Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[OH:16])([CH3:8])([CH3:7])[CH3:6].[CH:17](OCC)(OCC)[O:18]CC.Cl>ClC1C=CC=CC=1>[C:5]([C:9]1[C:10]([OH:16])=[CH:11][C:12]([CH3:15])=[C:13]([CH:14]=1)[CH:17]=[O:18])([CH3:8])([CH3:7])[CH3:6]
Reactant: Cc1ccc(C(C)(C)C)c(O)c1
Reactant: CCOC(OCC)OCC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: Cc1cc(O)c(C(C)(C)C)cc1C=O
Temperature: -10 °C
Reaction time: 6 h

Procedure:
Aluminum chloride (26.6 g, 200 mmol) was added to chlorobenzene (40 mL), and the mixture was cooled to −10° C. A solution of 2-tert-butyl-5-methylphenol (16.4 g, 100 mmol) in triethyl orthoformate (32.5 g, 220 mmol) was added dropwise. When addition was complete, the reaction mixture was warmed to 0° C. to 5° C. and kept at that temperature for 6 hours. Five percent HCl (100 mL) was added, and the mixture was extracted with 1:1 EtOAC:toluene. The organic phase was extracted with 23% KOH (3×50 mL) and water (25 mL), and the water extract was combined with the KOH extracts. The pH of the combined aqueous extracts was adjusted to 4 with 37% HCl. The resulting precipitate was filtered, washed with water (3×50 mL), and dried to give the title compound, mp 171-171° C.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([CH2:26][CH3:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)(=O)C.O.[OH-].[Li+]>CO.O>[C:32]([O:31][C:29]([NH:28][C:6]([CH2:26][CH3:27])([CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:14]=1)[CH2:5][OH:4])=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CCC(CCc1ccc(OCCCCc2ccccc2)cc1)(COC(C)=O)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(CO)(CCc1ccc(OCCCCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 116 %

Procedure:
To a solution of 2-tert-butoxycarbonylamino-2-ethyl-4-(4-(4-phenylbutyloxy)phenyl)butyl acetate (3.4 g) in methanol (50 ml) was added a solution of lithium hydroxide monohydrate (0.33 g) in water (10 ml) and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure to give the subject compound (3.6 g).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3](=[O:8])[C@@H:4]([CH2:6][OH:7])[NH2:5].S=[C:11]1[CH2:15][S:14][C:13](=[O:16])[NH:12]1>C(O)C>[O:16]=[C:13]1[N:12]=[C:11]([NH:5][C@@H:4]([C:3]([N:2]([CH3:9])[CH3:1])=[O:8])[CH2:6][OH:7])[CH2:15][S:14]1
Reactant: O=C1NC(=S)CS1
Reactant: CN(C)C(=O)[C@H](N)CO
Solvent: CCO
Product: CN(C)C(=O)[C@@H](CO)NC1=NC(=O)SC1
Yield: 70.8 %

