Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:14])[CH:4]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[OH-].[K+]>C(O)C>[CH2:8]([O:7][C:5](=[O:6])[CH:4]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:3]([OH:14])=[O:2])[CH3:9]
Reactant: CCOC(=O)C(CC(C)C)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(CC(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.7 %

Procedure:
2-Isobutylmalonic acid ethyl ester methyl ester (50.0 g, 231 mmol, 1.0 eq) was dissolved into 280 ml ethanol. To this solution was added solid KOH (12.7 g, 226 mmol, 0.98 eq) and the mixture was stirred at room temperature for 16 hours. The mixture was then concentrated under reduced pressure and redissolved in 500 mL water. The solution was washed 2×250 ml diethyl ether, acidified to pH 2 with 6N HCl, and extracted with 2×250 mL diethyl ether. The organic was dried over MgSO4, and concentrated to yield intermediate (3a) (40.3 g). 1H NMR (DMSO) δ (ppm): 1.0 (dd, 6H), 1.2 (t, 1H), 1.3 (t, 3H), 1.5-1.7 (m, 1H), 1.8 (t, 2H), 3.5 (m, 2H), 4.2 (quart, 2H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[C@@H:14]2[C@@H:9]([C:10]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:11]=3[CH2:12][CH2:13]2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:21][C:2]([F:1])([F:20])[C:3]([N:5]1[C@@H:14]2[C@@H:9]([C:10]3[CH:18]=[CH:17][C:16]([O:19][C:27]4[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)=[CH:15][C:11]=3[CH2:12][CH2:13]2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(N1CCC[C@@H]2c3ccc(O)cc3CC[C@@H]21)C(F)(F)F
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Oc2ccc3c(c2)CC[C@H]2[C@@H]3CCCN2C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of cis-2,2,2-trifluoro-1-(8-hydroxy-2,3,4a,5,6,10b-hexahydro-1H-benzo[f]quinolin-4-yl)-ethanone (0.98 g), 4-methoxyphenylboronic acid (1.00 g), pyridine (1.30 mL), copper(II) acetate (0.60 g), molecular sieves 3 Å (3.60 g), and dichloromethane (15 mL) is stirred in air at room temperature overnight. The mixture is diluted with dichloromethane and filtered over Celite. The filtrate is concentrated and the residue is chromatographed on silica gel (dichloromethane/methanol containing 1% NH3 99:1→95:5) to give the title compound as a colorless resin-like solid. Yield: 1.05 g (79% of theory); LC (method 1): tR=5.00 min; Mass spectrum (ESI+): m/z=406 [M+H]+.
Reaction SMILES: C([Li])CCC.C(NC1CCCCC1)(C)C.[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:17][CH3:18].[F:23][C:24]1[CH:38]=[CH:37][C:27]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[O:29])=[CH:26][CH:25]=1>O1CCCC1>[F:23][C:24]1[CH:38]=[CH:37][C:27]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)([OH:29])[CH:17]([CH3:18])[C:16]([O:20][CH2:21][CH3:22])=[O:19])=[CH:26][CH:25]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCOC(=O)CC
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
