Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([N:12]2[CH2:17][CH2:16][C@:15]([CH2:24][C:25](=[O:27])[CH3:26])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:14][C:13]2=[O:28])[CH3:11])=[CH:6][CH:5]=1.[CH3:30][Mg]Br>C1COCC1>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([N:12]2[CH2:17][CH2:16][C@:15]([CH2:24][C:25]([OH:27])([CH3:30])[CH3:26])([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:14][C:13]2=[O:28])[CH3:11])=[CH:6][CH:5]=1
Reactant: C[Mg]Br
Reactant: CC(=O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(OC(F)F)cc2)C(=O)O1
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(OC(F)F)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Yield: 10 %

Procedure:
To a solution of (S)-3-((S)-1-(4-(difluoromethoxy)phenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-one (150 mg, 0.39 mmol) in THF (10 mL) was added methylmagnesium bromide (1 M, 2.5 mL) under nitrogen at −78° C. The mixture was stirred at rt until the reaction was over. The reaction was quenched with satd aq NH4Cl. The organic phase was separated and concentrated to give crude product, which was purified by preparative HPLC to give (S)-3-((S)-1-(4-(difluoromethoxy)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (15 mg, 10%). 1H NMR (CDCl3): 1.05 (s, 3H), 1.10 (s, 3H), 1.45 (s, 3H), 2.10 (m, 1H), 2.16 (m, 2H), 2.20 (m, 1H), 2.33 (m, 1H), 2.76 (m, 1H), 5.60 (m, 1H), 6.16-6.58 (m, 1H), 6.78 (m, 2H), 6.86 (m, 2H), 7.26 (m, 5H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([CH2:9][CH2:10][CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH2:12]([O:19][C:20]1[CH:29]=[CH:28][C:23]([C:24](=O)[CH2:25]Br)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:10]([C:9]1[C:24]([C:23]2[CH:28]=[CH:29][C:20]([O:19][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:21][CH:22]=2)=[CH:25][N:5]2[C:4]=1[C:3]([CH2:2][OH:1])=[CH:8][CH:7]=[CH:6]2)[CH3:11]
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Reactant: CCCc1ncccc1CO
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)cn2cccc(CO)c12
Yield: 83 %

Procedure:
3-Hydroxymethyl-2-n-propylpyridin was reacted with 4-benzyloxyphenacylbromide by the general synthetic principles outlined in example 1, step 2, to afford 1-ethyl-2-(4-benzyloxyphenyl)-8-hydroxymethylindolizine as yellow crystals in 83% yield. M.p. 144-145° C. MS(SP): m/z 357 (M+). 1H--NMR (DMSO-d6, 200 MHz) δ: 1.08 (t, 3 H); 2.83 (q, 2 H); 4.73 (d, 2 H); 5.12 (s, 2 H); 5.22 (t, 1 H); 6.43 (dd, 1 H); 6.66 (d, 1 H); 7.07 (d, 2 H); 7.28-7.53 (m, 8 H); 8.04 (d, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1.C([O-])([O-])=O.[K+].[K+]>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.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccnc1
Reactant: Brc1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Brc1cccc(-c2cccnc2)c1
Temperature: 100 °C
Yield: 0.1 %

Procedure:
1-bromo-3-iodobenzene (1.118 g, 3.95 mol) and 3-pyridine boronic acid (0.559 g, 4.54 mol) were added to a 100 mL three neck round bottom flask. To this flask, dioxane (20 mL) and aqueous K2CO3 (2 N, 20 mL) were added. The mixture was stirred and degassed with a steam of argon for 30 minutes. Then under argon atmosphere, 50 mg (0.04 mmol) of Pd(PPh3)4 (1%) was added. The mixture was heated to 100° C. and stirred overnight. The next day, the solvent was removed by roto-evaporation and the residue was suspended into an equal amount of water (50 mL) and CH2Cl2 (50 mL). The organic layer was separated from aqueous layer and washed with brine (50 mL×3). After drying over Na2SO4, and removal of the drying agent, about 0.92 g of 3-(3-bromophenyl)pyridine product (100%) was afforded. 1H NMR (400 MHz, CDCl3) 8.85 (s, 1H), 8.65 (d, 1H), 7.87 (d, 1H), 7.75 (s, 1H), 7.57-7.52 (m, 2H), 7.41-7.35 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:12]([C:13]([CH:15](N)[CH3:16])=[O:14])=[C:11]2[N:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)[N:5]=1)[CH3:3].C(C1C=C2C=CC=CN2N=1)(C)C.[Cl:30]C(C)C=O.ClC(Cl)=O.ClC(C)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>>[Cl:30][CH:15]([CH3:16])[C:13]([C:12]1[C:4]([CH:2]([CH3:3])[CH3:1])=[N:5][N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=12)=[O:14]
Reactant: CC(Cl)C=O
Reactant: CC(N)C(=O)c1c(C(C)C)nn2ccccc12
Agent: CC(C)c1cc2ccccn2n1
Agent: CC(Cl)C(=O)Cl
Agent: O=C(Cl)Cl
Product: CC(Cl)C(=O)c1c(C(C)C)nn2ccccc12

