1F
Product: CN1c2cc(OCc3ccc(F)c(C#N)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 2-fluoro-5-(hydroxymethyl)benzonitrile and 7-chloro-1,2,2-trimethyl-2,3-dihydroi-midazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: Br[CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH:4]=1.[N-:22]=[N+:23]=[N-:24].[Na+].CN(C=O)C>C(OCC)(=O)C>[N:22]([CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH:4]=1)=[N+:23]=[N-:24]
Reactant: O=c1c(CBr)cn(-c2ccccc2Cl)c2cc(Cl)ccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cn(-c2ccccc2Cl)c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
To a 25 mL round-bottom flask containing the crude 3-bromomethyl-7-chloro-1-(2-chloro-phenyl)-1H-quinolin-4-one (410 mg, 1.07 mmol) was added sodium azide (83.5 mg, 1.28 mmol) and DMF (9 mL). The reaction mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate (100 mL) and washed with brine (100 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. The crude was purified by flash chromatography (silica gel, 24 g, 0-50% ethyl acetate in hexanes) to yield 3-azidomethyl-7-chloro-1-(2-chloro-phenyl)-1H-quinolin-4-one (215 mg, 58%) as a light yellow solid. 1H NMR (DMSO-d6) δ ppm 8.17-8.36 (m, 2H) 7.83 (ddd, J=9.8, 7.9, 1.7 Hz, 2H) 7.68 (ddd, J=9.8, 7.8, 1.6 Hz, 2H) 7.48 (dd, J=8.7, 1.8 Hz, 1H) 6.70 (d, J=1.8 Hz, 1H) 4.09-4.44 (m, 2H). MS calcd. for C16H10Cl2N4O [(M+H)+] 346.0, obsd. 345.0.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]2[C:8]([CH3:13])=[CH:9][C:10]([NH2:12])=[CH:11][C:6]=2[N:5]=[C:4]1[CH3:14].[I:15][C:16]1[CH:21]=[C:20](I)[N:19]=[CH:18][N:17]=1>C(O)CCC>[I:15][C:16]1[N:17]=[CH:18][N:19]=[C:20]([NH:12][C:10]2[CH:9]=[C:8]([CH3:13])[C:7]3[N:3]([CH3:2])[C:4]([CH3:14])=[N:5][C:6]=3[CH:11]=2)[CH:21]=1
Reactant: Ic1cc(I)ncn1
Reactant: Cc1cc(N)cc2nc(C)n(C)c12
Agent: Cl
Solvent: CCCCO
Product: Cc1cc(Nc2cc(I)ncn2)cc2nc(C)n(C)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
150 mg (0.700 mmol) 1,2,7-trimethyl-1H-benzimidazol-5-ylamine hydrochloride, 260 mg (0.800 mmol) 4,6-diiodopyrimidine, 0.300 mL (2.00 mmol) TEA and 5.0 mL 1-butanol were combined and stirred for 1 h at RT. The reaction mixture was evaporated down and the residue was extracted with DCM and 1N aqueous sodium hydroxide solution. The organic phase was dried on sodium sulphate, filtered and evaporated down.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([CH:14]([OH:16])[CH3:15])=[CH:12][N:11]=[C:10]3[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[CH:19][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:28]=O.O>C(O)C>[CH:1]1([N:7]2[C:8]3[C:9]4[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:25])[CH3:27])[C:10]=4[N:11]=[CH:12][C:13]=3[CH:14]([CH3:15])[O:16][CH2:28]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=O
Reactant: CC(O)c1cnc2c(ccn2COCC[Si](C)(C)C)c1NC1CCCCC1
Solvent: O
Solvent: CCO
Product: CC1OCN(C2CCCCC2)c2c1cnc1c2ccn1COCC[Si](C)(C)C
Temperature: 25 °C

Procedure:
1-(4-(Cyclohexylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanol (9 mg, 0.02 mmol) and aqueous formaldehyde (35 wt %, 0.3 mL, 4 mmol) in ethanol (1 mL) were stirred at 75° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and, after addition of water, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting pale yellow oil (9 mg) containing the title compound was used for the next step without further purification.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([S:17]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([Cl:30])[CH:26]=4)[CH:21]=3)(=[O:19])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.CS[C:40]1[NH:41][CH2:42][CH2:43][N:44]=1>C(O)C>[ClH:30].[Cl:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:17]([N:14]1[CH2:13][CH2:12][N:11]([C:9]([C@H:6]3[CH2:7][CH2:8][C@H:3]([NH:2][N:44]4[CH2:43][CH2:42][N:41]=[CH:40]4)[CH2:4][CH2:5]3)=[O:10])[CH2:16][CH2:15]1)(=[O:18])=[O:19])[CH:29]=[CH:28]2
Reactant: N[C@H]1CC[C@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Reactant: CSC1=NCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C([C@H]1CC[C@H](NN2C=NCC2)CC1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1