Butyl lithium (8.6 mL of 2.1M solution, 18 mmol) was added to a solution of N-isopropylcyclohexylamine (2.8 g, 20 mmol) in 20 mL tetrahydrofuran at -5° C. After stirring for 30 minutes and further cooling to -40° C., ethyl propionate (2.0 g, 20 mmol) was added and the solution stirred for 0.5 hr. After further cooling to -60° C., 4,4'-difluorobenzophenone (2.2 g, 10 mmol) was added and the solution stirred for 2 hours at -60 to -40° C. and for another 2 hours at -15° C. The reaction was quenched with 2N hydrochloric acid and the mixture extracted with diethyl ether. The extracts were dried with magnesium sulfate and concentrated in vacuo. The residue was crystallized from petroleum ether to give 1.95 g of the title compound as a white solid; m.p. =38°-40° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([CH2:25][C:26]#[N:27])[C:17]([NH:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:18].[Cl:28][C:29]1[C:30]([CH:51]=O)=[C:31]2[C:37]([C:38]([OH:40])=[O:39])=[CH:36][N:35]([S:41]([C:44]3[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[C:32]2=[N:33][CH:34]=1>C(Cl)Cl>[Cl:28][C:29]1[C:30]([CH2:51][NH:15][C@H:16]([CH2:25][C:26]#[N:27])[C:17]([NH:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)=[O:18])=[C:31]2[C:37]([C:38]([OH:40])=[O:39])=[CH:36][N:35]([S:41]([C:44]3[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=3)(=[O:42])=[O:43])[C:32]2=[N:33][CH:34]=1
Reactant: N#CC[C@@H](N)C(=O)NC1CCCC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C(=O)O)c3c(C=O)c(Cl)cnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(C(=O)O)c3c(CN[C@H](CC#N)C(=O)NC4CCCC4)c(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of sodium triacetoxyborohydride (26.5 mg, 0.125 mmol) and (R)-2-amino-3-cyano-N-cyclopentylpropanamide (22.70 mg, 0.125 mmol) in DCM (1 mL) was stirred at room temperature for 10 min. The reaction mixture was cooled to 0° C. A solution of 5-chloro-4-formyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (30 mg, 0.063 mmol) in DCM (1 mL) was added. The reaction mixture was stirred at 0° C. for 20 min and then concentrated to afford the title compound. [M+H] calc'd for C26H28ClN5O5S, 544; found, 544.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([N:13]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:30][CH:29]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21]C2CCCCO2)=[CH:17][CH:16]=1)(=[O:12])=[O:11].[ClH:42]>CO>[ClH:42].[OH:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:13]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]3[CH2:38][CH2:39][CH2:40][CH2:41]3)=[CH:30][CH:29]=2)[S:10]([C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])(=[O:12])=[O:11])=[CH:20][CH:19]=1
Reactant: Cc1cc(C)c(S(=O)(=O)N(Cc2ccc(OC3CCCCO3)cc2)c2ccc(OCCN3CCCC3)cc2)c(C)c1
Agent: Cl
Solvent: CO
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2ccc(O)cc2)c2ccc(OCCN3CCCC3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,4,6-Trimethyl-N-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-N-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-benzenesulfonamide was dissolved in methanol (30 mL) and 1N HCl (5 mL) was added. The reaction mixture was stirred for 30 minutes at room temperature and was concentrated in vacuo. The residue was triturated with methylene chloride followed by ether to obtain the title compound as the HCl salt. MS 495.4 (M+1)+
Reaction SMILES: O.[OH-].[Li+].[CH:4]1([C:7]2[S:8][CH:9]=[C:10]([C:12]([O:14]CC)=[O:13])[N:11]=2)[CH2:6][CH2:5]1.Cl>C1COCC1.O>[CH:4]1([C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)c1csc(C2CC2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1csc(C2CC2)n1
Reaction time: 8 h