Procedure:
To a solution of N,N-dimethyl-D-serinamide (645 mg) in ethanol (20 mL) was added 4-thioxo-1,3-thiazolidin-2-one (650 mg), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate), and the obtained powder was washed with ethyl acetate to give the title compound (799 mg).
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[CH:7]=[N:8][C:9]([N:12]3[CH2:17][CH2:16][N:15]([C:18]4[N:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]5[CH:26]=[N:27][N:28]([CH2:30][C@H:31]6[O:36][CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]6)[CH:29]=5)[N:19]=4)[CH2:14][CH2:13]3)=[N:10][CH:11]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]#[C:5][C:6]2[CH:11]=[N:10][C:9]([N:12]3[CH2:13][CH2:14][N:15]([C:18]4[N:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]5[CH:26]=[N:27][N:28]([CH2:30][C@H:31]6[O:36][CH2:35][CH2:34][NH:33][CH2:32]6)[CH:29]=5)[N:19]=4)[CH2:16][CH2:17]3)=[N:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(N4CCN(c5ncc(C#CC6CC6)cn5)CC4)n3)cn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C(#CC1CC1)c1cnc(N2CCN(c3ncnc(Nc4cnn(C[C@@H]5CNCCO5)c4)n3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
To a solution of (S)-tert-butyl 2-((4-(4-(4-(5-(cyclopropylethynyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (30 mg, 0.05 mmol) in dichloromethane (2 mL) was dropwise added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 0.5 hour and concentrated. The residue was purified by Prep-HPLC to afford (S)-4-(4-(5-(cyclopropylethynyl)pyrimidin-2-yl)piperazin-1-yl)-N-(1-(morpholin-2-ylmethyl)-1H-pyrazol-4-yl)-1,3,5-triazin-2-amine (14 mg, 57%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([CH3:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:16]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:16])=[C:7]([CH3:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C(C)(C)C)cc([N+](=O)[O-])c1O
Agent: [K+]
Solvent: CC(C)=O
Product: COc1c(C)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
4-tert-Butyl-2-methyl-6-nitro-phenol (209 mg, 1 mmol) was dissolved in 3 mL acetone. 552 mg K2CO3 (4 eq) was added, followed by addition of Mel (0.33 mL, 5 mmol). The reaction mixture was stirred vigorously at 60° C. overnight. After removal of the acetone, the residue was shaken with DCM. Filtration and evaporation of the solution yielded 221 mg product which was used as such.
Reaction SMILES: [CH3:1][N:2]([NH:4][C:5]([C:7]1[N:8]([CH3:24])[CH:9]=[C:10]([NH:12][C:13]([C:15]2[N:16]([CH3:23])[CH:17]=[C:18]([N+:20]([O-])=O)[N:19]=2)=[O:14])[N:11]=1)=[O:6])[CH3:3]>CO.[Pd]>[CH3:3][N:2]([NH:4][C:5]([C:7]1[N:8]([CH3:24])[CH:9]=[C:10]([NH:12][C:13]([C:15]2[N:16]([CH3:23])[CH:17]=[C:18]([NH2:20])[N:19]=2)=[O:14])[N:11]=1)=[O:6])[CH3:1]
Reactant: CN(C)NC(=O)c1nc(NC(=O)c2nc([N+](=O)[O-])cn2C)cn1C
Agent: [Pd]
Solvent: CO
Product: CN(C)NC(=O)c1nc(NC(=O)c2nc(N)cn2C)cn1C

Procedure:
A solution of N-(N',N'-dimethylamino)-1-methyl-4-[1-methyl-4-nitroimidazole-2-carboxamido]-imidazole-2-carboxamide (0.50 g, 1.49 mmol) and 5% Pd on charcoal (0.2 g) in chilled methanol (20 mL) was purged of air and hydrogenated at room temperature for 6 hours. The catalyst was removed by filtration and the methanol evaporated under reduced pressure to give N-(N',N'-dimethylamino)-1-methyl-4-[1-methyl-4-aminoimidazole-2-carboxamido]-imidazole-2-carboxamide as an unstable yellow solid.
Reaction SMILES: [CH2:1]([SH:5])[CH:2]([CH3:4])[CH3:3].[H-].[Na+].Cl[C:9]1[N:14]=[C:13]([Cl:15])[CH:12]=[C:11]([O:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[N:10]=1.O>C1COCC1>[Cl:15][C:13]1[N:14]=[C:9]([S:5][CH2:1][CH:2]([CH3:4])[CH3:3])[N:10]=[C:11]([O:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH:12]=1
Reactant: CC(C)CS
Reactant: CC(C)CCOc1cc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CCOc1cc(Cl)nc(SCC(C)C)n1
Temperature: 20 °C
Yield: 108.3 %

Procedure:
A solution of 6.7 ml (55.3 mmol) of isobutyl mercaptan in 40 ml of THF is added dropwise to a suspension of 2.2 g of NaH in 90 ml of THF. During this addition, the temperature is prevented from rising above 50° C. by cooling. The solution is cooled to 20° C. and added to a solution of 13.0 g of 2,4-dichloro-6-(3-methylbut-1-oxy)pyrimidine in 80 ml of THF at -10° C. When the temperature has slowly risen to 25° C., the reaction mixture is poured into 200 ml of water. Extraction three times with toluene, drying of the combined organic phases using MgSO4 and evaporation of the solvent give 17.3 g of a mixture. Separation on SiO2 (petroleum ether 80°-110° C.) gives 11.5 g (71.9% of theory) of the title product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([Na:10])[CH:9]=[CH:8][CH:7]=[CH:6]1)=[O:4].Cl[C:12]([O:14][CH3:15])=[O:13]>O1CCCC1>[CH3:15][O:14][C:12]([C:6]1[C:5]([C:3]([O:2][CH3:1])=[O:4])([Na:10])[CH:9]=[CH:8][CH:7]=1)=[O:13]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1([Na])C=CC=C1
Solvent: C1CCOC1
Product: COC(=O)C1=CC=CC1([Na])C(=O)OC
Yield: 28.5 %