Procedure:
To a solution of 1-(trans-4-aminocyclohexane-1-ylcarbonyl)-4-(6-chloronaphthalene-2-sulfonyl)piperazine hydrochloride (100 mg) and triethylamine (120 mg) in ethanol (10 ml) was added 2-methylthioimidazoline (116 mg), and the mixture was heated for 48 hours under reflux. The reaction solution was concentrated, and the residue was purified with silica gel column chromatography (dichloromethane/methanol containing 10% ammonia=10/1) and transformed into hydrochloride with 4 N hydrochloric acid in ethyl acetate to give a colorless solid of the title compound (30 mg).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:32].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:32])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccc(C#N)cc2)C(=O)O1
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(C#N)cc1)C(=O)O

Procedure:
In analogy with Example 1i), 0.50 g of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(p-cyanophenyl)methyl]dihydrofuran-2-(3H)-one in 19 ml of dimethoxyethane and 10 ml of water is hydrolysed with 4.8 ml of a 1M lithium hydroxide solution to form the title compound: TLC Rf (B)=0.3.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].O.O[Li].O>O1CCOCC1>[C:26]([N:23]1[CH2:22][CH2:21][CH:20]([N:10]([C:11]([CH:13]2[CH2:14][CH2:15][CH:16]([CH3:19])[CH2:17][CH2:18]2)=[O:12])[C:9]2[CH:8]=[C:7]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:25][CH2:24]1)#[N:27]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCN(C#N)CC1
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CC1CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)O)C2CCN(C#N)CC2)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
3-[(1-cyano-piperidin-4-yl)-(4-methyl cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (150 mg, 0.32 mmol) was dissolved in a 4:1 mixture of dioxane:H2O (3.2 ml) and treated with LiOH.H2O (20 mg, 0.48 mmol). After 2 hours of stirring at 50° C., the solvents were removed and then partitioned between 5 ml of H2O acidified to pH 4 and 5 ml of EtOAc. The organic layer was separated and the aqueous phase as washed twice with ethyl acetate (2×5 mL). The combined ethyl acetate layer was dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using (5% MeOH/CH2Cl2) to provide 3-[(1-Cyano-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (114.3 mg, 78% yield) as pale green foam. 1H NMR (DMSO-d6, 400 MHz): 7.80 (m, 2H), 7.45 (m, 4H), 4.44 (m, 1H), 3.35 (m, 2H), 3.13 (m, 2H), 1.96 (t, 1H), 1.88 (d, 1H), 1.75 (m, 1H), 1.70-1.40 (m, 6H), 1.20 (m, 3H), 0.70 (d, 3H), 0.60 (m, 2H).
Reaction SMILES: C(N=C=NCCCN(C)C)C.[F:12][C:13]1[CH:14]=[C:15]([CH:32]=[CH:33][C:34]=1[F:35])[C:16]([NH:18][C:19](=S)[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)=[O:17].[NH2:36][C:37]1[CH:38]=[C:39]([OH:43])[CH:40]=[N:41][CH:42]=1.CN(C)C=O>C(OCC)(=O)C>[F:12][C:13]1[CH:14]=[C:15]([CH:32]=[CH:33][C:34]=1[F:35])[C:16](/[N:18]=[C:19](\[NH:36][C:37]1[CH:42]=[N:41][CH:40]=[C:39]([OH:43])[CH:38]=1)/[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)=[O:17]
Reactant: O=C(NC(=S)Nc1cccc(C(F)(F)F)c1)c1ccc(F)c(F)c1
Reactant: Nc1cncc(O)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(/N=C(\Nc1cncc(O)c1)Nc1cccc(C(F)(F)F)c1)c1ccc(F)c(F)c1
Temperature: 65 °C

