Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[OH:11].[C:12](OC(=O)C)(=[O:14])[CH3:13].O.C(OC(C)C)(C)C>N1C=CC=CC=1>[C:12]([O:11][CH:6]1[C:7]2[C:3](=[C:2]([Br:1])[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1)(=[O:14])[CH3:13]
Reactant: OC1CCc2c(Br)cccc21
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: c1ccncc1
Product: CC(=O)OC1CCc2c(Br)cccc21

Procedure:
3.0 g of 4-bromo-1-indanol (RS) in 30 ml of pyridine is cooled to 0° C., 2 ml of acetic anhydride is introduced slowly with agitation for 17 hours at ambient temperature. It is then poured into 100 ml of water and 100 ml of isopropyl ether and decanted; the organic phase is washed with water, dried and concentrated to dryness. The residue is taken up in 1,2-dichloro ethane in order to eliminate the pyridine by azeotropy. 3.9 g of expected product is obtained.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[C:6]([CH3:13])([CH3:12])[C:7](OCC)=[O:8]>C(O)C>[CH3:12][C:6]1([CH3:13])[S:3][C:2](=[NH:4])[NH:1][C:7]1=[O:8]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: NC(N)=S
Solvent: CCO
Product: CC1(C)SC(=N)NC1=O
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A suspension of thiourea (19.0 g, 0.25 mole) in 150 ml of ethanol was heated under reflux until all of the thiourea had dissolved. Ethyl 2-bromo-isobutyrate (49.0 g, 0.25 mole) was then added over 10 minutes to the refluxing solution, after which time the solution was heated under reflux for six hours then allowed to stir at ambient temperature 36 hours. The solution was concentrated to dryness and the residue treated with water, then with aqueous NaHCO3 to adjust the pH to 7.0. The precipitated solid was collected by filtration, washed with water and dried to yield 5,5-dimethyl-2-iminothiazolidin-4-one: mp 252°-254° C.; 15.0 g (0.12 mole, 47%). Structure was confirmed by IR and NMR.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C1(OC)C=CC=CC=1.[CH:16]1[S:17][CH:18]=[C:19]2[C:25]=1[NH:24][C:23](=O)[C:22]1[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=1[NH:20]2.[OH-].[NH4+]>[Ti](Cl)(Cl)(Cl)Cl.CC(O)C.C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:23]2[C:22]3[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=3[NH:20][C:19]3=[CH:18][S:17][CH:16]=[C:25]3[N:24]=2)[CH2:4][CH2:3]1
Reactant: O=C1Nc2cscc2Nc2ccccc21
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: COc1ccccc1
Solvent: Cc1ccccc1
Product: CN1CCN(C2=Nc3cscc3Nc3ccccc32)CC1

Procedure:
To a mixture of 15.0 g. of N-methylpiperazine, 6.3 g. of titanium tetrachloride and 7 ml. of anisole in 67 ml. of toluene is added a mixture of 7.6 g. of N-methylpiperazine and 7.1 g. of 4H-thieno[3,4-b][1,4]benzodiazepin-9(10H)-one in 7 ml. of toluene. This mixture is stirred and refluxed for 2 hours, cooled and 11 ml. of 2-propanol, 5 g. of diatomaceous earth and 10.2 ml. of ammonium hydroxide are added. The mixture is filtered and the solid washed with toluene. The toluene filtrate and washings are washed with water, the toluene layer is separated and extracted with three 150 ml. portions of 3 N hydrochloric acid. The acidic extracts are combined, cooled, made alkaline with ammonium hydroxide and extracted with dichloromethane. This extract is dried, filtered, evaporated to 75 ml. and filtered through magnesium silicate. This filtrate is evaporated giving 9-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,4 ]benzodiazepine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[O-:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14].[C:20]1([I+]C2C=CC=CC=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)C>O.C([O-])(=O)C1C=CC=CC=1.[Cu+2].C([O-])(=O)C1C=CC=CC=1>[O-:15][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:14])=[O:12].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S+:6]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc([I+]c2ccccc2)cc1
Reactant: c1csc(Sc2cccs2)c1
Agent: [Cu+2]
Agent: O=C([O-])c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O
Solvent: CCOCC
Product: c1ccc([S+](c2cccs2)c2cccs2)cc1
Reaction time: 24 h
Yield: 77 %

Procedure:
Di-(2-thienyl)sulfide (2.1 g, 0.0104 mole), diphenyliodonium triflate (5.8 g, 0.0135 mole) and copper benzoate (0.08 g, 0.003 mole) are heated without solvent for 3 hours at 120-145° C. under a nitrogen atmosphere. After cooling down, 75 ml ethyl ether was added and the mixture vigorously stirred overnight to achieve solidification. Filtration and washing with ethyl ether yielded a brown solid, which was dissolved in hot water, the solution filtered and the water removed in vacuo. The resulting white solid was stirred in 50 ml ethyl ether for 24 hours, the mixture filtered and the residue washed with ethyl ether, yielding 3.4 g (78%) of the title compound, di(2-thienyl)phenylsulfonium triflate. The structure was confirmed by 1H/13C NMR spectroscopy.
