Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C[Si]([C:10]#[CH:11])(C)C.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[Cl-].N>O1CCCC1.CCCCCC>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][C:21]([C:10]#[CH:11])([OH:25])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: N
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#CC1(O)CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 71.1 %

Procedure:
In a dry ice-acetone bath, 40 ml of a 1.6 M hexane solution of n-butyllithium was added dropwise to a solution of 6.07 g of trimethylsilylacetylene in 100 ml of tetrahydrofuran. After the temperature was once elevated to 0° C., the mixture was cooled again in a dry ice-acetone bath and a solution of 5.97 g of 1-tert-butoxycarbonylpiperidin-3-one in 50 ml of tetrahydrofuran was added dropwise thereto. After 1 hour, aqueous ammonia chloride was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then evaporated. The residue was purified by silica gel column chromatography with 30% ethyl acetate/hexane. To the resulting compound were added 10 g of anhydrous potassium carbonate and 100 ml of methanol, followed by stirring for 2 hours. Water was added thereto, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated, to give 4.8 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:19])=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]1[CH:12]=[C:13]([C:16]([NH2:18])=O)[CH:14]=[CH:15][C:7]1=[N:6]2.P(Cl)(Cl)(Cl)=O.C(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([CH3:19])=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]1[CH:12]=[C:13]([C:16]#[N:18])[CH:14]=[CH:15][C:7]1=[N:6]2
Reactant: Cc1sc(C)c2c(=O)n3cc(C(N)=O)ccc3nc12
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1sc(C)c2c(=O)n3cc(C#N)ccc3nc12

Procedure:
1,3-Dimethyl-10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxamide (Example 50), 0.6 g (0.0022 mol), in 10 ml of pyridine, 25 ml of phosphorus oxychloride and 25 ml of chloroform is refluxed on a steam bath for two hours. The solvents are evaporated in vacuo and the residue is treated with 100 ml of water. The resulting precipitate is filtered to give 0.3 g of 1,3-dimethyl-10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carbonitrile with methanol (1:0.125); mp 242°-244° C. after recrystallization from methanol.
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.C[CH2:14][C:15]([CH2:20][O:21][CH2:22][CH:23]=[CH2:24])(CO)CO.[C:25]([OH:30])(=[S:29])[CH:26]([CH3:28])[OH:27]>CO.C1(C)C=CC=CC=1.CCCCCC>[CH2:20]([O:21][CH2:22][CH:23]=[CH2:24])[CH:15]=[CH2:14].[C:25]([OH:30])(=[S:29])[CH:26]([CH3:28])[OH:27]
Reactant: C=CCOCC(CC)(CO)CO
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CC(O)C(O)=S
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CO
Product: C=CCOCC=C
Temperature: 90 °C
Reaction time: 1 h

Procedure:
AIBN (1.5 g) was dissolved in trimethylolpropane monoallyl ether (497 g, 2.86 mol). This solution was slowly added, under nitrogen with stirring, to thiolactic acid (300 g, 2.83 mol) at such a rate that the temperature of the exothermal reaction was kept at 80° C. When the addition was completed, the temperature was raised to 90° C. and kept at 90° C. for 1 h. The product had 1H-NMR (CDCl3): δ 1.11 (t, 3H, CH3CH2), 1.53 (q, 2H, CH3CH2), 2.00-2.20 (m, 2H, CH2CH2CH2), 2.98-3.06 (m, 2H, 3.65-4.02 (m, 9H); and is soluble in methanol and toluene, not soluble in hexane.
Reaction SMILES: CN1CCOCC1.Cl.[CH3:9][O:10][C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13].C1C=CC2N(O)N=NC=2C=1.[C:26]([NH:33][C@@H:34]([C:39](O)=[O:40])[CH2:35][CH2:36][S:37][CH3:38])([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>CN(C=O)C>[NH:33]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:34]([C:39]([NH:13][C@H:12]([C:11]([O:10][CH3:9])=[O:15])[CH3:14])=[O:40])[CH2:35][CH2:36][S:37][CH3:38]
Reactant: COC(=O)[C@H](C)N
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)NC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
N-methylmorpholine (5.6 g), L-alanine methyl ester hydrochloride (3.9 g), HOBt (4.6 g) and 1-(3-dimethlylaminopropyl)-3-ethylcarbodiimide (5.3 g) was added to a solution of Boc-(D)-Methionine (7 g, 0.028 mol) in dry DMF (50 ml). The mixture was stirred overnight. Solvent was removed by evaporation and the residue was partitioned between dichloromethane (100 ml) and 5% aqueous acetic acid (5 ml). On standing HOBt crystallised and was removed by filtration, and the organic layer was separated and washed with aqueous sodium bicarbonate, dried (MgSO4) and evaporated. The residue (8.5 g) was purified by flash chromatography in a sinter funnel eluting with a mixture of dichloromethane and ether (0% to 100% ether). The fractions containing product were combined and evaporated to give Boc-(D)-Met-(L)-Ala-OMe (7.2 g) as a gum which crystallised on standing; NMR (CDCl3): 1.4 (d, 3H), 1.45 (s, 9H), 1.95 (m, 1H), 2.1 (s, 3H), 2.1 (m, 1H), 2.6 (m, 2H), 3.75 (s, 3H), 4.3 (bs, 1H), 4.6 (m, 1H), 5.3 (m, 1H), 6.9 (bs, 1H).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14](/[C:17](=[CH:21]\[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)/[C:18](O)=[O:19])=[CH:13][CH:12]=1.CO>C1(C)C=CC=CC=1>[Br:10][C:11]1[CH:12]=[CH:13][C:14](/[C:17](=[CH:21]\[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)/[CH2:18][OH:19])=[CH:15][CH:16]=1
Reactant: O=C(O)/C(=C/C1CCCCC1)c1ccc(Br)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: OC/C(=C/C1CCCCC1)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 18 h
Yield: 98.4 %