Procedure:
N1-((Ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (43 mg, 0.278 mmol), 3,4-difluoro-N-((3-(trifluoromethyl)phenyl)carbamothioyl)benzamide (100 mg, 0.278 mmol) and 5-aminopyridin-3-ol (31 mg, 0.278 mmol) and were combined in a glass vial and dry dimethylformamide (1.5 mL) was added. The vial was capped and the mixture was heated at 65° C. for 2 h. After cooling the mixture to room temperature, the mixture was diluted with ethyl acetate and washed with water then brine. The organic layer was evaporated onto silica gel and the product was purified by chromatography eluting with 50-100% ethyl acetate in hexanes to give (Z)-3,4-difluoro-N-(((5-hydroxypyridin-3-yl)amino)((3 (trifluoromethyl)phenyl)amino)methylene)benzamide as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:16]C.O>CN(C=O)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][O:10][CH3:16])=[CH:4][CH:3]=1
Reactant: CCI
Reactant: OCCCOc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In DMF (100 ml) was dissolved 3-(4-bromophenoxy)-1-propanol (10.0 g). To the mixture was added under ice-cooling 65% sodium hydride (2.4 g), and the mixture was stirred at room temperature for 2 hours. To the mixture was added dropwise iodoethane (3.8 ml), and the mixture was stirred for 3 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=4/1) to give 1-bromo-4-(3-methoxypropoxy)benzene (8.6 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19](O)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[N:28]1([CH2:34][CH2:35][NH2:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[S:18][C:17]([C:19]([NH:36][CH2:35][CH2:34][N:28]5[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]5)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: NCCN1CCCCC1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Product: O=C(NCCN1CCCCC1)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to 2-(piperidin-1-yl)ethanamine via General Procedure B. The product was purified via reverse phase HPLC to give 20.4 mg of 257. MS (Q1) 491.8 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:12][NH:13][O:14][CH3:15].CCN(CC)CC.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([N:13]([O:14][CH3:15])[CH3:12])=[O:5]
Reactant: CNOC
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc(C)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a cooled mixture of 2-chloro-5-methyl-benzoic acid (1 g, mmol), N,O-dimethylhydroxylamine (860 mg, 8.82 mmol) and Et3N (3.27 mL) in CH2Cl2 (10 mL) was added 1-propane phosphonic acid cyclic anhydride (4.49 mL, 7.05 mmol; 50 wt % solution in EtOAc) dropwise and stirred at room temperature for 3 h. The reaction mixture was filtered, washed with CH2Cl2 (mL), evaporated to dryness and subjected to column chromatography (SiO2, 40% EtOAc-hexanes) to obtain 2-chloro-N-methoxy-5,N-dimethyl-benzamide (1.19 g) as white crystalline solid in 95% yield. ESMS m/z (relative intensity): 214.1 (M+H)+ (100).
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:25][C:26]([N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1)([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28].C([O-])([O-])=O.[Cs+].[Cs+].O>C(COC)OC>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([C:36]5[CH:35]=[N:34][N:33]([C:26]([CH3:25])([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:37]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][C:16]([CH3:22])=[N:17]1)([CH3:21])[CH3:20]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Reactant: CCOC(=O)C(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(C)(C)n1cc(-c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)cn1

Procedure:
9-Bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 411 (500 mg, 0.001 mol) and ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoate (594 mg, 0.0015 mol) were reacted under palladium catalyzed Suzuki coupling conditions with Pd(dppf)C12 and Cs2CO3 water and dimethoxyethane to give ethyl 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate together with the corresponding acid. LC/MS (ESI+): m/z 490 (M+H)
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:20])[C:4]([C:13]([CH3:19])([CH3:18])[CH2:14][C:15]([OH:17])=[O:16])=[C:5]([CH3:12])[C:6](=[O:11])[C:7]=1[CH2:8][CH2:9][CH3:10].[Cl:21][CH2:22][CH2:23][N:24]([CH2:32][CH2:33][Cl:34])[C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1>>[CH3:1][C:2]1[C:3](=[O:20])[C:4]([C:13]([CH3:19])([CH3:18])[CH2:14][C:15]([O:17][C:28]2[CH:27]=[CH:26][C:25]([N:24]([CH2:23][CH2:22][Cl:21])[CH2:32][CH2:33][Cl:34])=[CH:30][CH:29]=2)=[O:16])=[C:5]([CH3:12])[C:6](=[O:11])[C:7]=1[CH2:8][CH2:9][CH3:10]
Reactant: Oc1ccc(N(CCCl)CCCl)cc1
Reactant: CCCC1=C(C)C(=O)C(C(C)(C)CC(=O)O)=C(C)C1=O
Product: CCCC1=C(C)C(=O)C(C(C)(C)CC(=O)Oc2ccc(N(CCCl)CCCl)cc2)=C(C)C1=O
Yield: 32 %