Reaction SMILES: CO[C:3]1([O:17][CH3:18])[CH2:8][CH2:7][CH:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5][CH2:4]1.C[Si]([C:23]#[N:24])(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:10]([O:9][CH:6]1[CH2:5][CH2:4][C:3]([O:17][CH3:18])([C:23]#[N:24])[CH2:8][CH2:7]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC1(OC)CCC(OCc2ccccc2)CC1
Reactant: C[Si](C)(C)C#N
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC1(C#N)CCC(OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
1.5 g of (4,4-Dimethoxy-cyclohexyloxymethyl)-benzene (38) were dissolved in 20 mL of dry dichloromethane and cooled to 0° C. 3.05 mL of trimethylsilyl cyanide were added dropwise and after stirring for 2 minutes, 1.31 mL of trimethylsilyl trifluoromethansulfonate were added dropwise. The mixture was stirred at 0° C. for 2 h, then 20 mL of saturated aqueous sodium bicarbonate solution were added dropwise. Phases were separated and the aqueous layer was extracted several times with dichloromethane. The combined organic layer was dried and evaporated to dryness to give 1.5 g of crude product, that was purified by silica gel chromatography to give 1.3 g of the desired compound as a cis-trans-mixture. Rt=4.68 min (Method D). Detected mass: 246.1 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[C:12](Cl)=[N:13][CH:14]=[N:15][C:16]=3Cl)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])[CH3:20]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[C:12]([NH:31][S:28]([C:25]4[CH:24]=[CH:23][C:22]([CH:19]([CH3:21])[CH3:20])=[CH:27][CH:26]=4)(=[O:29])=[O:30])=[N:13][CH:14]=[N:15][C:16]=3[O:1][CH2:5][CH2:4][OH:3])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Clc1ncnc(Cl)c1Oc1ccc2c(c1)OCO2
Reactant: CC(C)c1ccc(S(N)(=O)=O)cc1
Product: CC(C)c1ccc(S(=O)(=O)Nc2ncnc(OCCO)c2Oc2ccc3c(c2)OCO3)cc1

Procedure:
By reacting 5-(1,3-benzodioxol-5-yloxy)-4,6-dichloropyrimidine with p-isopropylbenzenesulfonamide and thereafter with ethylene glycol Na, there was obtained N-[5-(1,3-benzodioxol-5-yloxy)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-p-isopropylbenzenesulfonamide as a solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH2:3][CH2:4][O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:8]([NH2:24])[N:7]=1.Cl.[OH-].[Na+]>CO.O1CCOCC1>[NH2:24][C:8]1[N:7]=[C:6]([O:5][CH2:4][CH2:3][CH:2]([CH3:25])[CH3:1])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: COc1nc2c(N)nc(OCCC(C)C)nc2n1CC1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)CCOc1nc(N)c2[nH]c(=O)n(CC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
To a solution of 2-[(3-methylbutyl)oxy]-8-methoxy-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (52 mg) in dry MeOH (5.7 mL) was added 4N HCl in 1,4-dioxane (0.971 mL) and the reaction mixture was stirred at room temperature for 3 h. The reaction was neutralised to pH7 with 2M sodium hydroxide solution and concentrated in vacuo to give a white solid. The solid was washed with water (20 mL) and was filtered under reduced pressure to give the title compound as an off-white solid (31 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]2=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([N:11]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]2[C:12]1=[CH:13][CH:14]=[C:2]([Br:1])[CH:3]=2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Brc1ccc2[nH]c3c(c2c1)CCCC3
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)c1c(n2Cc2ccccc2)CCCC1

