Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:5])(=O)[CH:2]=[CH2:3].[Na+].Cl[Si:8]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11]>C1COCC1>[C:1]([Si:8]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])([CH:2]=[CH2:3])=[O:5]
Reactant: C=CC(=O)[O-]
Reactant: CCO[Si](Cl)(OCC)OCC
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC(=O)[Si](OCC)(OCC)OCC
Temperature: -70 °C

Procedure:
6.123 g (0.0651 mol) sodium acrylate is dissolved to 25 mL THF and cooled to −70° C. 12.8 mL (0.0651 mol, 12.938 g) chlorotriethoxysilane in THF (15 mL) is added dropwise to reaction solution. The solution is stirred for over night allowing it to warm up to room temperature. NaCl is removed by filtration and solution evaporated to dryness to result clear liquid, acryltriethoxysilane.
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=3)[CH:6]=[N:7]2)=[N:3][CH:2]=1.[CH:20]([N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:31]=2[C:37]([F:40])([F:39])[F:38])[CH2:25][CH2:24]1)([CH3:22])[CH3:21]>C(Cl)Cl.CO>[CH:20]([N:23]1[CH2:24][CH2:25][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:17](=[O:19])[CH2:16][C:13]3[CH:12]=[CH:11][C:10]([N:5]4[CH:6]=[N:7][C:8]5[C:4]4=[N:3][CH:2]=[N:1][CH:9]=5)=[CH:15][CH:14]=3)=[CH:32][C:31]=2[C:37]([F:40])([F:39])[F:38])[CH2:27][CH2:28]1)([CH3:22])[CH3:21]
Reactant: O=C(O)Cc1ccc(-n2cnc3cncnc32)cc1
Reactant: CC(C)N1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Solvent: CO
Solvent: ClCCl
Product: CC(C)N1CCN(Cc2ccc(NC(=O)Cc3ccc(-n4cnc5cncnc54)cc3)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (4-purin-9-yl-phenyl)-acetic acid and 4-(4-isopropyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (disclosed in WO 03/099771). Title compound: ES-MS: 538.1 [M+H]+; tR=2.93 min (System 1); Rf=0.12 (CH2Cl2/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[C:8]2[CH3:23])=[CH:4][CH:3]=1.[N+](=[CH2:28])=[N-]>CCOC(C)=O>[Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH2:19][C:20]([O:22][CH3:28])=[O:21])=[C:8]2[CH3:23])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CCC(=O)O)c(C)n2Cc1ccc(Br)cc1
Reactant: C=[N+]=[N-]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12

Procedure:
To a solution of the compound from Example 1 (75 mg, 0.19 mmol) in 10 mL EtOAc was added ethereal diazomethane solution until a yellow colour persisted. The solution was concentrated in vacuo and crystalized from ether/hexanes to provide 67 mg of the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]=1)[OH:4].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:4][CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]=1)[C:2]([F:17])([F:18])[F:1])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2cc(C(O)C(F)(F)F)ccc2c1
Solvent: ClCCl
Product: COc1ccc2cc(C(OS(C)(=O)=O)C(F)(F)F)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.8 %

Procedure:
To a solution of 2,2,2-trifluoro-1-(6-methoxynaphthalen-2-yl)ethanol (500 mg, 2 mmol) and TEA (610 mg, 6 mmol, 3 eq) in DCM (10 mL) was added MsCl (680 mg, 6 mmol, 2 eq) at 0° C. dropwise. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with sat. NaHCO3 (5 mL), washed with brine (5 mL*3), dried over Na2SO4 and concentrated to give 2,2,2-trifluoro-1-(6-methoxynaphthalen-2-yl)ethyl methanesulfonate (420 mg, yield: 65%) as a white solid. ESI-MS (M+1)+: 335.1. 1HNMR (400 MHz, CDCl3) δ: 7.90 (s, 1H), 7.83-7.78 (m, 2H), 7.54 (d, J=8.0 Hz, 1H), 7.22 (dd, J=8.4, 2.4 Hz, 1H), 7.16 (s, 1H), 5.90 (q, J=6.4 Hz, 1H), 3.94 (s, 3H), 2.93 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]([N:9]=[N+]=[N-])[CH3:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[Cl:1][C:2]1[S:6][C:5]([CH:7]([NH2:9])[CH3:8])=[CH:4][CH:3]=1
Reactant: CC(N=[N+]=[N-])c1ccc(Cl)s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(N)c1ccc(Cl)s1
Temperature: 60 °C
Yield: 75.5 %

