Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:12])=[CH:8][C:9]=2[Cl:11])[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:18](N(CC)CC)C.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.C(OCC)(=O)C>C(Cl)Cl>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](=[O:31])[CH2:18][NH:1][C:2]2[C:10]3[C:5](=[CH:6][C:7]([Cl:12])=[CH:8][C:9]=3[Cl:11])[NH:4][C:3]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
Dissolve 3-amino-2-carbethoxy-4,6-dichloroindole (2.2 g, 8 mmol) in methylene chloride (70 mL) and add triethylamine (1.16 mL, 8 mmol) followed by p-chlorobenzoyl chloride (0.976 mL, 8 mmol). Stir the reaction48 hours at room temperature. Dilute the reaction with ethyl acetate (300 mL), wash with water (100 mL), dry the organic phase over magnesium sulfate, filter and concentrate in vacuo. Recrystallize the residue from ethyl acetate/hexane to yield the title compound as a fluffy solid (2.7 g,79%).
Reaction SMILES: [OH:1][C:2]1[C:15]([OH:16])=[C:14](O)[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].[C:37](=[O:40])([O-])[O-].[K+].[K+].Cl>C(Cl)(Cl)Cl.CN(C=O)C>[CH2:19]([O:1][C:2]1[C:15]([O:16][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])=[C:14]([O:40][CH2:37][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: O=C([O-])[O-]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: O=C(c1ccccc1)c1ccc(O)c(O)c1O
Agent: Cl
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)c2ccccc2)c(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Temperature: 80 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To 2,3,4-trihydroxybenzophenone (1.60 g, 6.95 mmol) was added DMF (30 ml), 1-bromooctadecane (7.3 g, 21.9 mmol) and potassium carbonate (4.32 g, 31.3 mmol), and the mixture was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature, chloroform (100 ml) was added, and 1N hydrochloric acid (30 ml) was further added dropwise. After stirring, the mixture was partitioned, and the organic layer was washed with 1N hydrochloric acid (30 ml) and water (30 ml). The organic layer was evaporated under reduced pressure, and the residue was washed with methanol (30 ml). The obtained precipitate was slurry washed with methanol (45 ml) to give 2,3,4-trioctadecanoxybenzophenone (6.35 g, 6.43 mmol, yield 93%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:9]#[N:10].[C:11]([OH:20])(=[O:19])[CH:12]([CH:14]([C:16]([OH:18])=[O:17])[OH:15])[OH:13]>CO>[C:16]([CH:14]([CH:12]([C:11]([O-:20])=[O:19])[OH:13])[OH:15])([O-:18])=[O:17].[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[C:9]#[N:10]
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: N#CC1CC2CCN1CC2
Solvent: CO
Product: N#C[C@H]1CC2CCN1CC2
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Reaction time: 1.5 h
Yield: 20 %

Procedure:
In the same manner as in a document (Mi, Y.; Corey, E. J. Tetrahedron Lett. 2006, 47, 2515-2516), optical resolution by a diastereomer salt method was performed to synthesis the title compound. That is, to a solution of 1-azabicyclo[2.2.2]octane-2-carbonitrile (20.0 g) in methanol (100 mL) was slowly added a solution of (+)-tartaric acid (22.0 g) in methanol (100 mL) at 0° C. The reaction system was stirred for 90 min, and concentrated, and the obtained solid was crystallized 4 times from methanol. The precipitate was filtered off, and the filtrate was concentrated. To the residue was added water (150 mL), and sodium hydrogen carbonate was added to reach pH 8. The mixture was extracted with dichloromethane (200 mL×3), and the extract was washed with brine, dried, and concentrated. The obtained white solid (15.0 g) was dissolved in methanol (100 mL), and a solution of (−)-tartaric acid (16.5 g) in methanol (100 mL) was slowly added at 0° C. The reaction system was stirred for 90 min, and concentrated, and the obtained solid was crystallized 4 times from methanol to give (−)-tartrate of (2R)-1-azabicyclo[2.2.2]octane-2-carbonitrile (4.0 g, >90% ee). To the obtained solid was added water (50 mL), and sodium hydrogen carbonate was added to reach pH 8. The mixture was extracted with dichloromethane (100 mL×3), and the extract was washed with brine, dried, and concentrated. The obtained white solid (1.75 g) was dissolved in concentrated hydrochloric acid (50 mL), and the reaction mixture was heated under reflux overnight. After concentration, to the residue was slowly added a solution of sodium hydroxide (1.04 g) in water (10 mL) at 0° C. The mixture was concentrated, concentrated hydrochloric acid (5 mL) was added, and the mixture was concentrated again. The obtained white solid was extracted with methanol (10 mL). Insoluble material was filtered off, and the filtrate was concentrated to give the title compound (0.80 g).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:18]=[C:17]([Cl:19])[C:16]3[N:15]([CH3:20])[C:14]4[CH2:21][CH:22]5[NH:26][CH:25]([C:13]=4[C:12]=3[C:11]=2C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>>[ClH:19].[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([Cl:19])[CH:18]=2)[N:15]([CH3:20])[C:14]2[CH2:21][CH:22]4[NH:26][CH:25]([C:13]3=2)[CH2:24][CH2:23]4)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccccc4)cc(Cl)c31)C1CCC(C2)N1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: Cn1c2c(c3cc(S(=O)(=O)c4ccccc4)cc(Cl)c31)C1CCC(C2)N1

