Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[O:22][C:21]([C:23](=[O:25])[CH3:24])=[CH:20][CH:19]=3)=[CH:7][CH:8]=2)[N:3]=1.[F:26][C:27]1[CH:37]=[C:36]([NH:38][C:39]([NH:41][C:42]2[CH:47]=[CH:46][C:45](B3OC(C)(C)C(C)(C)O3)=[CH:44][CH:43]=2)=[O:40])[CH:35]=[CH:34][C:28]=1[C:29]([N:31]([CH3:33])[CH3:32])=[O:30].C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>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.O.CCO>[C:23]([C:21]1[O:22][C:18]([C:6]2[CH:5]=[C:4]3[C:9]([C:10]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:11][C:2]([C:45]4[CH:46]=[CH:47][C:42]([NH:41][C:39](=[O:40])[NH:38][C:36]5[CH:35]=[CH:34][C:28]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[C:27]([F:26])[CH:37]=5)=[CH:43][CH:44]=4)=[N:3]3)=[CH:8][CH:7]=2)=[CH:19][CH:20]=1)(=[O:25])[CH3:24]
Reactant: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1F
Reactant: CC(=O)c1ccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)c1ccc(-c2ccc3c(N4CCOCC4)nc(-c4ccc(NC(=O)Nc5ccc(C(=O)N(C)C)c(F)c5)cc4)nc3c2)o1
Temperature: 75 °C
Reaction time: 3 h
Yield: 5.7 %

Procedure:
To a 50 mL round bottom flask, 1-(5-(2-chloro-4-morpholino-quinazolin-7-yl)furan-2-yl)ethanone (0.1 g, 0.00028 mol), 2-fluoro-N,N-dimethyl-4-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido)-benzamide (0.144 g, 0.00034 mol), cesium carbonate (0.228 g, 0.0007 mol), toluene (7 mL) and EtOH (7 mL), and water (3 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (0.0098 g, 0.000014 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 75° C. for 3 h. The reaction mixture was cooled, diluted with chloroform, washed with water, brine and dried over anhydrous sodium sulfate. The organic layer was evaporated under reduced pressure to afford the crude product. The crude product was purified by column chromatography using 60-120 silica gel and 4% MeOH in chloroform. The compound was further purified by prep HPLC using 10 mM ammonium acetate in water and ACN to obtain the title compound [0.01 g, 6%]. 1H NMR (400 MHz, DMSO-d6): δ 9.04 (s, 1H), 8.96 (s, 1H), 8.46 (d, J=8.4 Hz, 2H), 8.28 (s, 1H), 8.13 (d, 1H, J=8.8 Hz), 7.92 (d, J=8.4 Hz, 1H), 7.64 (d, J=8.4 Hz, 3H), 7.55-7.52 (m, 3H), 7.38 (d, J=8.0 Hz, 2H), 3.85 (s, 8H), 2.97 (s, 6H), 2.56 (s, 3H). LC-MS (ESI): Calculated mass: 622.2; Observed mass: 623.2 (RT: 0.45 min).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[CH2:13]([C:15]1[C:23]([Cl:24])=[CH:22][C:18]([C:19](O)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=1)[CH3:14]>>[ClH:24].[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:19](=[O:20])[C:18]2[CH:22]=[C:23]([Cl:24])[C:15]([CH2:13][CH3:14])=[CH:16][C:17]=2[O:25][CH3:26])[CH2:7]1
Reactant: CN1CCc2c(N)cccc2C1
Reactant: CCc1cc(OC)c(C(=O)O)cc1Cl
Product: CCc1cc(OC)c(C(=O)Nc2cccc3c2CCN(C)C3)cc1Cl
Product: Cl

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 4-ethyl-2-methoxy-5-chlorobenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([Cl:7])[C:3]=1[Cl:8].[F:9][P-:10]([F:15])([F:14])([F:13])([F:12])[F:11].[CH3:16]COCC>>[F:9][P-:10]([F:15])([F:14])([F:13])([F:12])[F:11].[CH3:16][N+:5]1[S:6][C:2]([Cl:1])=[C:3]([Cl:8])[C:4]=1[Cl:7]
Reactant: Clc1nsc(Cl)c1Cl
Reactant: CCOCC
Agent: F[P-](F)(F)(F)(F)F
Product: C[n+]1sc(Cl)c(Cl)c1Cl
Yield: 61 %

Procedure:
Trichloroisothiazole (15 ml) and 6.2 g (0.03 mol) of trimethyloxomium hexafluorophosphate were heated at 90° for 1 hr under nitrogen. After cooling, ether (100 ml) was added and the solid collected to yield 6.3 g (61%) of product, mp >240. Spectral data (NMR & IR) were consistent with the assigned structure.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:2].[C:18](OCC)(=[O:20])[CH3:19]>[Pd]>[NH:9]([C:7]1[CH:6]=[CH:5][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:3]([C:1]#[N:2])[CH:8]=1)[C:18]([CH3:19])=[O:20]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1-c1ccccc1