Procedure:
To a tetrahydrofuran solution of methoxycarbonyl cyclopentadienyl sodium (28 mmol/28 ml) preparated by the Rausch method, a tetrahydrofuran solution of methyl chloroformate (2 g/30 ml) was added under cooling with ice. When the solution reached room temperature, it was filtered and concentrated under reduced pressure. Then, methylene chloride was added thereto to precipitate slightly pink precipitates. The precipitates were collected by filtration and dried to obtain 1.23 g of dimethoxycarbonylcyclopentadienyl sodium.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[C:9]1([S:15]([NH:18][CH:19]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C(Cl)CCl>[CH3:6][C:5]([C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[CH2:27][CH:19]([NH:18][S:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:16])=[O:17])[CH2:20]2)=[O:7]
Reactant: CC(=O)Cl
Reactant: O=S(=O)(NC1Cc2ccccc2C1)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
29.6 g (0.22 mol) of anhydrous aluminium chloride are suspended in 250 ml of ethylene chloride and 10.5 g (0.133 mol) of acetyl chloride and 24.2 g (0.0885 mol) of 2-(benzenesulphonamido)-indane are added successively. After the mixture has been stirred for approx 3 hours at room temperature, it is decomposed with ice and concentrated hydrochloric acid. The reaction product is obtained by concentrating the organic phase and subsequently crystallising the product from cyclohexane/ethyl acetate.
Reaction SMILES: [OH:1][CH:2]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=1)[CH2:3][N:4]([CH3:24])[C:5]([C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)=[N:9][C:10]([N:13]([CH3:15])[CH3:14])=[N:11][CH:12]=1)=[O:6].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:32]([O:31][C:27]1[CH:26]=[C:25]([CH:2]([OH:1])[CH2:3][N:4]([CH3:24])[C:5]([C:7]2[C:8]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)=[N:9][C:10]([N:13]([CH3:14])[CH3:15])=[N:11][CH:12]=2)=[O:6])[CH:30]=[CH:29][CH:28]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: CN(CC(O)c1cccc(O)c1)C(=O)c1cnc(N(C)C)nc1-c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CN(CC(O)c1cccc(OCc2ccccc2)c1)C(=O)c1cnc(N(C)C)nc1-c1ccc(Cl)c(Cl)c1
Reaction time: 5 h
Yield: 45.3 %

Procedure:
The mixture of 2-dimethylamino-4-(3,4-dichlorophenyl)pyrimidine-5-carboxylic acid [2-hydroxy-2-(3-hydroxyphenyl)ethyl]methylamide (0.92 g, 2 mmol), benzylbromide (1.71 g, 10 mmol), cesium carbonate (1.30 g, 4 mmol) and acetonitrile (25 ml) are boiled under stirring for 5 hours. The reaction mixture is evaporated in vacuum, dichloromethane (50 ml) is added to it, washed with water (3×50 ml), dried over sodium sulphate and evaporated. The residue is chromatographed on silicagel, using dichloromethane—methanol 100/1 mixture as eluent. 0.50 g (45.4%) of pale-yellow crystalline material is obtained, m.p.: 68-70° C.; [M+H]+ 551.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][CH2:13][C:12]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.P(Cl)(Cl)([Cl:31])=O>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][CH:13]=[C:12]2[Cl:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)C(=O)CC=N2
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(C)NC(C)C
Product: COc1cc2nccc(Cl)c2cc1OCc1ccccc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
6-Benzyloxy-7-methoxy-4-quinolone (2.4 g), diisopropylamine (5 eq, 7.4 ml), and phosphorus oxychloride (2.5 eq, 2.0 ml) were added, and the mixture was stirred at 110° C. for one hr. The stirred mixture was concentrated under the reduced pressure. Chloroform and iced water were then added to the concentrate. The mixture was rendered weakly alkaline by the addition of 28% aqueous ammonia, followed by extraction with chloroform. The extract was washed with saturated brine and was dried over sodium sulfate, and the solvent was then removed by evaporation under the reduced pressure. The crude thus obtained was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (1.6 g, yield 63%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:8]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[NH:7]1)=[O:5])[CH3:2].CC(C[AlH]C[CH:20]([CH3:22])[CH3:21])C.CO.[O-]S([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[S:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[CH:8]1[N:7]2[CH:6]1[CH:4]([OH:5])[O:3][CH:1]2[CH:2]1[CH:8]([C:9]2[S:10][CH:22]=[CH:20][CH:21]=2)[NH:7]1
Reactant: CC(C)C[AlH]CC(C)C
Reactant: CCOC(=O)[C@@H]1N[C@H]1c1cccs1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: OC1OC(C2NC2c2cccs2)N2C(c3cccs3)C12
Temperature: -78 °C