Procedure:
Add DIBAL in toluene (673 mL, 1.0 M, 673 mmol) to a solution of (E)-2-(4-bromo-phenyl)-3-cyclohexyl-acrylic acid (52 g, 168 mmol) in toluene (1.6 1) maintained at −78° C. Then allow the reaction mixture to slowly warm to room temperature, and stir, it for 18 h. Cool reaction mixture to 0° C. and add MeOH to destroy excess amounts of DIBAL. Add Rochelle's salt (100 mL) and HCl (2 N). Separate the layers and wash the organic layer with brine. Filter through hydrophobic filter and concentrate to obtain the title compound (48.8 g) as a white solid. MS (m/e): 277 (M+H−H2O).
Reaction SMILES: C([O:9][N:10]1[CH2:13][CH:12]([NH:14][C:15](=[O:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]1=[O:24])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[OH:9][N:10]1[CH2:13][CH:12]([NH:14][C:15](=[O:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]1=[O:24]
Reactant: O=C(Cc1ccccc1)NC1CN(OC(=O)c2ccccc2)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(Cc1ccccc1)NC1CN(O)C1=O

Procedure:
The N-benzoyloxy-3-(phenylacetylamino)-2-azetidinone is subjected to solvolysis with sodium carbonate in aqueous methyl alcohol by following the conditions described by Example 3 to provide the title compound.
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27]O)=[CH:23][CH:22]=3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1.[CH2:31]([N:33](CC)[CH2:34][CH3:35])[CH3:32].N1CC=CC1>C(Cl)Cl.CN(C=O)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][N:33]4[CH2:34][CH:35]=[CH:32][CH2:31]4)=[CH:23][CH:22]=3)=[N:17][CH:18]=2)=[CH:11][CH:12]=1
Reactant: OCCOc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Reactant: CCN(CC)CC
Agent: C1=CCNC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN4CC=CC4)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
23 μL (0.29 mmol) methanesulphonic acid chloride are added dropwise to a solution, cooled to 0° C., of 85 mg (0.24 mmol) 2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethanol and 41 μL (0.29 mmol) triethylamine in 10 mL DCM and the reaction mixture is stirred for 1 h at this temperature. 46 μL (0.58 mmol) 2,5-dihydro-1H-pyrrole are added dropwise, the mixture is heated to RT and stirred overnight. 1 mL of DMF is added and the mixture is heated for 8 h to 70° C. The mixture is evaporated down i. vac., the residue is combined with water, extracted exhaustively with EtOAc and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography on silica gel (EtOAc/MeOH/NH3 95:5:0.5).
Reaction SMILES: [C:1]1(=[O:29])[N:5]([CH2:6][C@H:7]([OH:23])[CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[C:12]([F:22])[CH:11]=2)[C:4](=[O:24])[C:3]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]12.[C:30](C1NC=CN=1)(C1NC=CN=1)=[O:31]>C(Cl)Cl>[F:22][C:12]1[CH:11]=[C:10]([N:9]2[CH2:8][C@H:7]([CH2:6][N:5]3[C:4](=[O:24])[C:3]4=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]4[C:1]3=[O:29])[O:23][C:30]2=[O:31])[CH:15]=[CH:14][C:13]=1[N:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H](O)CNc1ccc(N2CCOCC2)c(F)c1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reaction time: 20 h
Yield: 79.1 %