Procedure:
The second step in the synthesis of AV1013 involves reacting the intermediate (IPPP), with 2-chloro-propan-1-one under Friedel-Craft conditions to synthesize the corresponding chloroketone. Thus, reaction of isopropylpyrazolo[1,5-a]pyridine (IPPP) with 2-chloropropionyl chloride in the presence of aluminum chloride (Example 1, Step 2), gave 2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one (i.e., 2-chloro-desmethylibudilast). In an alternate strategy as described in Example 8, IPPP is allowed to react with propanoyl chloride under Friedel-Crafts acylation conditions to give desmethylibudilast. It should be noted that the terms desmethylibudilast and Nor-methyl ibudilast are used interchangeably throughout the specification. The obtained Nor-methyl ibudilast is then converted to the corresponding alpha-chloroketone (2-chloro-desmethylibudilast), by techniques known in the chemical art, for example, via chlorination.
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([CH2:22][CH2:23][CH:24]=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:24][CH2:23][CH2:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccccc1)N1CCNCC1
Reactant: O=CCCc1ccccc1
Product: O=C(Nc1ccccc1)N1CCN(CCCc2ccccc2)CC1

Procedure:
The title compound was prepared from piperazine-1-carboxylic acid phenylamide and 3-phenylpropionaldehyde. 1H NMR (400 MHz, CDCl3): 7.36-7.16 (m, 9H), 7.05-7.00 (m, 1H), 6.40 (br s, 1H), 3.52-3.47 (m, 4H), 2.65 (t, J=7.6 Hz, 2H), 2.47-2.38 (m, 4H), 2.39 (t, J=7.4 Hz, 2H), 1.88-1.79 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])=[CH:4][CH:3]=1.Br[C:16]1[S:17][C:18]([C:22]([NH:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[O:23])=[C:19]([CH3:21])[N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][N:9]([C:16]3[S:17][C:18]([C:22]([NH:24][CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:23])=[C:19]([CH3:21])[N:20]=3)[C:8]2=[O:12])=[CH:4][CH:3]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1cccnc1
Reactant: O=C1NCCC1Cc1ccc(F)cc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1nc(N2CCC(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 33.1 %