Procedure:
In a flame dried 100 ml Schlenk tube equipped with a magnetic stirring bar was placed 1c (0.6 g, 3.05 mmol) in 10 ml toluene. The solution was cooled to −78° C. and a 1.5M solution of DIBAL in toluene (4 ml, 6 mmol) was added dropwise along the wall of the vessel. Once the addition was complete, the reaction was allowed to stir at −78° C. for another hour at which point ESI MS showed the lack of starting material. MeOH was slowly added along the wall of the vessel at −78° C. The reaction mixture was then allowed to stir for 30 minutes while warming to room temperature. Saturated Na2SO4 was then added and the solution was allowed to stir for another 15 minutes. The reaction was then filtered and water and ether was added. The organic later was extracted from the partition three times, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting white solid may be crystallized from EtOAc or MeOH to afford the title compound in 92% (428 mg) yield as a white solid. Silica column chromatography is not recommended. Mp=149-153° C. (decomp.) 1H NMR (CDCl3, 200 MHz) (δ: 7.66 (d, J=11.6 Hz, 1H), 7.23-7.18 (m, 2H), 7.02-6.94 (m, 4H), 5.48 (d, J=11.6 Hz, 1H), 3.27 (dd, J=7.0 Hz, 3.4 Hz, 1H), 2.99 (dd, J=9.0 Hz, 3.4 Hz), 2.90 (d, J=2.6 Hz, 1H), 2.75 (d, J=2.6 Hz, 1H), 1.17 (t, J=6.6 Hz, 1H) ppm. 13C NMR (CDCl3, 75 MHz) δ: 141.5, 121.4, 127.7, 127.3, 125.9, 125.1, 124.8, 124.6, 96.9, 94.4, 54.0, 41.5, 37.5, 32.5 ppm. HRMS (EI) of aldehyde monomer: 152.9561
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[F:36][C:37]([F:41])([F:40])[CH2:38][NH2:39]>>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:39][CH2:38][C:37]([F:41])([F:40])[F:36])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: NCC(F)(F)F
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(NCC(F)(F)F)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (100 mg, 0.190 mmol) and 2,2,2-trifluoroethylamine (0.5 ml, 0.190 mmol) the title compound, was obtained as a white powder (70 mg, 0.116 mmol, 62.7% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.78 (s, 1H), 8.49 (d, J=5.2 Hz, 1H), 7.37-7.51 (m, 4H), 7.21-7.29 (m, 2H), 6.72 (d, J=5.2 Hz, 1H), 4.85 (q, J=8.9 Hz, 2H), 1.42 (s, 9H). MS (ESI): 602.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH:17]=O)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH2:17][N:29]4[CH2:28][CH2:27][C:26]([C:23]5[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=5)([OH:32])[CH2:31][CH2:30]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: O=CC12CC(c3ccccc31)c1ccc(Cl)cc12
Reactant: OC1(c2ccc(F)cc2)CCNCC1
Product: OC1(c2ccc(F)cc2)CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Yield: 27 %

Procedure:
Using a procedure similar to that described in example 21 except starting with 2-chloro-9-formyl-9,10-dihydro-9,10-methanoanthracene (described in example 1i) and 4-(4-fluorophenyl)-4hydroxypiperidine, the title compound hydrochloride salt was obtained in 27% yield as a white powder, mp 280°-281° C. elemental Analysis for C27H25ClFNO.HCl.0.5H2O: Calculated: C, 67.64; H, 5.68; N, 2.92 Found: C, 67.70; H, 5.40; N, 2.84.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:6][N:5]=1)(=[O:3])[CH3:2].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:24])=[C:19](B(O)O)[CH:20]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:6]([C:17]2[CH:16]=[C:15]([Cl:14])[CH:20]=[CH:19][C:18]=2[CH3:24])[N:5]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cc(C(C)=O)n[nH]1
Reactant: Cc1ccc(Cl)cc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(C)=O)nn1-c1cc(Cl)ccc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.8 %