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 3. Thus, 6-bromo-2,3,4,9-tetrahydro-1H-carbazole (1.876 g, 7.5 mmol) was reacted with k-t-butoxide (0.884 g, 7.875 mmol) and benzyl bromide (1.352 g, 7.875 mmol) in DMF (20 ml) to give the product (2.225 g, 6.539 mmol, 87%) as an oily, yellow solid. 1H NMR (DMSO-d6) δ 1.74-1.83 (m, 4H), 2.61-2.64 (m, 4H), 5.32 (s, 2H), 6.99 (d, J=7.6 Hz, 2H), 7.11 (dd, 1.8, 8.7 Hz, 1H), 7.21 (t, J=7.2 Hz, 1H), 7.27 (t, J=7.3 Hz, 2H), 7.33 (d, J=8.6 Hz, 1H), 7.55 (d, J=1.5 Hz, 1H); [ESI(+)], m/z 340/342 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1.Br[CH2:18][CH2:19][C@@H:20]1[CH2:24][C@@H:23]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:22][N:21]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].CC(C)([O-])C.[K+]>CN(C)C(=O)C>[C:36]([O:35][C:33]([N:21]1[CH2:22][C@H:23]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:24][C@H:20]1[CH2:19][CH2:18][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCBr
Reactant: Oc1ccc(F)cc1CCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCOc1ccc(F)cc1CCc1ccccc1
Yield: 83.9 %

Procedure:
1090 mg of 4-fluoro-2-(2-phenylethyl)phenol (prepared as described in Preparation 3), 1870 mg of (2S,4R)-2-(2-bromoethyl)-1-t-butoxycarbonyl-4-t-butyldimethylsilyloxypyrrolidine and 566 mg of potassium t-butoxide were allowed to react together in 10 ml of N,N-dimethylacetamide, and the resulting mixture was extracted in the same manner as described in step (a) of Example 2. The resulting oily substance was purified by silica gel column chromatography, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2090 mg (yield 84%) of the title compound as a colorless oily substance.
Reaction SMILES: O1CCN([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]3[CH:34]=[C:33]([C:35](=[O:48])[NH:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=4)[CH:32]=[CH:31][N:30]=3)[CH:8]=2)CC1.[NH:49]1[CH2:54][CH2:53][S:52][CH2:51][CH2:50]1>>[S:52]1[CH2:53][CH2:54][N:49]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]3[CH:34]=[C:33]([C:35](=[O:48])[NH:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:45])([F:47])[F:46])[CH:39]=4)[CH:32]=[CH:31][N:30]=3)[CH:8]=2)[CH2:50][CH2:51]1
Reactant: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCOCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: C1CSCCN1
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCSCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared according to the procedure described for the synthesis of 3-((3-((4-morpholino-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzyl)thio)propanoic acid 14, using thiomorpholine in place of morpholine. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.22 (s, 1H), 9.54 (t, 1H), 8.32 (d, J=3 Hz, 1H), 8.27 (m, 2H), 7.85 (m, 2H), 7.75 (m, 2H), 7.50 (m, 6H), 7.15 (m, 1H), 4.62 (d, J=6 Hz, 2H), 3.87 (s, 2H), 3.58 (m, 4H), 2.74 (m, 4H), 2.62 (m, 2H), 2.50 (m, 1H). MS (ES, m/z): 695 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].[Cl:15]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:3]=1[C:4]([Cl:15])=[N:5][OH:6]
Reactant: ON=Cc1cc(C(F)(F)F)ccc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: ON=C(Cl)c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 643 mg (3.10 mmol) of 2-fluoro-5-trifluoromethylbenzaldehyde oxime in 5 mL of dimethyl formamide (DMF) was added 456 mg (3.41 mmol) of N-chlorosuccinimide (see K.-C. Liu, B. R. Shelton, and R. K. Howe, J. Org. Chem. 1980, 45, 3916). The reaction mixture was stirred at room temperature overnight, and then diluted with ethyl acetate. The ethyl acetate solution was washed with saturated sodium chloride and dried over magnesium sulfate. The drying agent was filtered off, and solvent was removed by rotoevaporation to give 675 mg (2.79 mmol) of pure white crystalline 2-fluoro-5-trifluoromethyl-N-hydroxybenzene-carboximidoyl chloride.