Reactant: CCOC(C)=O
Agent: [Pd]
Product: CC(=O)Nc1ccc(-c2ccccc2)c(C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Cyano-4-nitrobiphenyl (0.067 moles, 15.0 g.) was dissolved in 100 ml ethyl acetate/100 ml ethanol and hydrogenated at 40 psi over 3.0 g of 10% palladium on carbon. The catalyst was removed by filtering though celite. The solvents were removed in vacuo. The residue was dissolved in 175 ml of methylene chloride. Acetic anhydride (15 ml) was added. The reaction was stirred at room temperature for 30 minutes and poured over ice. The organic layer was dried, concentrated, and then purified by HPLC over silica gel eluted with a gradient of 0-10% ethyl acetate in chloroform. (MS)
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[F:11][C:12]1[C:30]([F:31])=[C:29]([F:32])[C:28]([F:33])=[C:27]([F:34])[C:13]=1[O:14][C:15]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)(O)[O-].[Na+]>C(OCC)C.O>[CH:1]([N:18]1[CH2:17][CH2:16][C:15]([O:14][C:13]2[C:27]([F:34])=[C:28]([F:33])[C:29]([F:32])=[C:30]([F:31])[C:12]=2[F:11])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:20][CH2:19]1)=[O:2]
Reactant: Fc1c(F)c(F)c(OC2(c3ccccc3)CCNCC2)c(F)c1F
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CCOCC
Product: O=CN1CCC(Oc2c(F)c(F)c(F)c(F)c2F)(c2ccccc2)CC1
Temperature: 55 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
A mixture of 1.5 ml of formic acid and 3.5 ml of acetic anhydride was stirred at 55° C. for one hour, cooled and then treated with a solution of 4.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpiperidine in 50 ml of diethyl ether. After stirring at ambient temperature for three hours, the reaction mixture was poured into 100 ml of water, basified to a pH of about 10 by the addition of sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. High pressure liquid chromatography of the oil (silica gel; elution with ethyl acetate) afforded a solid which was recrystallized from isopropyl ether/hexanes (1:2) to yield 2.1 g (64%) of 1-formyl-4-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpiperidine, m.p. 118°-119° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][CH2:9]O.[Br-:11].[Br-:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>ClCCl>[Br:11][CH2:9][CH2:8][C:4]1[S:5][CH:6]=[CH:7][C:3]=1[CH2:2][Br:12]
Reactant: [Br-]
Reactant: OCCc1sccc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: BrCCc1sccc1CBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.8 %

Procedure:
2.0 g of the compound obtained in Example 2 was dissolved in 40 mL of dichloromethane, and the resulting solution was cooled to below 5° C. 13.4 g of triphenylphosphine dibromide was added thereto, and the resulting mixture was warmed to room temperature, stirred for 4 hours, and concentrated by evaporation under reduced pressure. To the residue, 5 mL of ethyl acetate and then 15 mL of n-hexane were added. The resulting mixture was stirred for 1 hour at room temperature and 2 hours at below 5° C., filtered and condensed under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, n-hexane:ethyl acetate=10:1) to obtain 2.9 g (yield of 80%) of the title compound as a yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[NH:4][C:5]1[S:6][C:7]([CH3:12])=[CH:8][C:9]=1[C:10]#[N:11].O1[CH2:21][CH2:20]CC1.O>CN1CCNCC1.C(O)(=O)C>[CH3:12][C:7]1[S:6][C:5]2[NH:4][C:3]3[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=3[N:1]=[C:10]([N:11]3[CH2:21][CH2:20][N:4]([CH3:5])[CH2:3][CH2:2]3)[C:9]=2[CH:8]=1