Procedure:
N-[3-pthalimido-2-(R)-hydroxypropyl]-3-fluoro-4-(morpholinyl)aniline (57 gm) is dissolved in methylene dichloride (600 ml), carbonyl diimidazole (32 gm) is added at ambient temperature and the reaction mixture is stirred for 20 hours. The reaction mass is washed with water and methylene dichloride is distilled to give 48 gm of (S)-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide as solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([CH2:13]Br)[CH2:12][CH2:11]1.Cl.[Cl:16][C:17]1[C:18]([F:48])=[C:19]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:46][CH3:47])=[C:31]([CH2:34][N:35]([CH3:45])[C:36]4([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[CH:32]=3)[N:27]=[CH:26][N:25]=2)[CH:20]=[CH:21][CH:22]=1>CN(C)C=O>[Cl:16][C:17]1[C:18]([F:48])=[C:19]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:46][CH3:47])=[C:31]([CH2:34][N:35]([CH3:45])[C:36]4([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][N:39]([CH2:13][CH:10]5[CH2:12][CH2:11]5)[CH2:38][CH2:37]4)[CH:32]=3)[N:27]=[CH:26][N:25]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCNCC1
Reactant: BrCC1CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCN(CC2CC2)CC1
Temperature: 100 °C
Yield: 27.9 %

Procedure:
DIPEA (0.068 g, 0.522 mmol) and cyclopropylmethylbromide (0.035 g, 0.260 mmol) were added to a stirred solution of 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-4-c arboxamide hydrochloride (0.10 g, 0.172 mmol) in dimethylformamide (1 ml). The reaction mixture was heated at 100° C. for 5 hours, cooled to room temperature and purified by preparative LCMS (standard acidic system) to give the title product (0.0253 g, 27.8%) as a white solid; 1H NMR Spectrum: (DMSO-d6) 0.00 (m, 2H), 0.41 (m, 2H), 0.76 (m, 1H), 1.77 (m, 2H), 2.03-2.13 (m, 7H), 2.81 (m, 2H), 3.32 (m, 2H), 3.61 (s, 2H), 3.91 (s, 3H), 7.06 (s, 1H), 7.14 (s, 2H), 7.26 (t, 1H), 7.47-7.53 (m, 2H), 8.32 (s, 1H), 8.38 (s, 1H), 9.70 (s, 1H); Mass Spectrum: (M+H)+ 527.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl:20][C:21]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:22]=1[C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.Cl.[C:47]1([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH:52]=[CH:51][C:50]([NH:53][C:54](=[O:64])[CH2:55][C:56](=[O:63])[N:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)=[CH:49][CH:48]=1>CN(C=O)C.O>[C:47]1([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH:48]=[CH:49][C:50]([NH:53][C:54](=[O:64])[CH2:55][C:56]([N:57]2[CH2:58][CH2:59][N:60]([C:23](=[O:25])[C:22]3[CH:26]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=[CH:29][C:21]=3[Cl:20])[CH2:61][CH2:62]2)=[O:63])=[CH:51][CH:52]=1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Reactant: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCN(C(=O)c2cc(C(F)(F)F)ccc2Cl)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
HOBt (34 mg, 0.25 mmol) and DIPEA (67.9 mg, 0.51 mmol) were added to a stirred solution of 2-chloro-5-trifluoromethylbenzoic acid (48 mg, 0.21 mmol) in DMF (3 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (48 mg, 0.25 mmol) followed by N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide hydrochloride (75 mg, 0.2 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water and extracted with ethyl acetate. The ethyl acetate was washed with brine solution, dried over Na2SO4 and evaporated. The residue was purified by column chromatography using silica gel 60-120 mesh (60% ethyl acetate in hexane) to afford 53 mg (48%) of N-biphenyl-4-yl-3-[4-(2-chloro-5-trifluoromethyl-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 530.14 (M+1)+ 98.5%, 1H NMR: (CDCl3): δ 9.6 (d, 1H), 7.6 (m, 8H), 7.43 (t, 2H), 7.33 (t, 1H), 4.0 (m, 2H), 3.7 (m, 4H), 3.5 (d, 2H), 3.3 (m, 2H).
Reaction SMILES: C1(C([N:9]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[C:17]=3[O:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)C)C=CC=CC=1.Cl.CCCCCC.C(OCC)(=O)C>C(O)(=O)C.[Zn]>[CH:21]1[C:22]2[NH:9][C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:16][C:17]=2[C:18]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:20]=1
Reactant: COC(=O)c1cccc2c1Oc1ccccc1N2C(C)c1ccccc1
Agent: Cl
Agent: [Zn]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1Oc1ccccc1N2

