Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([O:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])=[O:2].[CH:19]1([NH:25][C:26](=O)[CH2:27][NH2:28])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-:31].[Na+].[Na+]>O1CCCC1>[CH:19]1([N:25]([CH2:26][C:27]([NH2:28])=[O:31])[C:16](=[O:17])[CH2:15][CH2:14][CH2:13][O:12][C:5]2[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([CH:1]=[O:2])[CH:4]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=Cc1cc(OCCCC(=O)Cl)ccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Reactant: NCC(=O)NC1CCCCC1
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=O)CN(C(=O)CCCOc1ccc([N+](=O)[O-])c(C=O)c1)C1CCCCC1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 4-(3-formyl-4-nitrophenyl)oxybutyric acid chloride was added dropwise to a solution of N-cyclohexyl glycinamide (7.8 g) and sodium carbonate (6.90 g) in aqueous tetrahydrofuran cooled to 5° C. The reaction was stirred at room temperature for 1 hour, then extracted with ethyl acetate. The organic extract was washed with saturated sodium bicarbonate three times, 3×1M HCl and 2×brine, filtered and the solvent evaporated to give 2-(N-cyclohexyl-4-(3-formyl-4-nitrophenyl)oxybutyramidyl)acetamide as a solid, m.p. 104°-105° C. Similarly, treatment of cyclohexyl R7R8 -N-substituted acetamides from Preparation 2 gives the corresponding 2-(N-cyclohexyl-4-(3-nitro-4-formylphenyl)oxybutyramidyl-R7R8 -N-substituted acetamides.
Reaction SMILES: BrCCBr.Cl[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[CH3:13].[C:14]1(=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1>[Cl:12][C:8]1[C:7]([CH3:13])=[C:6]([C:14]2([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1c(Cl)cccc1Cl
Reactant: O=C1CCCCC1
Solvent: C1CCOC1
Solvent: BrCCBr
Product: Cc1c(Cl)cccc1C1(O)CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
96 g (4 moles) of Mg turnings in 60 ml of absolute tetrahydrofuran (THF) are initially taken under a nitrogen atmosphere. 1 ml of 1,2-dibromoethane is added at 65° C., after which a solution of 644 g (4 moles) of 2,6-dichlorotoluene in 1.5 1 of absolute THF is added dropwise in the course of 21/4 hours. Thereafter, the mixture is stirred for 4 hours under reflux and cooled to room temperature, and 352.8 g (3.6 moles) of cyclohexanone in 250 ml of absolute THF are added under nitrogen. When the reaction is complete, the Grignard reaction mixture is worked up in an aqueous medium in a conventional manner and the solvent is substantially removed by distillation under reduced pressure. The residue is subjected to incipient distillation (30°-107° C./0.27 mbar). The remaining crude product (676 g), which contains as much as 90% of 1-(3'-chloro-2'-methylphenyl)-cyclohexanol, can be further purified by column chromatography using toluene as the mobile phase.
Reaction SMILES: [O-2].[Nd+3:2].[O-2].[O-2].[Nd+3].[Nd].[CH2:7]([CH:9]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:10][O:11][P:12](=[O:23])([OH:22])[O:13][CH2:14][CH:15]([CH2:20][CH3:21])[CH2:16][CH2:17][CH2:18][CH3:19])[CH3:8].CC1CCCCC1.[N+]([O-])(O)=O>O>[CH2:7]([CH:9]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:10][O:11][P:12]([O-:23])([O:13][CH2:14][CH:15]([CH2:20][CH3:21])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:22])[CH3:8].[Nd+:2]
Reactant: CCCCC(CC)COP(=O)(O)OCC(CC)CCCC
Reactant: [Nd+3]
Agent: [Nd]
Agent: [O-2]
Solvent: O=[N+]([O-])O
Solvent: O
Solvent: CC1CCCCC1
Product: CCCCC(CC)COP(=O)([O-])OCC(CC)CCCC
Product: [Nd+]
Reaction time: 0.5 h
Yield: 95 %