Reactant: Cc1cc(C#N)c(Nc2ccccc2N)s1
Reactant: C1CCOC1
Agent: CN1CCNCC1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
2-(2-Aminoanilino)-5-methylthiophene-3-carbonitrile (2.0 g) is taken in N-methyl-piperazine (12 ml) and acetic acid (2 ml). The solution is heated at 120° C. until completion of reaction. The reaction mass is cooled and tetrahydrofuran is added. The reaction mixture is stirred for 30 minutes. The water is added at 45-50° C., the mixture is cooled up to room temperature and the solid is precipitated out. The solid is filtered off and washed with tetrahydrofuran-water mixture.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8]2)=[CH:3][CH:2]=1.CS(O)(=O)=O.N1C2C(=CC=CC=2)C=CC=1.[C:28](Cl)(Cl)=[O:29].[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([NH:39][C:40](=[O:48])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[NH2:47])=[N:37][CH:38]=1>ClCCl.C1(C)C=CC=CC=1>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([NH:39][C:40](=[O:48])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[NH:47][C:28]([O:12][CH:9]2[CH2:10][CH2:11][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8]2)=[O:29])=[N:37][CH:38]=1
Reactant: OC1CCN(c2ccncc2)C1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Reactant: O=C(Cl)Cl
Agent: CS(=O)(=O)O
Solvent: c1ccc2ncccc2c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OC1CCN(c2ccncc2)C1
Temperature: 25 °C
Reaction time: 0 h
Yield: 32.8 %

Procedure:
To as solution of 1-(4-pyridinyl)-3-hydroxypyrrolidine (330 mg, 2.01 mmol) in dichloromethane (30 mL) was added methanesulfonic acid (0.15 mL, 2.31 mmol). After 15 seconds, quinoline (0.3 mL, 2.54 mmol) was added, immediately followed by a toluene solution of phosgene (0.65 mL, 1.25 mmol). After 5 minutes, the reaction was placed in an oil bath at 35° C. After 45 minutes, the reaction was cooled to room temperature. N-(5-Chloropyridin-2-yl)-2-aminobenzamide (498 mg, 2.01 mmol) was added, followed by quinoline (0.3 mL, 2.54 mmol). After stirring overnight, the reaction was diluted with dichloromethane (150 mL) and washed with saturated aqueous sodium carbonate (2×25 mL). The organic layer was concentrated in vacuo and purified by flash column chromatography (100% CH2Cl2 to 9% MeOH/CH2Cl2) and then by HPLC to give the title product (181 mg, 0.41 mmol, 21%).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:14]=[C:13]([S:15]([N:18]3[CH2:23][CH2:22][NH:21][CH:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:19]3)(=[O:17])=[O:16])[S:12][C:11]=2[CH:28]=1.F[P-](F)(F)(F)(F)F.[Br:36][P+](N1CCCC1)(N1CCCC1)N1CCCC1.Br[C:54]1[CH:59]=[CH:58][N:57]=[C:56]([C:60]([OH:62])=O)[N:55]=1>C(N(CC)CC)C>[Br:36][C:59]1[CH:54]=[N:55][C:56]([C:60]([N:21]2[CH2:22][CH2:23][N:18]([S:15]([C:13]3[S:12][C:11]4[CH:28]=[C:7]([Cl:6])[CH:8]=[CH:9][C:10]=4[CH:14]=3)(=[O:17])=[O:16])[CH2:19][CH:20]2[CH2:24][CH:25]([CH3:26])[CH3:27])=[O:62])=[N:57][CH:58]=1
Reactant: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CC(C)CC1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1
Reactant: O=C(O)c1nccc(Br)n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CC1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1C(=O)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To an N,N-dimethylformamide solution (60 ml) of 1-[(6-chlorobenzo[b]thiophen-2-yl)sulfonyl]-3-(2-methylpropyl)piperazine (2.55 mg) were added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (607 mg, 1.17 mmol), (4-bromopyrimidin-2-yl)carboxylic acid (237 mg) and triethylamine (118 mg), followed by stirring at room temperature for 13 