Procedure:
A mixture of 1-(5-chloro-2-thienyl)ethyl azide (991 mg, 5.3 mmol) and triphenylphosphine (1.4 g, 5.3 mmol) in THF (10 mL) and water (0.4 mL) was heated to 60° C. for 1 h. After cooling to rt, the solution was concentrated in vacuo. The resulting residue was purified by flash chromatography (90% DCM:10% methanol) to provide the desired 1-(5-chloro-2-thienyl)ethanamine (646 mg, 4.0 mmol, 75% yield) as a pink liquid. 1H NMR (400 MHz, CDCl3): 6.71 (d, 1H), 6.64 (d, 1H), 4.26 (q, 1H), 1.64 (br s, 2H), 1.44 (d, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([NH2:29])=[O:28])[CH2:22]2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][N:40]([C:43](=[O:45])[CH3:44])[CH2:39][CH2:38]2)=[CH:33][CH:32]=1.C[Si](Cl)(C)C>CCCCO>[C:43]([N:40]1[CH2:39][CH2:38][N:37]([C:34]2[CH:35]=[CH:36][C:31]([NH:30][C:2]3[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([NH2:29])=[O:28])[CH2:22]4)[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=3)=[CH:32][CH:33]=2)[CH2:42][CH2:41]1)(=[O:45])[CH3:44]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N4CCCC(C(N)=O)C4)nc(Cl)nc32)cc1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(N4CCCC(C(N)=O)C4)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Yield: 6.8 %

Procedure:
A mixture of 1-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-3-carboxamide (125 mg, 0.288 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (100 mg, 0.456 mmol) and trimethylsilyl chloride (0.100 mL, 0.79 mmol) in n-BuOH (3 mL) was stirred at 116° C. for 20 h. n-BuOH was removed in vacuo. The residue was purified by HPLC to give 1-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-3-carboxamide (12 mg).
Reaction SMILES: [CH2:1]([OH:10])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[CH2:11]([NH:15][C:16]#[N:17])[CH2:12][CH2:13][CH3:14]>>[CH2:11]([NH:15][C:16]1[O:10][CH:1]=[C:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:17]=1)[CH2:12][CH2:13][CH3:14]
Reactant: O=C(CO)c1ccccc1
Reactant: CCCCNC#N
Product: CCCCNc1nc(-c2ccccc2)co1

Procedure:
The procedure as described in Example 1 was followed using phenacyl alcohol and butylcyanamide. A colourless oil was obtained after distillation of the product.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-])=O.[H][H]>CO.[Pd]>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[NH2:1])[C:6]#[N:7]
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: N#Cc1ccc(N)c(N)c1
Yield: 90.1 %