Procedure:
3.03 g of neodymium oxide containing 72.4% by weight of neodymium, 16.15 g of di(2-ethylhexyl)phosphoric acid (DEHPA), 80 g of methylcyclohexane (MCH) and 1.8 ml of nitric acid at 0.5 mol/l are introduced into a reactor made inert beforehand with argon. This amount of nitric acid corresponds to 0.06 molar equivalent of HNO3 relative to the neodymium. The mixture is stirred and brought to 80° C. until the presence of solid can no longer be distinguished visually, i.e., in this case, 3 h. The mixture is cooled. Three washes with 20 g of water are successively carried out in order to remove the inorganic residues. Each wash comprises a step of stirring for 30 minutes and then a step of separating by settling out, also for 30 minutes. 20 g, 19.5 g and then 19.5 g are thus recovered. The water/MCH azeotrope is subsequently distilled with a Dean Stark apparatus. A solution of neodymium di(2-ethylhexyl)phosphate in MCH, with a clear appearance, is thus obtained. It is characterized by a content of neodymium in solution of 2.05%, a residual free acidity expressed as percentage by weight of DEHPA of 1.59%, and a water content of 209 ppm. In this case, the molar ratios are the following: DEHPA/Nd=0.34 and water/Nd=0.08. The attack yield is 95%.
Reaction SMILES: [CH3:1][C:2]1([NH:14]C(=O)OC(C)(C)C)[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[N:12][CH:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1([NH2:14])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[N:12][CH:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1
Reactant: CC1(NC(=O)OC(C)(C)C)CCN(c2cnccn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(N)CCN(c2cnccn2)CC1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
To a solution of tert-butyl [4-methyl-1-(2-pyrazinyl)-4-piperidinyl]carbamate obtained in Example 10-6 (508 mg) in dichloromethane (1 mL), was added trifluoroacetic acid (5 mL), and the mixture was stirred for 30 minutes at 20° C. The resulting mixture was evaporated in vacuo. The residue was neutralized with sodium hydrogencarbonate and extracted with chloroform three times. The organic layer was washed with brine, dried over MgSO4, and concentrated to give the title compound as a pale yellow solid (281 mg).
Reaction SMILES: [O:1]1[C@@H:7]2[C@H:2]1[C:3]([CH3:15])([CH3:14])[O:4][C:5]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:6]=12.[C:16]([N:18]=[C:19]1[NH:23][CH2:22][CH2:21][S:20]1)#[N:17]>C(N(CC)CC)C>[C:16]([N:18]=[C:19]1[N:23]([C@@H:7]2[C:6]3[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:5]=3[O:4][C:3]([CH3:15])([CH3:14])[C@H:2]2[OH:1])[CH2:22][CH2:21][S:20]1)#[N:17]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H]2O[C@@H]21
Reactant: N#CN=C1NCCS1
Solvent: CCN(CC)CC
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCSC2=NC#N)[C@@H]1O
Yield: 56.9 %

Procedure:
A mixture of (3S,4S)-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.603 g) and 2 -cyanoiminothiazolidine (0.762 g) in triethylamine (4.2 ml) was heated under reflux for 9 hours. The resulting precipitates were collected by filtration, and washed with water, and recrystallized from ethanol to give (3S,4R)-4(2-cyanoiminothiazolidin-3-yl)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.56 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29].CCCP(=O)=O>O1CCCC1>[CH2:28]([N:30]([CH2:31][CH3:32])[C:25]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=[C:11]2[CH:10]=1)=[O:24])=[O:27])[CH3:29]
Reactant: CCNCC
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 20 h
Yield: 80.7 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), diethylamine (142 μl, 1.38 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7 ml) is stirred for 20 hours at 70° C. under nitrogen atmosphere. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried affording N4,N4-diethyl-1-methyl-N5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (93 mg, 80.7%) as a white solid. mp.: 177-9° C. MS: m/z=418.3 (M+H+).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>C(Cl)Cl>[CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([N:42]4[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]4)=[O:24])=[CH:26][CH:27]=3)=[O:18])[CH2:15][CH2:16]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Reactant: C1CNCCN1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N3CCNCC3)cc2)CC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
4-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid (1.5 g) was dissolved in methylene chloride (50 ml) and then, triethylamine (0.7 ml) was added and cooled. Pivaloyl chloride (0.58 ml) was added slowly to the solution at 0~5° C. and the mixture was stirred at 5° C. for 2 hours. With the addition of piperazine (0.9 g), the solution was stirred at 5~10° C. for 3 hours. The reaction mixture was washed with water and aqueous sodium bicarbonate and the solvent was concentrated under reduced pressure. The concentrated residue was crystallized by treatment with ether and further recrystallized using isopropanol and ether. The recrystallized product was filtered and dried to give 1.48 g (yield: 83%) of the desired compound as white crystal.
Reaction SMILES: [Cl:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][NH2:30])[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O>[ClH:1].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][CH2:29][NH:30][C:2]2[N:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([N:6]([CH3:8])[CH3:7])=[O:5])[CH2:25][CH2:26]1
Reactant: COc1ccccc1N1CCN(CCCN)CC1
Reactant: CN(C)C(=O)c1cccnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccccc1N1CCN(CCCNc2ncccc2C(=O)N(C)C)CC1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 66.7 %