Procedure:
The product of step F was subjected to Boc-deprotection with TFA following the procedure of Example 28, step B. The crude free base was purified by flash column chromatography (SiO2, 90:9:1 dichloromethane/methanol/ammonium hydroxide) and the product treated directly with 1.25 M HCl in methanol. The solution was concentrated in vacuo to give 2-phenylsulfonyl-4-chloro-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (123 mg, 97%, HPLC, AUC >99%.) as a white solid: mp 258-264° C. dec; 1H NMR (DMSO-d6, 300 MHz): δ 9.70 (br s, 1H), 9.20 (br s, 1H), 8.38 (d, J=1.2 Hz, 1H), 7.94-8.02 (m, 2H), 7.58-7.69 (m, 4H), 5.37 (d, J=3.3 Hz, 1H), 4.42-4.57 (m, 1H), 3.82 (s, 3H), 3.30-3.40 (m, 1H), 3.00 (d, J=12.6 Hz, 1H), 2.20-2.33 (m, 2H), 2.03-2.12 (m, 1H), 1.73-1.86 (m, 1H); ESI MS m/z 387 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[C:5]([N:7]([CH3:19])[C@@H:8]([C:16](O)=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].[OH-].[Li+].C(O)C.Cl.C[O:31][C:32](=[O:42])[C@H:33]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH2:34]>CO.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[C:5]([N:7]([CH3:19])[C@@H:8]([C:16]([NH:34][C@H:33]([C:32]([OH:31])=[O:42])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: Cc1cc(C)cc(C(=O)N(C)[C@H](Cc2ccccc2)C(=O)O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Solvent: O
Product: Cc1cc(C)cc(C(=O)N(C)[C@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)O)c1

Procedure:
Coupling of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-phenylalanine (derived from the corresponding methylester described in example 78 by hydrolysis with lithium hydroxide in methanol/water: [a]D =+88° (c=1.0, ethanol)) with (L)-phenylalanine methyl ester hydrochloride according to example 1 followed by hydrolysis of the methyl ester moiety according to example 12 gives N-(3,5-dimethylbenzoyl)-N-methyl-(D)-phenylalanyl-(L)-phenylalanine; FAB-MS m/e 457 (M-H)-.
Reaction SMILES: [C:1]([NH:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[C@@H:18]([O:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:17]2)=[C:9](N)[N:8]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(ON=O)CCCC.[I:43]CI.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[C:1]([NH:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[C@@H:18]([O:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:17]2)=[C:9]([I:43])[N:8]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Nc1nc(N)c2ncn([C@H]3C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O3)c2n1
Reactant: ICI
Agent: CCCCCON=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1nc(I)c2ncn([C@H]3C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O3)c2n1
Temperature: 60 °C
Yield: 34.4 %