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. Distilled water and methylene chloride were added to the residue. The water layer thus obtained was extracted three times with methylene chloride. The organic layers were combined and washed with distilled water. After drying over anhydrous magnesium sulfate, the solvent was distilled under off under reduced pressure. The residue was subjected to chromatography on a silica gel column (methanol:methylene chloride=1:100), followed by crystallization from ethyl acetate—diethyl ether, whereby the title compound (326 mg) was obtained as brown crystals.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br)=[CH:10][CH:9]=1.[CH3:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C>[Br-:1].[Br-:1].[CH3:21][N+:22]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N+:22]3([CH3:21])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:10][CH:9]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: BrCCCCCCc1ccc(CCCCCCBr)cc1
Reactant: CN1CCCCC1
Solvent: CCO
Product: C[N+]1(CCCCCCc2ccc(CCCCCC[N+]3(C)CCCCC3)cc2)CCCCC1
Product: [Br-]
Reaction time: 72 h
Yield: 59.9 %

Procedure:
First, 0.28 g of 1,4-bis(6-bromohexyl)benzene and 0.5 g of N-methylpiperidine were dissolved in 4 ml of absolute ethanol, and the mixture was refluxed for 2 hours and evaporated under a reduced pressure to remove the solvent. After adding acetone and then ethanol, the whole was allowed to stand in a freezer for 3 days. The resulting crystal was collected by filtration, washed with acetone and dried under a reduced pressure to obtain 0.125 g of the title compound as a colorless crystal.
Reaction SMILES: [N:1]1([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[NH:21][C:20]3=[O:28])=[CH:15][CH:14]=2)[C:5]2=[N:6][C:7]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[N:4]2[CH2:3][CH2:2]1.I[CH2:30][CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[N:1]1([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[N:21]([CH2:30][CH3:31])[C:20]3=[O:28])=[CH:15][CH:14]=2)[C:5]2=[N:6][C:7]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[N:4]2[CH2:3][CH2:2]1
Reactant: CCI
Reactant: O=c1[nH]c2cccnc2n1-c1ccc(N2CCn3c2nc2cccnc23)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(N3CCn4c3nc3cccnc34)cc2)c2ncccc21
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A mixture of 3-[4-(2,3-dihydro-1H-imidazo[2′,1′:2,3]imidazo[4,5-b]pyridin-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (165 mg), iodoethane (0.054 mL) and cesium carbonate (291 mg) in DMF (3 mL) was stirred at 50° C. for 6 h. The mixture was poured into water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residual crystals were dissolved in THF, and the solution was filtered through NH-silica gel. The filtrate was concentrated under reduced pressure. The residual crystals were recrystallized from EtOH to give the title compound (94 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cl:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([NH2:29])=[O:28].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C(C)=CC=CC=1>[ClH:22].[ClH:22].[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:23][CH2:24][O:25][CH2:26][C:27]([NH2:29])=[O:28])[CH2:13][CH2:14]2)=[CH:16][CH:17]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: NC(=O)COCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: Cl
Product: NC(=O)COCCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 140 °C
Yield: 89.9 %

Procedure:
A suspension of 11.0 g (0.038 mol) of 1-[bis-(4-fluorophenyl)methyl]piperazine, 10.5 g (0.076 mol) of 2-(2-chlorethoxy)acetamide and 8.1 g of anhydrous sodium carbonate In 40 ml of xylene is heated under reflux at 140° C. for 4 hours. The precipitate which forms is filtered off and then washed with toluene. The filtrate and toluene used for washing are combined. The resulting organic phase is extracted with 80 ml of IN aqueous hydrochloric acid, and the aqueous phase is washed twice with toluene. Toluene is added to the resulting aqueous phase, then 80 ml of a 1N aqueous sodium hydroxyde solution are added, and the aqueous mixture is extracted once with toluene. The organic phase is washed once with water, dried over anhydrous sodium sulphate and the solvents are evaporated off with a rotative evaporator until dryness. At this stage, the evaporation residue consists of 2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxyacetamide, which may be converted into its dihydrochloride salt as follows: the evaporation residue is taken up with 50 ml isopropanol and filtered; a 4.38 N alcoholic hydrochloric acid solution (17.5 ml) is added to the isopropanol solution and the mixture is allowed to crystallize. The precipitate is filtered, washed with isopropanol and diethyl ether, then dried in vacuo. This way, 15.8 g (90%) 2-[4-[bis(4-fluorophenyl)methyl]-1 -piperazinyl]ethoxyacetamide dihydrochloride are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.CCCCCC.C([Li])CCC.[CH3:19][S:20]SC>C(OCC)C.O>[CH3:19][S:20][C:4]1[S:5][CH:6]=[CH:7][C:3]=1[O:2][CH3:1]
Reactant: COc1ccsc1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccsc1SC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 21 g of 3-methoxythiophene in diethyl ether at -40° C. was added 115 ml of a 1.6 molar hexane solution of n-butyllithium. The mixture was warmed slowly over 10 minutes to 0° C., then refluxed for 1 hour, was cooled to -78° C. and a solution containing 21.4 g of dimethyldisulphide in 100 ml of diethyl ether was added. The reaction mixture was warmed to room temperature and stirred for 30 minutes, was poured into water and the organic layer washed with water, with brine, and was then dried over magnesium sulphate and evaporated to dryness.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])N.[CH:12]([C:15]([CH3:17])=O)([CH3:14])[CH3:13]>C(O)C.S(=O)(=O)(O)O>[CH3:17][C:15]1[C:12]([CH3:14])([CH3:13])[C:4]2[C:3](=[CH:11][CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])[N:1]=1
Reactant: NNc1cccc(C(=O)O)c1
Reactant: CC(=O)C(C)C
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CC1=Nc2cccc(C(=O)O)c2C1(C)C
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A solution of 3-hydrazinobenzoic acid (30.0 g, 197 mmol), isopropylmethylketone (31.7 mL, 296 mmol) in ethanol (500 mL) and sulfuric acid (5 mL) was heated under reflux in an oil bath for 20 h. After cooling to ambient temperature the solvent was evaporated off under reduced pressure to a small volume of ˜200 mL. Collected the solid with a filter funnel, washed with iPrOH (3×30 mL) and ethyl ether (3×30 mL) and dried. Further drying of the solid in an oven at 45° C. under high vacuum for 18 h provided 32.59 g (81.3%) of the product. (This is [0148]1.2)
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[CH:3]=1.ClC1C=C(N2[C:22]([C:23]3[CH:28]=[C:27]([O:29][C:30](F)([F:32])[F:31])[CH:26]=[C:25](F)[CH:24]=3)=[CH:21][C:20]([C:35]([OH:37])=[O:36])=N2)C=CC=1F>>[Cl:1][C:25]1[CH:24]=[C:23]([C:22]2[N:8]([C:4]3[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=3)[N:9]=[C:20]([C:35]([OH:37])=[O:36])[CH:21]=2)[CH:28]=[C:27]([O:29][CH:30]([F:32])[F:31])[CH:26]=1
Reactant: Cl
Reactant: O=C(O)c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1
Reactant: NNc1cccnc1
Product: O=C(O)c1cc(-c2cc(Cl)cc(OC(F)F)c2)n(-c2cccnc2)n1