Procedure:
A mixture of 2-chloro-N,N-dimethylnicotinamide (174.3 g, 0.94 mmol), prepared as in Example 13, 3-[4-(2-methoxyphenyl)piperazin-1-yl]propylamine (224 g, 0.9 mmol), prepared as in Example 7, and potassium carbonate (250.5 g, 1.81 mmol) in 4 L of xylenes was heated at gentle reflux (133° to 136° C.) for 39 hours. The mixture was allowed to cool to 50° C. and then 1 L of water was added. The organic layer was separated, washed with water (2×500 mL) and concentrated under reduced pressure. The residue was dissolved in 6 L of ethyl acetate and the solution was washed with water (3×1 L) and saturated sodium chloride (2×250 mL), dried (MgSO4) and filtered. The filter was rinsed with 1 L of ethyl acetate and the combined filtrate was concentrated to approximately 4.8 L. A solution of 3.8N hydrochloric acid (175 mL, 0.67 mmol) in ethanol was added and the mixture was aged at room temperature for 90 minutes and then filtered. The filtered residue was washed with ethyl acetate (4×500 mL), dried under reduced pressure at 79° C. for 18 hours to give 2-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propylamino}-N,N-dimethylnicotinamide hydrochloride (259.4 g, 0.6 mmol), m.p. 204°-206° C. Anal.: Calcd. for C22H31N5O2.HCl: C, 60.89; H, 7.43; N, 16.14%; Found: C, 61.14; H, 7.46; N, 15.96%.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5](F)[CH:4]=1)#[N:2].C(=O)([O-])[O-:13].[K+].[K+]>CN(C)C=O.O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([OH:13])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)c(F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C=O)c(O)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 4-cyano-2-fluorobenzaldehyde (11.73 g, 78.7 mmol) and potassium carbonate (14.12 g, 102.3 mmol) was dissolved in dry dimethylformamide (35 ml). To this was added water (6.63 ml, 368.5 mmol). The resulting solution was heated to 90° C. with stirring. A further equivalent of water (1.42 ml) was added after 2 hours, then a further two equivalents of water (2.84 ml) 1 hour later. The resulting solution was left overnight. After 24 hours a further 2 equivalents of water (2.84 ml) was added, then heated for a further 2 hours at 90° C. The cooled solution was diluted with water to form a murky yellow solution. The solid precipitate was filtered. The remaining yellow filtrate was acidified with concentrated hydrochloric acid to produce a yellow solid. This was filtered, then dried at 40° C. overnight to give 4-cyano-2-hydroxybenzaldehyde as a yellow solid.
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@H:7]1[CH2:15][CH2:14][CH2:13][C@@:12]2([CH3:16])[C@H:8]1[CH2:9][CH2:10][C@@H:11]2[C@H:17]([CH3:20])[CH2:18][OH:19])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH:54][C:55]([CH3:60])([CH3:59])[C:56](O)=[O:57]>C1COCC1.O>[C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@H:7]1[CH2:15][CH2:14][CH2:13][C@@:12]2([CH3:16])[C@H:8]1[CH2:9][CH2:10][C@@H:11]2[C@H:17]([CH3:20])[CH2:18][O:19][C:56](=[O:57])[C:55]([OH:54])([CH3:60])[CH3:59])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Reactant: CC(C)(O)C(=O)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](COC(=O)C(C)(C)O)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Temperature: 0 °C
Yield: 0.1 %