Procedure:
Lithium hydroxide monohydrate (0.13 g) was added to a solution of ethyl 2-cyclopropylthiazole-4-carboxylate (example 57, step b) (0.15 g) in a mixture of THF (8 mL) and water (2 mL) and the resulting mixture was stirred overnight. The reaction was acidified with aqueous HCl (2M, 3 mL) and the solvent evaporated. The residue was partitioned between brine (20 mL) and ethyl acetate (30 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (2×30 mL). The combined organic solutions were dried over sodium sulphate, filtered and evaporated to give the subtitled compound as an off white solid. Yield 0.12 g.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH:19]=1)=[CH:16][C:15]([C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)=[CH:14][CH:13]=3)=[O:6].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[I-].[K+]>O1CCCC1>[N:26]1([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[NH:11][C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20](=[O:25])[CH2:21][CH2:22][CH2:23][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:14][CH:13]=4)=[O:6])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCNCC1
Reactant: O=C(CCCCl)c1ccc2[nH]c3ccc(C(=O)CCCCl)cc3c2c1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(CCCN1CCCCC1)c1ccc2[nH]c3ccc(C(=O)CCCN4CCCCC4)cc3c2c1

Procedure:
A solution of 15.0 g (0.04 mole) of 3,6-bis(4-chlorobutyryl)carbazole, 85.0 g (1.0 mole) of piperidine and 2.0 g of potassium iodide in 15 ml of tetrahydrofuran is heated at 110°C in a reaction bomb for 24 hours with stirring. Upon cooling, the reaction mixture is filtered and diluted with 700 ml of ice water. The resulting solid is washed with water, dried over magnesium sulfate and recrystallized from chloroform-petroleum ether (75°-90°C) and then from acetone to give 3,6-bis(4-piperidinobutyryl)carbazole, M.P. 171°-173°C.
Reaction SMILES: Cl[CH2:2][C:3](=[O:12])[C:4]([CH:7]1[O:11][CH2:10][CH2:9][O:8]1)([CH3:6])[CH3:5].[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[N:13]1([CH2:2][C:3](=[O:12])[C:4]([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)([CH3:6])[CH3:5])[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: CC(C)(C(=O)CCl)C1OCCO1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C(=O)Cn1cncn1)C1OCCO1
Yield: 71.5 %

Procedure:
180.6 g (0.94 mol) of 1-chloro-3-(dioxolan-2-yl)-3-methyl-butan-2-one, 64.9 g (0.94 mol) of 1,2,4-triazole and 142.7 g (1 mol) of potassium carbonate in 1,000 ml of methyl ethyl ketone are heated under reflux for 16 hours. The solid is filtered off under suction and the solvent is distilled off, the oily residue is taken up in 700 ml of methylene chloride, and the organic phase is extracted with twice 1,000 ml of water. The solvent is distilled off from the organic phase. 151.3 g (71.5% of theory) of 1-(1,2,4-triazol-1-yl)-3-(dioxolan-2-yl)-3-methyl-butan-2-one are obtained as an oil with a purity of 99% according to gas chromatography. ##STR23##
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:7]4[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:8]=4[C:9]([OH:17])=[CH:10][C:11]=3[C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].Cl>O.C(COC)OC>[CH3:23][O:22][C:20]1[CH:19]=[CH:18][C:8]2[C:9]([OH:17])=[CH:10][C:11]3[C:12]([CH3:15])([CH3:16])[C:13]4[CH:14]=[C:2]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[O:25][CH3:24])[CH:3]=[CH:4][C:5]=4[C:6]=3[C:7]=2[CH:21]=1
Reactant: COc1ccccc1B(O)O
Reactant: COc1ccc2c(O)cc3c(c2c1)-c1ccc(Br)cc1C3(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc2c(O)cc3c(c2c1)-c1ccc(-c2ccccc2OC)cc1C3(C)C
Temperature: 25 °C
Yield: 88.5 %

Procedure:
The product of Step 3 of Example 5, (9-bromo-2-methoxy-7,7-dimethyl-7H-benzo[c]fluoren-5-ol (6 g)) and 2-methoxyphenyl boronic acid (2.8 g) were added to a solution of dimethoxyethane (40 mL) and water (20 mL) in a 250 mL round bottom 3-necked flask, followed by addition of Na2CO3 (3.5 g). The resulting solution was bubbled with nitrogen for 10 minutes and then the Palladium catalyst, Pd[PPh3]4, 0.5 g, was added to the reaction mixture. Then the reaction mixture heat to reflux temperatures under a nitrogen atmosphere. The reaction was monitored by TLC analysis. By the end of reaction, the reaction was cooled to room temperature and quenched by adding water (30 mL). The pH of reaction mixture was adjusted to 5-6 by adding hydrochloric acid (37%, 7.5 g) slowly. The product was extracted with ethyl acetate (2×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to yield the product, 2-methoxy-9-(2-methoxyphenyl)-7,7-dimethyl-7H-benzo[c]fluoren-5-ol (5.7 g) which was used for next reaction as is.
Reaction SMILES: [Br:1]Br.[CH3:3][CH:4]([CH3:19])[C:5]([C:7]1[CH:18]=[CH:17][C:10]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=1)=[O:6]>C(Cl)(Cl)(Cl)Cl>[Br:1][C:4]([CH3:19])([CH3:3])[C:5]([C:7]1[CH:18]=[CH:17][C:10]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=1)=[O:6]
Reactant: COC(=O)COc1ccc(C(=O)C(C)C)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)COc1ccc(C(=O)C(C)(C)Br)cc1
Reaction time: 16 h