Procedure:
A mixture of ethyl 3-acetyl-1H-pyrazole-5-carboxylate (364 mg, 2.0 mmol), (5-chloro-2-methylphenyl)boronic acid (680 mg, 4.0 mmol), copper(II) acetate (571 mg, 3.0 mmol) and pyridine (0.32 mL, 4 mmol) in DCM (10 mL) was stirred at r.t. under an air atmosphere for 48 h. After removal of the insolubles by filtration, the filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by flash chromatography (hexane/AcOEt, 90/10) to obtain ethyl 3-acetyl-1-(5-chloro-2-methylphenyl)-1H-pyrazole-5-carboxylate as a white solid (269 mg, 43%),
Reaction SMILES: [C:1]([Si:5]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][O:14]C1CCCCO1)([CH3:4])([CH3:3])[CH3:2]>CCOCC>[Si:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][OH:14])([C:1]([CH3:3])([CH3:4])[CH3:2])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)[Si](OCCCCC#CCOC1CCCCO1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: CC(C)(C)[Si](OCCCCC#CCO)(c1ccccc1)c1ccccc1
Yield: 87.8 %

Procedure:
Removal of the THP ether from tert-butyldiphenyl(7-(tetrahydro-2H-pyran-2-yloxy)hept-5-ynyloxy)silane (10 g, 22.22 mmol) as described above furnished 7-(tert-butyldiphenylsilyloxy)hept-2-yn-1-ol (7.15 g, 88%) as a colorless oil. TLC: 30% EtOAc/hexanes, Rf≈0.40; 1H NMR (CDCl3, 300 MHz) δ 7.65-7.67 (m, 4H), 7.33-7.42 (m, 6H), 4.22-4.26 (m, 2H), 3.64 (t, 2H, J=6.4 Hz), 2.12-2.16 (m, 2H), 1.40-1.46 (m, 4H), 1.03 (s, 9H).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][N:36]=1)[C:29]#[N:30].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:30]=[C:29]([C:28]2[CH:31]=[CH:32][C:33]([O:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:37][N:36]=3)=[C:26]([O:25][CH3:24])[CH:27]=2)[N:2]([CH3:1])[N:3]=1
Reactant: COc1cc(C#N)ccc1Oc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: COc1cc(-c2nc(-c3c(F)cccc3Cl)nn2C)ccc1Oc1ccc(C(F)(F)F)cn1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (3.75 g), 3-methoxy-4-(5-trifluoromethylpyridine-2-yloxy)benzonitrile (3.03 g), anhydrous iron (III) chloride (1.70 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (300 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent and washed with hexane to give 2.80 g of desired compound.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:13][N:14]([CH3:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]([OH:24])=O.Cl.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[F:50])[CH:42]2[CH:38]([CH2:39][NH:40][CH2:41]2)[C:37](=[O:43])[CH2:36][CH2:35]1.C(N(CC)CC)C>ClCCl>[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[F:50])[CH:42]2[CH:38]([CH2:39][NH:40][CH:41]2[C:22](=[O:24])[CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([CH3:13])[CH3:25])[C:37](=[O:43])[CH2:36][CH2:35]1
Reactant: CN(C)c1ccccc1CC(=O)O
Reactant: O=C1CCC(c2ccccc2F)(c2ccccc2F)C2CNCC12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1ccccc1CC(=O)C1NCC2C(=O)CCC(c3ccccc3F)(c3ccccc3F)C21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
N,N-Carbonyldiimidazole (0.44 g) is added to a solution of (2-dimethylaminophenyl)acetic acid (0.49 g) in dry dichloromethane (20 cc) cooled to +4° C. The mixture is stirred for 1 hour at 25° C. and a solution of 7,7-bis-(2-fluorophenyl)-4-perhydroisoindolone hydrochloride (1 g) and triethylamine (0.76 cc) in dry dichloromethane (25 cc) is then added dropwise. The reaction mixture is stirred for 20 hours at 25° C. and washed with water (2×100 cc) and with saturated sodium chloride solution (100 cc). The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.063 mm, diameter 2 cm, height 23 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (50/50) and collecting 10 cc fractions. Fractions 14 to 36 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-7,7-bis-(2-fluorophenyl)-2-(2-dimethylaminophenyl)acetyl-4-perhydroisoindolone (1 g), from which the hydrochloride is prepared by dissolving in ethyl acetate (2 cc) and adding a 3N solution of hydrochloric acid in isopropyl ether. The precipitate is drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-bis-(2-fluorophenyl)-2-(2-dimethylaminophenyl)acetyl-4-perhydroisoindolone hydrochloride (0.87 g) is obtained in the form of a white solid.