Procedure:
Using an analogous procedure to that described in Example 5, 3-(2,5-dimethyl-3-propyl-1,4-benzoquinonyl)-3-methylbutyric acid was reacted with 4-[bis(2-chloroethyl)amino]phenol to give 4-[bis(2-chloroethyl)amino]phenyl 3-(2,5-dimethyl-3-propyl-1,4-benzoquinonyl)-3-methylbutyrate in 32% yield; NMR Spectrum: (CDCl3) 0.91 (t, 3H), 1.39 (m, 2H), 1.52 (s, 6H), 1.95 (s, 3H), 2.18 (s, 3H), 2.35 (t, 2H), 3.2 (s, 2H), 3.55-3.73 (m, 8H), 6.6 (d, 2H), 6.84 (d, 2H); Mass Spectrum: (M+H+) 498, 496, 494.
Reaction SMILES: [CH:1]1([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[OH:11])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:14][O:15][CH2:16]Cl.O>CN(C)C=O>[CH:1]1([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:11][CH2:14][O:15][CH3:16])[CH2:2][CH2:3][CH2:4]1
Reactant: COCCl
Reactant: Oc1ccccc1C1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccccc1C1CCC1
Reaction time: 0.5 h

Procedure:
2-cyclobutylphenol (871 mg) was dissolved in N,N-dimethylformamide (5 mL), and 60% sodium hydride (1.30 g) was added to the solution at 0° C. After stirring the mixture for 30 minutes, chloromethyl methyl ether (2.1 mL) was added and the mixture was stirred for 14 hours. Water was added to the reaction solution, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1) to obtain the title compound (1.13 g) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1.P(Cl)(Cl)Cl>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:13]=2)[C:34](=[O:35])[CH2:33][C:30]2[CH:31]=[CH:32][C:27]([OH:26])=[CH:28][CH:29]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: Clc1ccc(NCCc2cccc(OCc3ccccc3)c2)cc1Cl
Solvent: ClP(Cl)Cl
Solvent: Clc1ccccc1
Product: O=C(Cc1ccc(O)cc1)N(CCc1cccc(OCc2ccccc2)c1)c1ccc(Cl)c(Cl)c1
Temperature: 135 °C
Yield: 98.7 %

Procedure:
To a solution of (3,4-dichlorophenyl) {2-[3-(phenylmethoxy)phenyl]ethyl}amine (4.32 g, 0.011 mol) in chlorobenzene (40 ml) was added 4-hydroxy phenyl acetic acid (2.43 g, 0.014 mol), followed by phosphorus trichloride (5 ml, 0.005 mol). The reaction was allowed to reflux at 135° C. overnight. Solvent was removed and the reaction was basified with 10% sodium hydroxide solution. The reaction was diluted with ethyl acetate and water. The organic was washed with brine, dried with MgSO4, filtered, and concentrated to provide the title compound (5.5 g, 99% yield): ES-MS (m/z) 506 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[CH:34]=[CH:33][C:14]3[N:15]([C:18]4[CH:32]=[CH:31][C:21]([O:22][CH:23]5[CH2:26][CH:25]([C:27](OC)=[O:28])[CH2:24]5)=[CH:20][CH:19]=4)[CH:16]=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:2]=1.[BH4-].[Na+].CO>C1COCC1>[OH:28][CH2:27][CH:25]1[CH2:24][CH:23]([O:22][C:21]2[CH:20]=[CH:19][C:18]([N:15]3[C:14]4[CH:33]=[CH:34][C:11]([C:9]([NH:8][CH2:7][C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)=[O:10])=[CH:12][C:13]=4[N:17]=[CH:16]3)=[CH:32][CH:31]=2)[CH2:26]1
Reactant: COC(=O)C1CC(Oc2ccc(-n3cnc4cc(C(=O)NCc5cccnc5)ccc43)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1ccc(OC2CC(CO)C2)cc1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
Methyl 3-(4-{5-[(pyridin-3-ylmethylamino)carbonyl]-1H-benzimidazol-1-yl}phenoxy)cyclobutanecarboxylate (150 mg, 0.33 mmol) and sodium borohydride (25 mg, 0.66 mmol) were dissolved in THF (3 mL), put under a N2 atmosphere, and heated to 60° C. Methanol (13 μL, 0.33 mmol) was then added and the reaction was stirred at 60° C. for 48 h. The reaction was cooled to rt and concentrated in vacuo. Methanol (2 mL) was then added followed by sodium hydroxide (3M, 5 mL) and the methanol was removed in vacuo. The resultant aqueous solution was extracted with ethyl acetate (3×), dried over MgSO4, filtered, and concentrated in vacuo. The crude solid was purified using the Waters mass-directed HPLC purification system to provide 1-(4-{[3-(hydroxymethyl)cyclobutyl]oxy}phenyl)-N-pyridin-3-ylmethyl-1H-benzimidazole-5-carboxamide as a white solid. MS (ES+): m/z 429 (90) [MH+].
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([O:9][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8]
Reactant: NCC(=O)CCC(=O)O
Reactant: OCc1ccccc1
Agent: Cl
Product: NCC(=O)CCC(=O)OCc1ccccc1
Reaction time: 23 h