Procedure:
200 mg (0,612 mmol) of (S)-2-[(1R,3aR,4S,7aR)-4-(tert-butyl-dimethyl-silanyloxy)-7a-methyl-octahydro-inden-1-yl]-propan-1-ol was dissolved in THF (2 ml). PPh3 (169 mg; 0,643 mmol) was added and the mixture cooled to 0° C. To this, a solution of DEAD (95 mg; 0,612 mmol) and 2-hydroxy-isobutyric acid (64 mg; 0,612 mmol) in THF (2 ml) was added dropwise via cannula. After four hours the reaction mixture was poured in cold water, extracted with ether and dried over Na2SO4. Removal of the solvent and silica gel column chromatography (eluent hexane/ethyl-acetate 85/15) of the residue afforded 232 mg (91%) of 2-hydroxy-2-methyl-propionic acid(S)-2-[(1R,3aR,4S,7aR)-4-(tert-butyl-dimethyl-silanyloxy)-7a-methyl-octahydro-inden-1-yl]-propyl ester (K1) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH:7]=1.[CH:22]([N:25]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][N:37]=1)[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:24])[CH3:23].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.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:28]([O:27][C:26]([N:25]([CH:22]([CH3:24])[CH3:23])[C:33]1[S:34][C:35]([C:2]2[CH:3]=[C:4]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]3[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=3)[CH:7]=2)=[CH:36][N:37]=1)=[O:32])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)N(C(=O)OC(C)(C)C)c1ncc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: CCOC(=O)c1cn2cc(Br)cc(-c3ccccc3)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cn2cc(-c3cnc(N(C(=O)OC(C)(C)C)C(C)C)s3)cc(-c3ccccc3)c2n1
Temperature: 80 °C
Yield: 51 %

Procedure:
A solution of ethyl 6-bromo-8-phenylimidazo[1,2-a]pyridine-2-carboxylate (0.10 g, 0.29 mmol) and tert-butyl isopropyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate (0.128 g, 0.34 mmol) in toluene (3 mL) and ethanol (1 mL) was bubbled nitrogen for 20 mins. The mixture was then treated with Pd(PPh3)4 (30 mg, 0.026 mmol) and K3PO4 (2 M, 1 mL, 2 mmol) and heated at 80° C. overnight. The reaction was cooled, poured into ethyl acetate (200 mL), washed with brine, separated, and concentrated. The residue was purified by column chromatography on silica gel using ethyl acetate in hexanes (10-50%) as eluent. The product containing fractions were concentrated to give 75 mg (53% yield) of ethyl 6-(2-(tert-butoxycarbonyl-(isopropyl)amino)thiazol-5-yl)-8-phenylimidazo[1,2-a]pyridine-2-carboxylate as a white solid. LCMS (Conditions C): 4.30 min (RT); (M+H)+=507.38 (100%).
Reaction SMILES: COS(OC)(=O)=O.[Br:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)[CH:12]=[CH:13][CH:14]=1.[C:20]1(C)C=CC=CC=1.[OH-].[Na+]>O>[Br:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([CH3:20])[CH:19]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccccc1
Reactant: Brc1cccc(-c2c[nH]cn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: Cn1cnc(-c2cccc(Br)c2)c1
Temperature: 100 °C
Yield: 33 %

Procedure:
Using the method of Hazeldine et al., J. Chem. Soc., 125, 1431-41 (1924) a mixture of dimethylsulphate (145 μl, 1.53 mmol) and 4-m-bromophenyl imidazole (341 mg; 1.54 mmol) was stirred under N2 until the reaction mixture became extremely viscous. Toluene (150 μl) was added, and the mixture was heated at 100° C. for 1 hour. After cooling to ambient temperature, H2O (5 ml) was added, and the reaction mixture was brought to pH 9 with NaOH solution. It was then extracted with CH2Cl2 (2×10 ml). The organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo to give 262 mg crude product mixed with starting material. Purification using preparative TLC on 2-1000μ Si Gel GF plates (eluting with 5% MeOH in CH2Cl2 and extracting with 10% MeOH in CH2Cl2) provided the product, 4-m-bromophenyl-1-methylimidazole (121 mg, 33% yield) as the least polar band.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[CH:18]=[CH:19][C:20]([N+:32]([O-:34])=[O:33])=[C:21]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:22]=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:17]2[CH:18]=[CH:19][C:20]([N+:32]([O-:34])=[O:33])=[C:21]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[CH:22]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(OCc3ccccc3)cc2)ccc1[N+](=O)[O-]
Yield: 92.5 %