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)(=[O:8])=[O:7].[H-].[Na+].[Br:20][C:21]1[C:22](Cl)=[N:23][C:24]([Cl:27])=[N:25][CH:26]=1.[Na+].[Cl-]>CN(C=O)C>[Br:20][C:21]1[C:22]([O:1][CH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)(=[O:7])=[O:8])=[N:23][C:24]([Cl:27])=[N:25][CH:26]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)NCCCO)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(S(=O)(=O)NCCCOc2nc(Cl)ncc2Br)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 272 mg (1.05 mmol) of N-(3-hydroxy-propyl)-3-nitro-benzenesulfonamid in 5 ml DMF is mixed with 49 mg of a 60% dispersion of sodium hydride in mineral oil (1.22 mmol) and stirred for 5 minutes at room temperature. It is mixed with a solution of 220 mg (0.97 mmol) of 5-bromo-2,4-dichloro-pyrimidine in 5 ml of DMF and stirred for another 2 hours. The batch is mixed with saturated NaCl solution and then extracted with ethyl acetate (2×). The combined organic phases are washed with NaCl solution, dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (hexane/ethyl acetate 1:1, Flashmaster II). 75 mg (0.16 mmol, corresponding to 16% of theory) of the product is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NCc1ccccc1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with benzylamine following general procedure B to afford 4-benzylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (220 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (180 mg) following general procedure E. The above ethylamide (0.54 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 1-benzyl-3-ethyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (60 mg). LCMS: m/z 362 [M+1]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:23])([F:22])[O:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:46]=[C:47]([N:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1)[CH2:48][NH:49][C:50]([C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:54][CH:53]=1)=[O:51]>CN(C=O)C.O>[O:46]=[C:47]([N:64]1[CH2:69][CH2:68][N:67]([C:15](=[O:17])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12][C:11]([F:10])([F:23])[F:22])[CH2:66][CH2:65]1)[CH2:48][NH:49][C:50]([C:52]1[CH:53]=[CH:54][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:56][CH:57]=1)=[O:51]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1ccccc1OC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2OC(F)(F)F)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 2-trifluoromethoxy-benzoic acid (53.09 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 50% EtOAc in hexane as eluent) to afford 45 mg (34.1% yield) of biphenyl-4-carboxylicacid {2-oxo-2-[4-(2-trifluoromethoxy-benzoyl)-piperazin-1-yl]-ethyl}-amide, LC-MS purity: 99.18%, 1H NMR: (DMSO) δ 8.7 (s, 1H), 8.0 (s, 2H), 7.8 (s, 4H), 7.4 (s, 7H), 4.2 (d, 2H), 3.8-3.4 (m, 6H), 3.2 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[CH3:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=O>>[Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH:16]4[CH2:17][CH2:18][N:19]([CH2:24][C:25]5[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=5[CH3:27])[CH2:20][CH2:21]4)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: Cc1ccccc1C=O
Reactant: O=c1[nH]c2cc(Br)ccc2n1C1CCN(C2CCNCC2)CC1
Product: Cc1ccccc1CN1CCC(N2CCC(n3c(=O)[nH]c4cc(Br)ccc43)CC2)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 18, using 5-bromo-1-[1-(piperidin-4-yl)piperidin-4-yl]-1,3-dihydro-2-H-benzimidazol-2one and 2-methylbenzaldehyde.