Procedure:
Bromine (2.09 ml) was added dropwise over ten minutes to a stirred solution of the product of step (i) above (9.44 g) in carbon tetrachloride (200 ml). The solution was stirred for 16 hours, then the solvent was evaporated in vacuo to give an orange oil. A solution of this oil, in a small volume of dichloromethane, was filtered through silica and the clear filtrate, on evaporation, gave methyl 4-(2-bromo-2,2-dimethylacetyl)phenoxyacetate, 11.3 g, as a white crystalline solid: m.p. 46°-50° C.; NMR (d6DMSO) δ 8.09 (2H, d), 7.05 (2H, d), 4.92 (2H, s), 3.72 (3H, s), 2.00 (6H, s).
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([OH:19])([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15].[CH3:20][C:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:25])[CH2:22][CH:23]=O>CO.CC(O)=O.CCOC(C)=O>[OH:19][C:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[NH:5][CH2:23][CH2:22][C:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:25])[CH3:20])([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15]
Reactant: CC(C)(CC=O)NC(=O)OC(C)(C)C
Reactant: CCCC(O)(CCC)c1ccccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CCCC(O)(CCC)c1ccccc1NCCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.40 g (22.27 mmol) of sodium cyanoborohydride is added to a solution of 3.10 g (14.05 mmol) of 4-(2-aminophenyl)heptan-4-ol and 3.60 g (17.88 mmol) of tert-butyl (1,1-dimethyl-3-oxopropyl)carbamate in MeOH (40 mL) and AcOH (6 mL). The mixture is stirred for 16 hours at RT, diluted with EtOAc, and washed with 0.5 M aqueous KHSO4 and saturated aqueous NaCl, dried with sodium sulfate, and evaporated down in vacuo. The crude product is used in the next reaction step without any further purification. Yield: 6.00 g (quantitative yield).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.N1CCCCC1.C1CCN2C(=NCCC2)CC1.[CH:27]([OH:31])(CC)[CH3:28]>>[CH:3]1[CH:2]=[CH:9][C:8]2[O:31][CH2:27][CH2:28][C:6](=[O:7])[C:5]=2[CH:4]=1
Reactant: CCC(C)O
Reactant: O=Cc1ccc(I)cc1
Solvent: C1CCNCC1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCOc2ccccc21
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of protected hydroxyarylketone (1.0 equiv), 4-iodobenzaldehyde (1.0 equiv), piperidine (0.35 equiv), and DBU (0.35 equiv) in s-butanol (1.0 M) was heated at reflux. Using a Dean-Stark trap, half of the solvent was removed over 30-40 min, and the reaction was kept at reflux without further concentration for additional 4-8 h. The reaction mixture was cooled to 90° C., i-propanol (0.7-1.0 fold of s-butanol v/v) was added, and the reaction was allowed to cool to room temperature. Any large pieces of material were broken down with a spatula, and the suspension was stirred overnight (Note #1 & 2). The precipitate was collected by filtration to give the corresponding chromanone.
Reaction SMILES: [CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.[OH:6][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[OH:6][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH:8]1[CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1=CCCC1
Reactant: OC1CCCc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: OC1c2ccccc2CCC1C1CCCC1

Procedure:
40 g of cyclopentene are added dropwise at 120° C to 148 g of 1-hydroxytetraline and 10 g of p-toluene sulphonic acid. The catalyst is removed by washing with sodium hydrogen carbonate solution. The reaction mixture is fractionated. At 161° C (2 mm Hg) 58 g of 1-hydroxy-2-cyclopentyltetraline are obtained.
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:14]=[C:15]1[N:20]([CH2:21][CH:22]=O)[C:19]2[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=2[O:17][CH2:16]1>C(O)C.C(Cl)Cl>[C:2]1([CH:8]2[CH2:9][CH2:10][N:11]([CH2:22][CH2:21][N:20]3[C:19]4[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=4[O:17][CH2:16][C:15]3=[O:14])[CH2:12][CH2:13]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=CCN1C(=O)COc2ccccc21
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: O=C1COc2ccccc2N1CCN1CCC(c2ccccc2)CC1
Reaction time: 2 h