Procedure:
2-isobutyrylamino-6-amino-9-(2-deoxy-3,5-di-O-isobutyryl-β-D-ribofuranosyl]purine (17) [Babara L. Gaffney, Luis A. Marky and Roger A. Jones, Tetrahedron, 40, 3-13 (1984)] 2.38 g (5 mmol) was heated at 60° C. under argon atmosphere. n-pentylnitrite 13.5 ml (0.10 mol) and diiodomethane 25 ml (0.31 mol) were rapidly added and suspended. The mixture was irradiated by visible light using 200 W halogen tungsten lump at the distance from light source 2 cm for 3 hours under well stirring at 60° C. To the reaction mixture, saturated aqueous sodium sulfite 30 ml was added and stirred at room temperature for 3 hours. Thereafter, saturated aqueous sodium sulfite 120 ml and chloroform 150 ml were added to separate the layers. The aqueous layer was extracted twice with chloroform. The thus obtained organic layer was dried with anhydrous magnesium sulfate and concentrated. The residue was purified by short column (developer: ethyl acetate:dichloromethane=1:4) to obtain the product (18) 1.01 g (1.72 mmol) (34.4%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]=O)=[CH:2]1.Cl.[NH2:13][OH:14]>N1C=CC=CC=1.C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]=[N:13][OH:14])=[CH:2]1
Reactant: O=Cc1csc2ccccc12
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=Cc1csc2ccccc12
Yield: 98.6 %

Procedure:
Benzothiophene-3-carbaldehyde (4.0 g, 24.6 mmol) was dissolved in a mixture of pyridine (25 ml) and ethanol (25 ml). Hydroxylamine hydrochloride (3.4 g, 49.2 mmol) was added, while stirring. The mixture was stirred for 30 minutes at RT and then heated under reflux for eight hours. A red-brown solution formed. For working up, the solution was concentrated and the residue was freed from residual pyridine by distillation with ethanol (3×50 ml). Water (50 ml) was added to the oily residue and the mixture was stirred vigorously overnight. The pink solid present was filtered off with suction, washed with water and dried in vacuo. 4.3 g benzothiophene-3-carbaldehyde oxime were obtained (m.p. 87-89° C.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[OH:11])[S:7][C:6]=2[C:14]=1[Cl:15].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)CC>[Cl:1][C:2]1[C:3]([O:16][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([OH:11])([CH3:13])[CH3:12])[S:7][C:6]=2[C:14]=1[Cl:15]
Reactant: CC(C)(O)c1cc2cc(O)c(Cl)c(Cl)c2s1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cc2cc(C(C)(C)O)sc2c(Cl)c1Cl

Procedure:
To a mixture of 6,7-dichloro-5-hydroxy-α,α-dimethylbenzo[b]thiophene-2-methanol in 250 ml of 2-butanone is added a solution of 7.7 g of t-butyl bromoacetate in 50 ml 2-butanone and the resultant mixture is placed in a preheated oil-bath at 95°. To the mixture is added 6.7 g of potassium carbonate and 3 ml of dimethylformamide and the reaction mixture is refluxed at 95° for 21/2 hrs. The cooled mixture is filtered and 100 ml of water is added. The layers are separated and the aqueous phase is extracted two times with ethyl ether. The organic extracts are washed, dried over anhydrous magnesium sulfate, filtered and concentrated to give a solid. Recrystallization from ethyl ether and pentane gives 11.5 g of t-butyl [[6,7-dichloro-2-(1-hydroxy-1-methylethyl)benzo[b]thien-5-yl]oxy]acetate, mp 137°-138°.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=1)([O-])=O.[H-].[Na+].[CH3:15]I>C1COCC1.CO.[Pd]>[CH3:15][N:8]1[C:7]2[CH:11]=[CH:12][C:4]([NH2:1])=[CH:5][C:6]=2[N:10]=[CH:9]1.[CH3:15][N:10]1[C:6]2[CH:5]=[C:4]([NH2:1])[CH:12]=[CH:11][C:7]=2[N:8]=[CH:9]1
Reactant: CI
Reactant: O=[N+]([O-])c1ccc2nc[nH]c2c1
Agent: [Pd]
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cnc2cc(N)ccc21
Product: Cn1cnc2ccc(N)cc21
Reaction time: 12 h
Yield: 21 %
Yield: 11 %