Procedure:
To 1.25 g of methyl N-(α-phenylethyl)phenoxazine-4-carboxylate in 25 ml of glacial acetic acid was added 500 g of zinc dust with stirring. To this stirred mixture, concentrated hydrochloric acid (2 ml) was added dropwise over a 5 minutes period. At this time examination of the reaction mixture by TLC [silica gel, hexane:ethyl acetate (1:9)] showed that the starting material was consumed. The mixture was poured onto water, extracted with ethyl acetate, the extracted material was dried over sodium sulfate and the solvent removed under reduced pressure. Column chromatographic purification of the residue on silica gel (150 g) gave using the solvent system described above as the eluant gave a yellow solid, methyl phenoxazine-4-carboxylate, having mp 113°-114° C. after recrystallization from ethyl ether.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:7])=[N:4][NH:5][CH:6]=1.[CH2:8]=[O:9]>CO>[OH:9][CH2:8][N:5]1[CH:6]=[C:2]([Cl:1])[C:3]([CH3:7])=[N:4]1
Reactant: C=O
Reactant: Cc1n[nH]cc1Cl
Solvent: CO
Product: Cc1nn(CO)cc1Cl
Yield: 95 %

Procedure:
116 g (1.0 mol) of 4-chloro-3-methylpyrazole in 50 ml of methanol were dissolved in 100 g (1.0 mol) of formalin solution (30%) at room temperature. Water and methanol were then evaporated. The title compound remained as a white solid (yield 95%).
Reaction SMILES: [CH3:1][Si:2]([Cl:5])(Cl)[Cl:3].C(OCC)C.Cl[Mg][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15]>CCCCCC>[CH3:13][Si:14]([CH2:17][Si:2]([CH3:1])([Cl:5])[Cl:3])([CH3:16])[CH3:15]
Reactant: C[Si](C)(C)C[Mg]Cl
Reactant: C[Si](Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: CCOCC
Product: C[Si](C)(C)C[Si](C)(Cl)Cl
Reaction time: 2 h
Yield: 43 %

Procedure:
In a 1-1 flask equipped with a dropping funnel, reflux condenser, stirrer and nitrogen gas introducing tube were placed 149 g (1 mol) of methyltrichlorosilane and 250 ml of diethyl ether. While stirring the mixture, the above chlorotrimethylsilylmethyl magnesium was dropwise added thereto over a period of 2 hours. After completion of the addition, the mixture was refluxed with heating and stirring for 36 hours. After cooling, 200 ml of hexane was added to the reaction mixture, and the salts formed were filtered off. The filtrate was condensed and vaccum-distilled. 11.7 g (yield: 43%) of (trimethylsilylmethyl)methyldichlorosilane was obtained.
Reaction SMILES: N[C:2](N)=[O:3].[C:5]1([CH:11]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH:21][C:22]3[C:23]([NH2:32])=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)[CH2:14][CH2:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.ClC(Cl)Cl>O>[C:33]1([CH:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][N:21]3[C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][C:23]=4[NH:32][C:2]3=[O:3])[CH2:14][CH2:13]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NC(N)=O
Reactant: Nc1cc(C(F)(F)F)ccc1NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 190 °C

Procedure:
A mixture of 5.4 parts of urea and 13.7 parts of N1 -{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-4-(trifluoromethyl)-1,2-benzenediamine is stirred and heated for 4 hours at 190° C. The reaction mixture is cooled to room temperature and diluted with water. After the addition of trichloromethane, the layers are separated. The aqueous phase is extracted with trichloromethane. The combined organic phases are washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-5-(trifluoromethyl)-2H-benzimidazol-2-one; mp. 152.7° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:3]=1.O.[CH3:30][N:31](C=O)C>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.[C-]#N.[C-]#N.[Zn+2]>[CH3:11][C:8]1[N:7]([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)[C:6]2[CH:5]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:3]=[C:2]([C:30]#[N:31])[C:10]=2[N:9]=1
Reactant: CN(C)C=O
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: Cc1nc2c(C#N)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
A mixture of 4-bromo-2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole (prepared following the same procedure as for Example 19, 300 mg, 0.69 mmol), Pd(PPh3)4 (80 mg, 0.069 mmol) and Zn(CN)2 (162 mg, 1.38 mmol) in DMF (30 mL) was stirred at 80° C. under N2 for 18 h. After cooling to rt, the mixture was poured into water and filtered. The filter cake was purified by silica gel chromatography eluted with petroleum ether:EtOAc=1:1 to give the product (180 mg, 68%), as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 2.44 (s, 3H), 3.07 (t, 4H, J=4.5 Hz), 3.68 (t, 4H, J=4.5 Hz), 6.04 (s, 2H), 6.32 (d, 1H, J=7.2 Hz), 7.31-7.40 (m, 3H), 7.60-7.71 (m, 2H), 7.86 (d, 1H, J=8.4 Hz), 8.01 (d, 1H, J=7.2 Hz), 8.22 (d, 1H, J=8.4 Hz); LC-MS: m/e=383 [M+1]−
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([CH3:8])=[CH2:7])=[CH:4][CH:3]=1.[C:11]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:12]>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:23]2[CH:24]=[C:19]([C:11]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:12])[CH3:13])[CH:20]=[CH:21][C:22]=2[OH:25])([CH3:8])[CH3:7])=[CH:4][CH:3]=1
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Reactant: C=C(C)c1ccc(F)cc1
Product: CC(C)(C)CC(C)(C)c1ccc(O)c(C(C)(C)c2ccc(F)cc2)c1
Yield: 76 %