Procedure:
Following the procedure of Synthetic Comm. 23 (6), 789-795, 1993, to a solution of 4-phenylpiperidine hydrochloride Compound 1-9 (290 mg, 1.5 mmol) and Compound 1-4 (300 mg, 1.5 mmol) in 10 mL of absolute ethanol was added BAP (154 μL, 1.5 mmol). After stirring for 2 hrs, an additional equivalent of aldehyde Compound 1-4 and BAP was added. The reaction mixture was stirred overnight and concentrated to give an oily residue. The residue was taken up in DCM, washed with saturated sodium bicarbonate solution NaHCO3 and brine, dried over Na2SO4, and concentrated. The residue was purified on silica gel (elution with 30% EtOAc in hexane) to yield Compound 86 as a glass-like oil (287 mg, 57%) of a glass-like oil. 1H NMR (300 MHz, CDCl3) δ 7.25-7.11 (m, 5H), 7.04-6.91 (m, 4H), 4.53 (s, 2H), 4.04 (m, 2H), 3.04 (m, 2H), 2.58 (m, 2H), 2.45-2.40 (m, 1H), 2.15, (t of d, J=11 and 3 Hz, 2H), 1.83-1.64 (m, 4H); MS (ES+) m/z 337.2 (M+1); Anal Calcd. for C21H24N2O2.0.51H2O: C, 73.02; H, 7.29; N, 8.11. Found: C, 72.98; H, 7.11; N, 8.00.
Reaction SMILES: OC([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10][C:9]=2[CH:19]=1)C#N.C.[C:21]([OH:24])(=[O:23])[CH3:22]>[Pd]>[C:13]1([C:11]2[O:12][C:8]3[CH:7]=[CH:6][C:5]([CH2:22][C:21]([OH:24])=[O:23])=[CH:19][C:9]=3[N:10]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N#CC(O)c1ccc2oc(-c3ccccc3)nc2c1
Reactant: CC(=O)O
Agent: [Pd]
Product: O=C(O)Cc1ccc2oc(-c3ccccc3)nc2c1
Reaction time: 4 h

Procedure:
A solution of α-hydroxy-2-phenyl-5-benzoxazolyl-acetonitrile (2 g.) in acetic acid (30 ml.) containing palladium or charcoal was hydrogenated for 4 hours. The catalyst was filtered off and the solution was evaporated to dryness. The residue was recrystallised to give pure 2-phenyl-5-benzoxazolylacetic acid m.p. 175° C.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2.[CH3:17][C:18]1[C:19](=O)[CH2:20][CH2:21][C:22]=1[CH3:23].Cl.N>C1COCC1>[N:15]1[C:16]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[C:19]2[CH2:20][CH:21]=[C:22]([CH3:23])[C:18]=2[CH3:17])[CH:12]=[CH:13][CH:14]=1
Reactant: Brc1cccc2cccnc12
Reactant: CC1=C(C)C(=O)CC1
Agent: Cl
Agent: N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=CCC(c2cccc3cccnc23)=C1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.4 %