Procedure:
A solution of 5-nitrobenzimidazole (3.0 g, 18.4 mmol) in 100 ml of THF was stirred with NaH (2.7 g, 36.8 mmol) for 0.5 h at 25° C. To the solution was added methyl iodide (2.0 ml, 20.3 mmol) and resulting mixture was stirred for 12 h. The reaction mixture was concentrated in vacuo to provide an oil, which was dissolved in 200 ml of MeOH and stirred with 0.3 g of 10% Pd/C under H2 for 12 h. The reaction mixture was filtered and concentrated in vacuo, yielding a dark oily residue which was subjected to column chromatography (3% MeOH/CHCl,) to provide 0.69 g (3.9 mmol, 21%) of 1-methyl-5-aminobenzimidazole and 0.36 g (2.0 mmol, 11%) of 3-methyl-5-aminobenzimidazole.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:16](=[O:22])[CH2:17]C(OC)=O)[CH:8]=[C:9]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)[CH:10]=1)=[O:4].CO.S(=O)(=O)(O)O.C(OCC)(=O)C>O>[C:16]([C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)[CH:8]=1)[C:3]([O:2][CH3:1])=[O:4])(=[O:22])[CH3:17]
Reactant: COC(=O)CC(=O)c1cc(C(=O)OC)cc(-n2cccc2)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(C(C)=O)cc(-n2cccc2)c1
Temperature: 25 °C
Yield: 24.9 %

Procedure:
A solution of methyl 3-[3-methoxycarbonyl-5-(pyrrol-1-yl)phenyl]-3-oxopropionate (0.1 g) in a mixture of water (1 ml), methanol (3 ml) and concentrated sulfuric acid (40 mg) was refluxed for 16 hours. After being cooled to room temperature, the reaction mixture was poured into a mixture of ethyl acetate (50 ml) and water (50 ml). The organic layer was successively washed with a saturated aqueous sodium hydrogencarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo to afford methyl 3-acetyl-5-(pyrrol-1-yl)benzoate (20.1 mg).
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@:3]1([CH2:19][OH:20])[O:4][C@H:5]2[N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:18].C[Si](Cl)(C)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.N>N1C=CC=CC=1>[OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@:3]1([CH2:19][OH:20])[O:4][C@H:5]2[N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH:18][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@@]2(CO)CO[C@@H]1[C@@H]2O
Agent: C[Si](C)(C)Cl
Agent: N
Solvent: c1ccncc1
Product: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@@]2(CO)CO[C@@H]1[C@@H]2O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of nucleoside 61A (0.32 g, 1.15 mmol) in anhydrous pyridine (1 cm3) was added trimethylsilyl chloride (0.73 cm3, 5.73 mmol) and the mixture was stirred at room temperature for 20 min. Benzoyl chloride (0.67 cm3, 5.73 mmol) was added at 0° C., and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0° C. and ice-cold water (15.0 cm3) was added. After stiffing for 5 min, a 32% (w/w) aqueous solution of ammonia (1.5 cm3) was added and the mixture was stirred for 30 min. The mixture was evaporated to dryness and the residue was dissolved in water (25 cm3). After evaporation of the mixture under reduced pressure, the residue was purified by silica gel chromatography using dichloromethane/methanol (97:3, v/v) as eluent to give nucleoside 61B as a white solid material (0.55 g). FAB-MS m/z 384 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.C([Li])(C)(C)C.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=1)[CH2:19][N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1>C(OCC)C>[Cl:8][C:4]1[CH:3]=[C:2]([C:23]2([OH:26])[CH2:22][CH2:21][N:20]([CH2:19][C:18]3[CH:27]=[CH:28][CH:29]=[C:16]([O:15][CH3:14])[CH:17]=3)[CH2:25][CH2:24]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cccc(Br)c1
Reactant: COc1cccc(CN2CCC(=O)CC2)c1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: COc1cccc(CN2CCC(O)(c3cccc(Cl)c3)CC2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To 1-bromo-3-chlorobenzene (480 mg, 2.51 mmol) in diethyl ether (10 mL), at −78° C., was added t-butyllithium (3.0 mL of a 1.7 M solution in hexanes, 5.0 mmol) dropwise. After 1 h, a solution of 1-(3-methoxybenzyl)piperidin-4-one (500 mg, 2.28 mmol) in diethyl ether (5 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 0.5 h, warmed to ambient temperature and quenched with saturated ammonium chloride. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (10% ethyl acetate/methylene chloride to ethyl acetate) gave 4-(3-chlorophenyl)-1-(3-methoxybenzyl)piperidin-4-ol (668 mg, 80%) as an oil: 1H NMR (CDCl3, 300 MHz) δ 7.53-7.52 (m, 1H), 7.40-7.36 (m, 1H), 7.30-7.20 (m, 3H), 6.96-6.93 (m, 2H), 6.82-6.79 (m, 1H), 3.82 (s, 3H), 3.58 (s, 2H), 2.82-2.70 (m, 2H), 2.49-2.41 (m, 2H), 2.18-2.08 (m, 2H), 1.73-1.67 (m, 2H), 1.60 (s, 1H).
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([O:20][CH:21]3[CH2:26][CH2:25][N:24]([S:27]([CH:30]=[CH2:31])(=[O:29])=[O:28])[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:5]=2[N:4]=1.[CH3:39][S:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:42])=[O:41]>>[F:38][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:9]=[C:10]([O:20][CH:21]3[CH2:22][CH2:23][N:24]([S:27]([CH2:30][CH2:31][N:46]4[CH2:47][CH2:48][N:43]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:44][CH2:45]4)(=[O:29])=[O:28])[CH2:25][CH2:26]3)[N:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:13]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:5]=2[N:4]=1
Reactant: C=CS(=O)(=O)N1CCC(Oc2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Reactant: CS(=O)(=O)N1CCNCC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(OC2CCN(S(=O)(=O)CCN3CCN(S(C)(=O)=O)CC3)CC2)nc(N2CCOCC2)n1
Yield: 28 %