Procedure:
350 mg (0.80 mmol) of the compound from example 5A is reacted with 128 mg (0.88 mmol) 3-pyridylhydrazine hydrochloride in a manner analogous to the synthesis of the compound from example 8A. Following hydrolysis, 176 mg (60% of theoretical yield) of the title compound is produced.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[C:7](=[O:8])[O:6][CH:5]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH3:25])[CH2:14][C:15](C)=[CH:16]C(C)=CC(OC)=O.[O:26]=[O+][O-]>[Zn].C(O)(=O)C>[CH3:1][O:2][CH2:3][CH:4]1[C:7](=[O:8])[O:6][CH:5]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH3:25])[CH2:14][C:15](=[O:26])[CH3:16]
Reactant: COCC1C(=O)OC1CCCCC(C)CC(C)=CC(C)=CC(=O)OC
Reactant: O=[O+][O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: COCC1C(=O)OC1CCCCC(C)CC(C)=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 400 mg (1.135 mmole) of methyl 11-(3-methoxymethyl-4-oxo-2-oxetanyl)-3,5,7-trimethyl-2,4-undecadienoate in 10 ml of CHCl2 at -78° C., was bubbled ozone for 8 minutes. The resulting mixture was stirred for 30 minutes at -78° C. then at room temperature for another 30 minutes. Acetic acid and zinc dust were added. After stirring for 1 hour at room temperature, the solution was filtered and the filtrate was concentrated to dryness. The product was purified by flash column chromatography to give 8-(3-methoxymethyl-4-oxo-2-oxetanyl)-4-methyl-2-octanone as a colorless oil. ##STR11##
Reaction SMILES: [C:1]1([CH2:7][C:8]2[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:15](OCC)(OCC)OCC.[CH3:25][C:26]1([CH2:31][NH2:32])OCCO1>[Ti](Cl)(Cl)(Cl)Cl>[CH3:25][C:26]1[N:10]([C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=[N:32][CH:31]=1
Reactant: CC1(CN)OCCO1
Reactant: Nc1ccccc1Cc1ccccc1
Reactant: CCOC(OCC)OCC
Agent: Cl[Ti](Cl)(Cl)Cl
Product: Cc1cncn1-c1ccccc1Cc1ccccc1

Procedure:
In the manner given in Example 3, α-phenyl-o-toluidine is reacted with triethyl orthoformate, the resulting oil is heated with 2-methyl-2-(aminomethyl)-1,3-dioxolane, and the resulting product treated with titanium tetrachloride to give 5-methyl-1-(α-phenyl-o-tolyl)imidazole.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2OC)=[CH:2]1.C(N(CC)CC)C.[C:50]([O:53][C:54](=O)[CH3:55])(=O)C.[O:57]1CCCC1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH:23][C:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:12][NH:13][C:14](=[O:57])[CH2:15][CH2:20][C:19]2[CH:18]=[CH:17][CH:16]=[CH:55][C:54]=2[O:53][CH3:50])=[CH:2]1
Reactant: C1CCOC1
Reactant: COc1ccccc1CNCC(Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccccc1CCC(=O)NCC(Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 87 %

Procedure:
To a stirring solution of 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]-2-(N-triphenylmethylamino)propane (0.404 mole) in anhydrous tetrahydrofuran (1.2 liters) under a nitrogen atmosphere at 0° C. was added triethylamine (66.5 ml, 0.477 mole) and acetic anhydride (45.0 ml, 0.477 mole). After 4 hours, the mixture was concentrated on a rotary evaporator, redissolved in methylene chloride and ethyl acetate, washed with water (2×) and brine (2×), dried over anhydrous sodium sulfate, filtered, and concentrated to a solid on a rotary evaporator. The resulting solid was dissolved in chloroform and loaded onto silica gel 60 (230-400 mesh) and eluted with a 1:1 mixture of ethyl acetate and hexanes. The product was then crystallized from an ethyl acetate/hexanes mixture. The resulting product of 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane was crystallized and isolated over three crops giving 208.97 grams (87% yield) of analytically pure material.