Procedure:
From benzyl alcohol (50 ml) and 5-amino-4-oxopentanoic acid hydrochloride (10.0 g; 60 mmol). After 23 h at 90°, excess benzyl alcohol was distilled off at 90° (bath temperature) and 0.33 mm Hg. The yield was 8.1 g (53%) of tan powder.
Reaction SMILES: [CH2:1]([CH:8]([CH:13]=O)[C:9]([O:11]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([O:22][CH2:23][CH2:24][CH2:25][N:26]([CH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1)[S:27]([C:30]1[CH:31]=[N:32][C:33]([NH:36][NH2:37])=[CH:34][CH:35]=1)(=[O:29])=[O:28])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:1]([C:8]1[C:9](=[O:11])[N:36]([C:33]2[N:32]=[CH:31][C:30]([S:27]([N:26]([CH2:25][CH2:24][CH2:23][O:22][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)(=[O:29])=[O:28])=[CH:35][CH:34]=2)[NH:37][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(C=O)Cc1ccccc1
Reactant: NNc1ccc(S(=O)(=O)N(CCCOCc2ccccc2)C2CCCC2)cn1
Product: O=c1c(Cc2ccccc2)c[nH]n1-c1ccc(S(=O)(=O)N(CCCOCc2ccccc2)C2CCCC2)cn1
Yield: 53.7 %

Procedure:
According to the process described in Example 1.3, starting with 0.19 g of methyl 2-benzyl-3-oxopropanoate and 0.4 g of N-[3-(benzyloxy)propyl]-N-cyclopentyl-6-hydrazinylpyridine-3-sulfonamide, 0.29 g of 6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-[3-(benzyloxy)propyl]-N-cyclopentylpyridine-3-sulfonamide is obtained in the form of a beige-coloured solid.
Reaction SMILES: CNC1N=C(C2C=CC=CN=2)C=C(C2C=NC=C(C3C=CC(C(N4CCN(C)CC4)=O)=CC=3)C=2)C=1.Br[C:37]1[CH:38]=[C:39]([C:43]2[CH:48]=[C:47]([N:49]3[CH2:53][CH2:52][CH2:51][CH2:50]3)[N:46]=[C:45]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=3)[CH:44]=2)[CH:40]=[N:41][CH:42]=1.[CH:60]([N:63]1[CH2:68][CH2:67][N:66]([CH2:69][C:70]2[CH:75]=[CH:74][C:73](B(O)O)=[CH:72][CH:71]=2)[CH2:65][CH2:64]1)([CH3:62])[CH3:61]>>[CH:60]([N:63]1[CH2:64][CH2:65][N:66]([CH2:69][C:70]2[CH:75]=[CH:74][C:73]([C:37]3[CH:38]=[C:39]([C:43]4[CH:48]=[C:47]([N:49]5[CH2:53][CH2:52][CH2:51][CH2:50]5)[N:46]=[C:45]([C:54]5[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=5)[CH:44]=4)[CH:40]=[N:41][CH:42]=3)=[CH:72][CH:71]=2)[CH2:67][CH2:68]1)([CH3:62])[CH3:61]
Reactant: CC(C)N1CCN(Cc2ccc(B(O)O)cc2)CC1
Reactant: Brc1cncc(-c2cc(-c3ccccn3)nc(N3CCCC3)c2)c1
Agent: CNc1cc(-c2cncc(-c3ccc(C(=O)N4CCN(C)CC4)cc3)c2)cc(-c2ccccn2)n1
Product: CC(C)N1CCN(Cc2ccc(-c3cncc(-c4cc(-c5ccccn5)nc(N5CCCC5)c4)c3)cc2)CC1

Procedure:
is prepared analogously to [4-(6′-Methylamino-[2,2′;4′,3″]terpyridin-5″-yl)-phenyl]-(4-methyl-piperazin-1-yl)-methanone (Example 2.1) by replacing (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 2.1, step1) with 5″-Bromo-6′-pyrrolidin-1-yl-[2,2′;4′,3″]terpyridine and by replacing (4-Methyl-piperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone with 4-(4-Isopropyl-piperazin-1-ylmethyl)-phenyl boronic acid (Intermediate B3).