Procedure:
After 4-amino-3-nitrobenzonitrile (3.26 g, 20 mmol) was treated with hydrogen in MeOH (300 mL) in the presence of 5% palladium on active carbon (1 g) at room temperature for 16 hours, the reaction mixture was filtered and the filtrate was concentrated to give 3,4-diaminobenzonitrile (2.4 g, 90% yield). A solution of 3,4-diaminobenzonitrile (2 g, 15 mmol) in THF (100 mL) was treated with carbonyldiimidazole (CDI, 3.2 g, 19 mmol) at room temperature for 18 hours. The mixture was diluted with EtOAc (150 mL), washed with 1N HCl (30 mL) and brine, and dried over MgSO4. Filtration and concentration gave 5-cyanobenzimidazolinone (1.9 g, 80%). 1H NMR (CD3OD) δ 7.40 (dd, J=8.1 Hz, J=1.5 Hz, 1H), 7.34 (d, J=1.5 Hz, 1H), 7.15 (d, J=8.1 Hz, 1H); MS: 160.1 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(=O)[C:16]1[C:17]([O:22][CH3:23])=[CH:18][CH:19]=[CH:20][CH:21]=1>CN1CCCC1=O>[C:1]1([N:7]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=[C:15]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: COc1ccccc1C(=O)Cl
Solvent: CN1CCCC1=O
Product: COc1ccccc1-c1nc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-phenyl-1,2-phenylenediamine (25 g, 0.136 mol) was dissolved in 100 ml N-methyl-2-pyrrolidinone (NMP) and o-anisoyl chloride (23.2 g, 0.136 mol) was then added to the solution at room temperature under nitrogen. The reaction mixture was stirred for 30 minutes at room temperature and then the temperature was increased to 220° C. for three hours during which time a white solid precipitated out of solution. After cooling, 150 ml of water was added to the reaction mixture and product was extracted with 300 ml of dichloromethane. The organic layer was washed with water and then dried with sodium sulfate. After removal of the solvents, the desired product o-(1-phenyl-2-benzimidazolyl) anisole was obtained.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:29]([OH:31])=O)[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:28])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1.C(N(CC)CC)C.[CH3:43][O:44][CH:45]1[CH2:50][CH2:49][N:48]([CH:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH2:47][CH2:46]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:28])[CH:21]=3)[C:29]([N:54]3[CH2:53][CH2:52][CH:51]([N:48]4[CH2:49][CH2:50][CH:45]([O:44][CH3:43])[CH2:46][CH2:47]4)[CH2:56][CH2:55]3)=[O:31])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Reactant: COC1CCN(C2CCNCC2)CC1
Solvent: CCN(CC)CC
Product: COC1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
Prepared analogously to Example 1i from 80 mg (0.17 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 77 μL (0.55 mmol) triethylamine and 46 mg (0.17 mmol) 4-methoxy-[1,4′]bipiperidinyl (used as the bis-hydrochloride salt).
Reaction SMILES: I[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]([F:28])([F:27])[C:17]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:25]([O:24][C:22]([C:20]1[N:19]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[N:18]=[C:17]([C:16]([F:27])([F:28])[F:15])[CH:21]=1)=[O:23])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(I)CC1
Reactant: CCOC(=O)c1cc(C(F)(F)F)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(C(F)(F)F)nn1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 39.9 %

Procedure:
tert-Butyl 4-iodopiperidine-1-carboxylate (5.683, 18.26 mmol, E.G. Corley et al, JOC, 2004, 69, 5120-5123) in DMF (30.7 ml) was added to a mixture of ethyl 3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (3.2 g, 15.37 mmol, M.-A. Plancquaert et al, Tetrahedron, 52, 4383-4396) and potassium carbonate 95.31 g, 38.4 mmol) and the mixture was stirred at 80° C. for 16 h. After cooling, water was added and the mixture was extracted with EtOAc, and the organic extraxts were dried, filtered and concentrated. Chromatographic purification of the residue by Biotage (5-20% EtOAc in Hexanes, 25M column) gave compound 93 as colorless oil (2.4 g, 39.9% yield). LRMS (ESI): calc. 391.4; found 414.1 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:25][CH2:24]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:33]3[CH:32]=[CH:31][C:30]([CH2:29][N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[CH:35][CH:34]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: CN1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(CN4CCN(C)CC4)cc3)c3cc(Br)cnc32)cc1

Procedure:
5-Bromo-3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (200 mg, 0.419 mmol), 1-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperazine (160 mg, 0.503 mmol) and dichlorobis(triphenylphosphine)palladium (II) (30 mg, 0.042 mmol) were combined in CH3CN (5 ml) and 1 M Na2CO3 (5 ml) and stirred at 60° C. for 2 hrs. EtOAc was added and the organic phase was washed with water, dried and evaporated.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13](=[O:20])[NH:12][C:11]2[CH:21]=[CH:22][CH:23]=[N:24][C:10]1=2)=[O:8].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]3[CH:21]=[CH:22][CH:23]=[N:24][C:10]2=3)=[O:8])[CH2:28][CH2:27]1
Reactant: O=C1Nc2cccnc2N(C(=O)CCCCCCl)c2ccccc21
Reactant: CN1CCNCC1
Product: CN1CCN(CCCCCC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 36 %