Procedure:
Reaction of 2-(difluoromethyl)-4-methoxy-1-(4-(4-morpholinyl)-6-{[1-(vinylsulfonyl)-4-piperidinyl]oxy}-1,3,5-triazin-2-yl)-1H-benzimidazole with 1-(methylsulfonyl)piperazine as in Example 12 gave 2-(difluoromethyl)-4-methoxy-1-[4-{[1-({2-[4-(methylsulfonyl)-1-piperazinyl]ethyl}sulfonyl)-4-piperidinyl]oxy}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole in 28% yield: mp (MeOH) 251-254° C.; 1H NMR (DMSO-d6) δ 7.96 (d, J=8.3 Hz, 1H), 7.71 (t, JHF=52.8 Hz, 1H), 7.45 (t, J=8.3 Hz, 1H), 6.99 (d, J=7.9 Hz, 1H), 5.28-5.22 (m, 1H), 3.98 (s, 3H), 3.85-3.84 (m, 4H), 3.74-3.70 (m, 4H), 3.52-3.46 (m, 2H), 3.34-3.20 (m, 4H), 3.13-3.11 (m, 4H), 2.86 (s, 3H), 2.78-2.74 (m, 2H), 2.56-2.54 (m, 4H), 2.13-2.08 (m, 2H), 1.88-1.80 (m, 2H); Anal. Calcd. for C28H39F2N9O7S2: C, 47.0; H, 5.5; N, 17.6. Found: C, 47.2; H, 5.4; N, 17.4%.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[Br:21]N1C(=O)CCC1=O>C(#N)C.CCOC(C)=O>[F:20][C:2]([F:1])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:21])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Reaction time: 8 h
Yield: 97.3 %

Procedure:
A solution of N-trifluoroacetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1.25 g, 4.35 mmol) in acetonitrile (40 mL) was treated with N-bromosuccinimide (0,852 g, 4.79 mmol) and stirred overnight at 20 C. The product mixture was diluted with EtOAc (200 mL), washed with saturated aqueous sodium bisulfite (100 mL) and brine (100 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 1.55 g of a clear oil. 1H NMR (400 MHz, CDCl3, mixture of rotamers) d 7.34 (s, 1 H), 6.65 (m, 1 H), 3.87 (s, 3 H), 3.8) (m, 1 H), 3.55 (m, 1.3 H), 3.37 (m, 0.7 H), 3.2-2.9 (bm, 4 H), 1.30 (m, 3 H). MS calculated for C14H15BrF3NO2+H: 366, observed: 366.
Reaction SMILES: Cl.[F:2][C:3]([F:28])([F:27])[C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22]3)[C:6]=2[CH:5]=1.[C:29](Cl)(=[O:40])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>>[F:28][C:3]([F:27])([F:2])[C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH:23]([O:26][C:29](=[O:40])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:22]3)[C:6]=2[CH:5]=1
Reactant: OC1CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)C1
Reactant: CCCCCCCCCCC(=O)Cl
Agent: Cl
Product: CCCCCCCCCCC(=O)OC1CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)C1

Procedure:
According to the procedure of Example 5, 10.8 g of 2-trifluoromethyl-10-[3-(3-hydroxypyrrolidino)-propyl]-phenothiazine.hydrochloride and 6.2 g of undecanoylchloride were subjected to the reaction, to object the object as the free base. (Yield: 11.2 g)