Reaction SMILES: C([Li])CCC.[C:6]1([C:12]([N:21]([CH3:30])[CH:22](C2C=CC=CC=2)C)([C:15]2C=CC=CC=2)[PH2]=O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([C:40]2[CH:41]=[N:42][C:43]([C:46]3[C:47]([CH3:70])=[N:48][N:49]([C:51]([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[CH:50]=3)=[CH:44][CH:45]=2)=O)=[CH:34][CH:33]=1>O1CCCC1>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([C:40]2[CH:41]=[N:42][C:43]([C:46]3[C:47]([CH3:70])=[N:48][N:49]([C:51]([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[CH:50]=3)=[CH:44][CH:45]=2)=[CH:30][N:21]([CH3:22])[CH:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:15])=[CH:34][CH:33]=1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(C(=O)c2ccc(Cl)cc2)cn1
Reactant: CC(c1ccccc1)N(C)C([PH2]=O)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(C(=CN(C)C(C)c2ccccc2)c2ccc(Cl)cc2)cn1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (0.47 ml, 0.76 mmol, 1.6M in Hexanes) was added dropwise to a solution of (R) (Diphenyl-phosphinoylmethyl)-methyl-(1-phenyl-ethyl)-amine* (0.18 g, 0.51 mmol) in dry tetrahydrofuran (9 ml) at −15° C. After 15 minutes a solution of (4-Chloro-phenyl)-[6-(3-methyl-1-trityl-1H-pyrazol-4-yl)-pyridin-3-yl]-methanone (0.14 g, 0.25 mmol) in tetrahydrofuran (0.9 ml) was added and the reaction mixture was stirred for a further 30 minutes at −15° C. before warming to room temperature over 1 hour. The reaction mixture was quenched with water, extracted with diethyl ether, organic extracts were combined, dried (MgSO4) and concentrated to afford the title compound, which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[N:4][CH:3]=1.[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:7]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCc1ccccc1
Reactant: Clc1cncc(N2CCNCC2)n1
Product: c1ccc(COc2cncc(N3CCNCC3)n2)cc1
Temperature: 125 °C
Reaction time: 4.5 h
Yield: 90.5 %

Procedure:
A mixture of the product from example 13, step 2 (0.73 g, 3.68 mmol), benzyl alcohol (9.4 g, 87 mmol) and K-t-BuO was stirred at 125° C. for 4.5 h. The reaction mixture was purified by silica gel chromatography (13×5 cm) using CHCl3/MeOH (7:3 followed by 9:1) as eluent. Solvents were evaporated off and the residue was redissolved in ethyl acetate. Filtration and concentration in vacuo furnished 0.90 g (90%) of the title compound as a beige oil. HRMS m/z calcd for C15H18N4O (M)+ 270.1481, found 270.1482. Anal. (C15H18N4O) C, H, N. *This compound was also characterized as its maleate salt: mp 155-156° C. HRMS m/z calcd for C15H18N4O (M)+ 270.1481, found 270.1482. Anal. (C15H18N4O.C4H4O4) C, H, N.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[C:17][Si](C)(C)C)=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+]>CO>[C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[O:9])=[CH:15][CH:14]=1)#[CH:17]
Reactant: CN1CCN(C(=O)c2ccc(C#C[Si](C)(C)C)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C(=O)N2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
(4-Methylpiperazin-1-yl){4-[(trimethylsilyl)ethynyl]phenyl}methanone (1.29 g, 4.26 mmol) in MeOH (20 mL) was treated with solid K2CO3 (0.118 g, 0.85 mmol). After stirring at room temperature for 3 h the volatiles were removed by evaporation, the residue was taken up with DCM (40 mL), washed with water (30 mL), brine, dried over sodium sulfate and evaporated. The crude was purified by flash chromatography on silica gel (DCM/MeOH 95/5) to afford the title compound as white solid (0.690 g, 71%).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]1[C:10]([S:11][CH3:12])=[N:9][N:8]=[C:7]1[CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C.Cl(O)(=O)(=O)=O>>[CH3:12][S:11][C:10]1[N:6]2[C:7]([CH:13]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[CH:4]=[CH:5]2)=[N:8][N:9]=1
Reactant: CCOC(Cn1c(SC)nnc1C(c1ccccc1)c1ccccc1)OCC
Agent: [O-][Cl+3]([O-])([O-])O
Product: CSc1nnc2n1C=Cc1ccccc1C2c1ccccc1

Procedure:
By a procedure similar to that described in Example 1, 20.0 g of the 4-(2,2-diethoxyethyl)-3-diphenylmethyl-5-methylthio-4H-1,2,4-triazole prepared in Reference Example 16 was added to 50 ml of a 70% aqueous solution of perchloric acid under ice-cooling and the mixture was heated at 60°-65° C. for 20 minutes. The cyclization reaction mixture was further treated as described to obtain 3-methylthio-11-phenyl-11H-s-triazolo[3,4-b][3]benzazepine as crystals. Recrystallization from ethanol yielded colorless platelets melting at 169°-170° C.