Procedure:
Using the procedure of Example 9, the product of Step A was reacted with 1-methyl-piperazine to obtain a 36% yield of 5,11-dihydro-11-[6-(4-methyl-1-piperazinyl)-caproyl]-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one melting at 179°-181° C. after crystallization from ethyl acetate.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:9][C:8]2[CH:7]=[C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:5]=[CH:4][C:3]1=2.Cl.[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C>[CH2:40]([O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]1[N:2]([CH3:1])[C:3]2[CH:4]=[CH:5][C:6]([N:17]([CH2:18][CH2:19][Cl:20])[CH2:21][CH2:22][Cl:23])=[CH:7][C:8]=2[N:9]=1)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCCCCCCCCCCCCCCCOC(=O)CCCc1nc2cc(N(CCCl)CCCl)ccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A 250 mL three neck round bottom flask was equipped with an overhead stirrer, thermocouple, temperature controller and nitrogen sweep then charged with 10.0 g (25.34 mmol) of bendamustine hydrochloride, 6.2 g (25.6 mmol, 1.01 eq) of hexadecanol, 5.3 g (25.6 mmol, 1.01 eq) of dicyclohexylcarbodiimide (DCC), 100 mL of MDC and 0.31 g (2.54 mmol, 0.1 eq) of DMAP. The reaction was stirred at room temperature overnight at which time an in process analysis indicated the reaction was complete. Solids were removed by vacuum filtration and washed with 25 mL of MDC. The filtrate was washed with saturated aqueous sodium bicarbonate solution (2×100 mL), DI water (1×100 mL) and brine (1×100 mL) before drying over sodium sulfate, filtering and concentrating to dryness in vacuo to an off-white solid. This solid was triturated with 25 mL of MDC and the solid impurities were removed by vacuum filtration and washed with 5 mL of MDC. The filtrate was concentrated to dryness in vacuo to yield 13.1 g (22.5 mmol, 88.8%) of the product as an off-white solid with an HPLC purity of 94.0A %. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J=8.76 Hz, 1H), 7.08 (d, J=2.32 Hz, 1H), 6.78 (dd, J=2.36, 8.72 Hz, 1H), 4.05 (t, J=6.8 Hz, 2H), 3.72 (m, 4H), 3.69 (s, 3H), 3.63 (m, 4H), 2.91 (t, J=7.4 Hz, 2H), 2.49 (t, J=7.08 Hz, 2H), 2.18 (m, 2H), 1.60 (m, 2H), 1.32 (m, 26H), 0.88 (t, J=6.68 Hz, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:6].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[I-].[K+]>C(Cl)(Cl)Cl>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:22]2[CH2:23][CH2:24][N:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=3)[CH2:20][CH2:21]2)[CH:8]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(CCCCl)c1cccnc1
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C(CCCN1CCN(c2ccccn2)CC1)c1cccnc1
Yield: 44.1 %