Procedure:
By using 1.60 g of 4-benzyloxyphenol, 2.29 g of t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate, 0.35 g of sodium hydride (55% by weight) and 20 ml of anhydrous N,N-dimethylformamide, reaction and purification were carried out in a similar manner to that described in Reference Example 6, whereby 3.33 g of the title compound were obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:16](O)[CH2:17][OH:18]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:17]1[O:18][C:12]2([CH2:13][CH2:14][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=3)=[CH:10][CH2:11]2)[O:15][CH2:16]1
Reactant: N#Cc1cccc(C2=CCC(=O)CC2)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1cccc(C2=CCC3(CC2)OCCO3)c1
Yield: 87.5 %

Procedure:
4-(3-cyanophenyl)-3-cyclohexene-1-one (from step 1 of method 2, 1.8 g, 9.0 mmole), ethylene glycol (2.8 g, 45 mmole) and p-toluenesulfonic acid monohydrate (0.1 g, 0.5 mmole) were dissolved in 50 ml toluene. The reaction was refluxed for 2 hours. The organic layer was washed with water (2×50 mL) and dried over sodium sulfate. The residue from the organic layer was purified by column chromatography using ethyl acetate/hexane (15/85) as the eluent to afford 4-(3-cyanophenyl)-3-cyclohexene-1-one ethylene ketal(1.9 g, 87%).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[Cl:12][C:13]1[CH:26]=[CH:25][C:16]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[CH:15][CH:14]=1.O>CCCCCC.C(OCC)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:8]2[N:7]([CH3:6])[CH:11]=[CH:10][N:9]=2)[OH:18])=[CH:25][CH:26]=1
Reactant: Cn1ccnc1
Reactant: O=C(c1ccccc1)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: Cn1ccnc1C(O)(c1ccccc1)c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
A solution of 25.5 g (0.08 mol) of 20% butyl lithium in n-hexane in 50 ml. of anhydrous diethyl ether was added at room temperature to a solution of 5 g (0.06 mol) of 1-methylimidazole in 50 ml. of anhydrous diethyl ether. The reaction mixture was stirred for one hour and then a solution of 15.6 g (0.07 mol) of 4-chlorobenzophenone in diethyl ether was added dropwise. The reaction mixture was stirred for 3 hours and it was then poured into a mixture of ice and water. The solid matter was filtered off and crystallised from ethanol. α-(p-Chlorophenyl)-1-methyl-α-phenylimidazole-2-methanol was obtained. Melting point 185°-186° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[O:23][CH3:24]>[N+](C1C=CC=CC=1)([O-])=O>[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([C:20]2[CH:21]=[C:16]([F:15])[C:17]([O:23][CH3:24])=[CH:18][C:19]=2[F:22])=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: COc1cc(F)ccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1cc(F)c(C(=O)c2ccc(Br)cc2)cc1F
Temperature: 25 °C

Procedure:
75 ml of nitrobenzene are cooled in an ice bath and treated in succession 25 with 17.3 g of aluminium chloride and 4-bromobenzoyl chloride in 25 ml of nitrobenzene at a maximum 6° C. The mixture is stirred for 10 min., whereupon 15.7 g of 2,5-difluoroanisole are added in such a manner that the temperature does not exceed 6° C. The solution is left to warm to room temperature overnight, then poured on to ice-water and extracted with methylene chloride. The organic phase is washed with water and 10% sodium chloride solution, dried over sodium sulphate and concentrated. After crystallization from cyclohexane there are obtained 28.4 g of (4-bromo-phenyl)-(2,5-difluoro-4-methoxy-phenyl)-methanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:22])[C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Cl.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:22])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:33][C:32]4[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=4[Cl:30])=[C:15]([O:20][CH3:21])[CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:23]=1
Reactant: COc1cc(C(=O)N2CCCCc3cc(Cl)ccc32)ccc1O
Reactant: ClCc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)N2CCCCc3cc(Cl)ccc32)ccc1OCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-chloro-1-(3-methoxy-4-hydroxybenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.7 g) in dry dimethylformamide (20 ml) are added potassium carbonate (0.35 g) and 2-chlorobenzyl chloride (0.32 ml), and the mixture is stirred at room temperature overnight. To the reaction solution is added water, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried, and evaporated to remove the solvent. The residue is recrystallized from acetone/diethyl ether to give 7-chloro-1-[3-methoxy-4-(2-chlorobenzyloxy)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.76 g) as white powder.