Procedure:
5 ml of n-BuLi (2.5 M in hexane, 12.5 mmol) were added at −95° C. dropwise to a solution of 2.5 g of 8-bromoquinoline (12 mmol) in 120 ml of THF; this was stirred for 15 minutes, and then 1.3 g of 2,3-dimethylcyclopent-2-enone (12 mmol), dissolved in 10 ml of THF, was added. After warming to room temperature, the solution was heated for one hour in ref lux. The cooled reaction mixture was hydrolized with ice, acidified with hydrochloric acid, and then neutralized with ammonia solution. The aqueous phase was extracted with diethyl ether, and the combined organic phases were dried. Distillation at 150° C. and 0.05 mbar yielded 1.1 g of 1-(8-quinolyl)-2,3-dimethylcyclopentadiene (40%) in the form of a yellow, viscous oil.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]([OH:19])[C:13]3[N:14]([N:16]=[CH:17][CH:18]=3)[CH:15]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(#N)C.ClCCl>[Br:20][C:18]1[CH:17]=[N:16][N:14]2[CH:15]=[C:10]([C:8]3[CH:7]=[N:6][N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=3)[CH:11]=[C:12]([OH:19])[C:13]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)n1cc(-c2cc(O)c3ccnn3c2)cn1
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)n1cc(-c2cc(O)c3c(Br)cnn3c2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(1-tert-butyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol (138 mg, 0.538 mmol) in acetonitrile (6 mL) was added N-bromosuccinimide (105 mg, 0.590 mmol). The solution was stirred at room temperature for 1 h. The reaction was diluted with dichloromethane, washed with water and 2N NaOH. The combined aqueous layers were neutralized and extracted with ethyl acetate. The combined organic layers were washed with brine, dried, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 3-bromo-6-(1-tert-butyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][N:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[C@H:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1O.Cl>C1C=CC=CC=1.CCOCC.C(OCC)(=O)C.CC(C)=O>[ClH:46].[Cl:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[O:20][C@@H:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][C@H:16]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccccc1Cl
Reactant: CN1CC[C@H](O)[C@H](c2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CN1CC[C@@H](Oc2ccccc2Cl)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4.79 g of diethyl azodicarboxylate in 125 ml of anhydrous benzene is added dropwise at 4° C. under nitrogen over a 90 minute period to a mixture of 4.78 g of cis-1-methyl-3-phenyl-4-piperidinol of Example 1g, 7.21 g of triphenylphosphine, 3.54 g of 2-chlorophenol and 125 ml of anhydrous benzene. The mixture is stirred 18 hours at room temperature under nitrogen and then is filtered. The solid is washed well with hexane and the filtrate is concentrated in vacuo. The residue is triturated 18 hours with 250 ml of hexane and then filtered. The solid is washed well with hexane, triturated with ether and then filtered. The filtrates are combined and concentrated in vacuo to an oil. An ether solution of this material is made and is then extracted with 2 N HCl solution. The acid extracts are washed with ether, followed by extraction with dichloromethane. The dichloromethane extracts are washed with 10% aqueous NaOH solution, then with saturated NaCl solution, dried over anhydrous Na2SO4 and concentrated in vacuo to an oil. This material is chromatographed on silica gel, using acetone as a solvent to obtain an oil. This oil is dissolved in ether and treated dropwise with an HCl-saturated ether solution to yield a salt. The salt is filtered and washed with ether to afford a solid, mp s 230°, 232°-234° C. This material suspended in 25 ml of boiling ethyl acetate and acetone is gradually added to the boiling mixture until a solution is obtained. The solution is filtered hot and boiled down to start crystallization to yield a solid, mp 233°-235.5° C. of trans-4-(2-chlorophenoxy)-1-methyl-3-phenylpiperidine hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7](Cl)[N:6]=1)[CH3:2].[Na+].[I-:15].C(Cl)(=O)C>CC#N.CCOC(C)=O>[Cl:11][C:10]1[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:13])=[N:6][C:7]([I:15])=[CH:8][CH:9]=1
Reactant: [I-]
Reactant: CCOC(=O)c1nc(Cl)ccc1Cl
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(I)ccc1Cl
Temperature: 100 °C
Yield: 26.8 %

Procedure:
To a solution of 3,6-dichloropicolinic acid ethyl ester (5.0 g, 24 mmol) in CH3CN (45 mL) was added NaI (10 g, 66.7 mmol) and acetyl chloride (2.5 mL). The reaction mass was heated in a sealed tube at 100° C. for 48 h. The reaction mass was diluted with EtOAc and was washed with saturated solutions of Na2S2O3 and NaHCO3. The organic layer was separated, dried, filtered and concentrated to afford 2 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.04 (d, J=8.4 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 4.38 (q, J=7.5 Hz, 2H), 1.32 (t, J=6.9 Hz, 3H).