Procedure:
A solution of 4-chloro-1-(3-pyridinyl)-1-butanone (Example B) (9 g, 0.049 mol), 1-(2-pyridinyl)piperazine (24 g, 0.147 mol), and potassium iodide (0.8 g, 0.005 mol) is heated to 120° C. for 5 minutes. The residue is taken up in chloroform (40 mL) and the precipitate is filtered. The filtrate is evaporated in vacuo and purified by column chromatography (silica gel, 2% methanol/dichloromethane). The major product is crystallized from 2-propanol/diethyl ether to give 6.7 g 1-(3-pyridinyl)-4-[4-(2-pyridinyl)-1-piperazinyl]-1-butanone as a white solid; mp 89° C.
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]([NH:5][CH2:6][CH2:7][NH:8][C:9]([C:11]1[N:16]=[C:15]([CH2:17][N:18]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[CH:14]=[C:13]([C:41]2[C:46]([O:47][CH3:48])=[CH:45][C:44]([O:49][CH3:50])=[CH:43][C:42]=2[O:51][CH3:52])[CH:12]=1)=[O:10])=[O:4]>FC(F)(F)C(O)=O>[N:18]1([CH2:17][C:15]2[N:16]=[C:11]([C:9]([NH:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:53])([F:1])[F:54])=[O:10])[CH:12]=[C:13]([C:41]3[C:42]([O:51][CH3:52])=[CH:43][C:44]([O:49][CH3:50])=[CH:45][C:46]=3[O:47][CH3:48])[CH:14]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: COc1cc(OC)c(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)CC3)nc(C(=O)NCCNC(=O)C(F)(F)F)c2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(-c2cc(CN3CCNCCNCC3)nc(C(=O)NCCNC(=O)C(F)(F)F)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 17 (1.0 g; 1.3 mmol) was dissolved in trifluoroacetic acid (25 mL) and the mixture was stirred at room temperature for 30 min. Solvent was evaporated to dryness. ESI-MS: [M+H]+ 569.28 calc. for C26H36F3N6O5+ 569.27.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: OCC1CCCCO1
Product: N=C(OCC1CCCCO1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and 2-hydroxymethyl-tetrahydropyran, there is obtained 2-tetrahydro-2H-pyranylmethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 336 (30), 237 (78), 194 (100), 99 (60);
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1)=[O:7].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:11]2[N:10]=[N:9][C:8]([C:6](=[O:7])[NH:5][CH2:4][CH2:3][CH:2]([CH3:15])[CH3:1])=[CH:13][CH:12]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazine-1-carboxylic acid t-butyl ester, the title compound was obtained as a white solid (83% yield). 1H NMR (500 MHz, CDCl3) δ 8.03, 7.86, 6.97, 3.75, 3.56-3.63, 3.49, 1.65-1.76, 1.52, 0.94. MS (ES+) m/z 378 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6](=[O:12])[C:7]([CH3:11])([CH3:10])[CH2:8][F:9].[Br:18]Br.O>C(Cl)(Cl)Cl>[Br:18][CH:5]([O:4][C:3]1[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:2]=1[Cl:1])[C:6](=[O:12])[C:7]([CH3:11])([CH3:10])[CH2:8][F:9]
Reactant: BrBr
Reactant: CC(C)(CF)C(=O)COc1ccc(Cl)cc1Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(CF)C(=O)C(Br)Oc1ccc(Cl)cc1Cl
Yield: 80.7 %

Procedure:
199.5 g (0.71 mol) of 1-(2,4-dichlorophenoxy)-3,3-dimethyl-4-fluoro-2-butanone were dissolved in 500 ml of chloroform and 114 g (0.71 mol) of bromine were added dropwise at 20° to 30° C., while stirring and cooling. The mixture was subsequently stirred at 20° C. for 2 hours, 200 ml of water were carefully added to the chloroform phase was washed several times with ice-water and dried over sodium sulphate. After distilling off the solvent in vacuo, 205.2 g (78% of theory) of 1-bromo-1-(2,4-dichlorophenoxy)-3,3-dimethyl-4-fluoro-2-butanone were obtained as an oil which was further reacted directly. ##STR83##
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4](=[O:16])[CH:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1B(O)O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4](=[O:16])[CH:3]=1
Reactant: OB(O)c1cc(Cl)ccc1Br
Reactant: CC(C)(C)OC(=O)Cn1ccc(Br)cc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)Cn1ccc(-c2cc(Cl)ccc2Br)cc1=O

Procedure:
3.8 g (12 mmol) of tert-butyl (4-bromo-2-oxopyridin-1(2H)-yl)acetate and 3.4 g (14.4 mmol) of 2-bromo-5-chlorophenylboronic acid in the presence of tetrakis(triphenylphosphine)palladium(0) were reacted according to General Method 2A. Yield: 3.9 g (purity 94%, 76% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.Br[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH2:27][CH2:28][N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: BrCCN1CCOCC1
Reactant: NC(=O)c1sc(-n2cnc3ccc(O)cc32)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)c1sc(-n2cnc3ccc(OCCN4CCOCC4)cc32)nc1-c1cccc(Cl)c1

Procedure:
To a mixture of 0.037 (0.1 mmole) of 4-(3-chloro-phenyl)-2-(6-hydroxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.25d), 0.039 g (0.2 mmole) of 4-(2-bromo-ethyl)-morpholine and 1 mL of dimethylformamide was added 0.16 g (0.5 mmole) of cesium carbonate. The mixture was heated at 100 degrees for 3 hours. The mixture was cooled, the solid was removed by filtration and the filtrate purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 30:70-100:0) to give 0.014 g of 4-(3-chloro-phenyl)-2-[6-(2-morpholin-4-yl-ethoxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.26) as a white powder. MH+/Z=484