Procedure:
4-Fluoro-α-methylstyrene (18 g) as prepared in Example 2 and 20.6 g of 4-tert-octyl-phenol are reacted according to the procedure of Example 3 to yield 26 g of the title compound as a reddish, viscous oil whose structure is consistent with 1Hnmr and mass spectroscopy.
Reaction SMILES: C[O:2][C:3](=O)[N:4]=[C:5](SC)[C:6]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C:17]=1[F:36])=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1.Cl.Cl.[CH2:42]([O:49][C:50]([C:52]1[CH:53]=[N:54][NH:55][C:56]=1[NH:57][NH2:58])=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.COC(=O)N=C(SC)C(C1C=C(OC)C=C(OCCCO[Si](C(C)(C)C)(C)C)C=1F)=NC1C=CC(C2N=C(C)ON=2)=CC=1.Cl.Cl.C(OC(C1C(NN)=NNC=1)=O)C>>[CH2:42]([O:49][C:50]([C:52]1[CH:53]=[N:54][NH:55][C:56]=1[N:57]1[C:3](=[O:2])[NH:4][C:5]([CH:6]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][Si:29]([C:32]([CH3:34])([CH3:33])[CH3:35])([CH3:31])[CH3:30])[C:17]=2[F:36])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][CH:13]=2)=[N:58]1)=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: NNc1[nH]ncc1C(=O)OCc1ccccc1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(OCCCO[Si](C)(C)C(C)(C)C)c1F
Agent: CCOC(=O)c1c[nH]nc1NN
Agent: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCCO[Si](C)(C)C(C)(C)C)c1F
Agent: Cl
Product: COc1cc(OCCCO[Si](C)(C)C(C)(C)C)c(F)c(C(Nc2ccc(C#N)cc2)c2nn(-c3[nH]ncc3C(=O)OCc3ccccc3)c(=O)[nH]2)c1

Procedure:
The same procedure was carried out as in Example (177b), except that (2-{3-[3-(t-butyldimethylsilanyloxy)propoxy]-2-fluoro-5-methoxyphenyl}-2-(4-cyanophenylimino)-1-methylsulfanylethylidene)carbamic acid methyl ester (Example (163c)) and 5-hydrazino-1H-pyrazole-4-carboxylic acid benzyl ester bishydrochloride were used instead of respectively (2-{3-[3-(t-butyldimethylsilanyloxy)propoxy]-2-fluoro-5-methoxyphenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene)carbamic acid methyl ester and 3-hydrazino-1H-pyrazole-4-carboxylic acid ethyl ester bishydrochloride, to give the title compound as a light yellow solid.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)[CH3:16].II>CO>[C:18]([C:19]1[CH:20]=[CH:21][C:22]([N:25]=[C:3]2[CH:4]=[C:5]3[C:14](=[N:13][C:12]4[C:7]([S:6]3)=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:1]=[CH:2]2)=[CH:23][CH:24]=1)([O:17][CH2:15][CH3:16])=[O:26]
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: II
Solvent: CO
Product: CCOC(=O)c1ccc(N=c2ccc3nc4ccccc4sc-3c2)cc1

Procedure:
To a warm and stirred suspension of 4 g (0.02 mole) finely powdered phenothiazine and 4 g (0.024 mole) ethyl-p-aminobenzoate in 200 ml methanol was added a solution of 10 g of iodine in 150 ml methanol. After stirring at room temperature for 2 hours, the dark precipitate was filtered, washed repeatedly with methanol, and dissoved in 100 ml chloroform and 10 ml triethylamine. The chloroform solution was shaken with water and separated. Purification through alumina and recrystallisation from ether gave purple leaflets. Yield 5.5 g (76%).