Procedure:
A mixture of 3-(4-fluorobenzyl)pyrrolidin-2-one (0.074 g, 0.39 mmol), 2-bromo-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide (0.10 g, 0.32 mmol), cesium carbonate (0.16 g, 0.48 mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (1:1) (0.005 g, 0.006 mmol) and xantphos (0.007 g, 0.013 mmol) in anhydrous toluene (2 mL) was subjected to microwave irradiation at 80° C. for 35 min. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (ethyl acetate/hexanes (3/1)) to afford the title compound as a white solid (0.045 g, 33%): mp 169-170° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.52 (d, J=4.5 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.30-7.23 (m, 1H), 7.14 (dd, J=8.0, 5.5 Hz, 2H), 6.95 (t, J=8.8 Hz, 2H), 6.16 (t, J=5.6 Hz, 1H), 4.59 (d, J=5.6 Hz, 2H), 4.07-3.95 (m, 1H), 3.92-3.79 (m, 1H), 3.20 (dd, J=13.9, 4.5 Hz, 1H), 3.07-2.93 (m, 1H), 2.83-2.74 (m, 1H), 2.61 (s, 3H), 2.32-2.18 (m, 1H), 1.98-1.82 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 174.8, 163.4, 162.5, 155.5, 153.2, 149.3, 149.1, 135.7, 133.8, 133.7, 130.4, 123.7, 118.2, 115.6, 45.9, 44.4, 41.5, 35.6, 24.2, 17.3; MS (ES+) m/z 425.3 (M+1).
Reaction SMILES: C([O:8][C:9]([C:11]1[C@H:12]2[CH2:24][C@@H:23]3[O:25][C@:22]3([CH3:26])[C@@H:13]2[C@H:14]([O:17][C:18](=[O:21])[NH:19][CH3:20])[O:15][CH:16]=1)=[O:10])C1C=CC=CC=1>[C].[Pd].C(OCC)(=O)C>[O:25]1[C@@:22]2([CH3:26])[C@@H:23]1[CH2:24][C@@H:12]1[C:11]([C:9]([OH:10])=[O:8])=[CH:16][O:15][C@@H:14]([O:17][C:18](=[O:21])[NH:19][CH3:20])[C@H:13]12
Reactant: CNC(=O)O[C@@H]1OC=C(C(=O)OCc2ccccc2)[C@H]2C[C@@H]3O[C@]3(C)[C@H]12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNC(=O)O[C@@H]1OC=C(C(=O)O)[C@H]2C[C@@H]3O[C@]3(C)[C@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 113.6 %

Procedure:
35 mg of 5% palladium-carbon catalyst were added to an ethyl acetate solution containing 350 mg of (1S,4aS,6S,7R,7aR)-6,7-epoxy-7-methyl-1-(methylcarbamoyloxy)-1,4a,5,6,7,7a-hexahydrocyclopenta [c]-pyrane-4-carboxylic acid benzyl ester followed by stirring for 2 hours at room temperature under hydrogen gas atmosphere at 1 atm. After filtering out the insoluble matter, the filtrate was concentrated under reduced pressure to obtain a colorless powder in the form of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy) cyclopenta [c]-pyrane-4-carboxylic acid (298 mg; yield: 99%). The physicochemical properties of this compound are described in Table 1, Compound No. 1.
Reaction SMILES: O=[C:2]1[CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][C:13](=O)[N:12]2[CH2:21][CH2:22][S:23][CH2:24][CH2:25][S:26][CH2:27][CH2:28][N:3]1[CH2:4][CH2:5][S:6][CH2:7][CH2:8][S:9][CH2:10][CH2:11]2.[H]1[BH2][H][BH2]1>O1CCCC1>[N:3]12[CH2:4][CH2:5][S:6][CH2:7][CH2:8][S:9][CH2:10][CH2:11][N:12]([CH2:21][CH2:22][S:23][CH2:24][CH2:25][S:26][CH2:27][CH2:28]1)[CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:2]2
Reactant: O=C1COCCOCC(=O)N2CCSCCSCCN1CCSCCSCC2
Solvent: C1CCOC1
Product: C1COCCN2CCSCCSCCN(CCO1)CCSCCSCC2
Yield: 95 %

Procedure:
A solution of 0.6 g. of the bicyclic diamide obtained in Example 34 in 10 ml. tetrahydrofuran is slowly added to 10 ml. of the freshly prepared B2H6 solution (1.5 M) under nitrogen atmosphere and at a temperature of 0°C. The mixture is refluxed for two hours. The excess reagent is destroyed by adding 5 ml. of water and the solution is evaporated on a rotatory evaporator under vacuum. The solid residue is treated with 50 ml. 6 N hydrochloric acid under reflux for two hours. The mixture is evaporated to dryness under vacuum on a rotatory evaporator. The residue is treated with a solution of tetraethylammonium hydroxide until a basic reaction is obtained. The mixture containing a precipitate, is extracted several times with chloroform. The solutions are filtered through alumina and evaporated to dryness leaving the title compound as a crystalline residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8]S(C)(=O)=O)[C:5](I)=[CH:4][N:3]=1.[C:14]([C:16]1[CH:17]=[N:18][N:19](C(OC(C)(C)C)=O)[CH:20]=1)#[CH:15].C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1.[NH4+].[Cl-]>CN(C=O)C.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.[Cu](I)I>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][NH:19][CH:20]=3)[NH:8][C:6]=2[CH:7]=1
Reactant: CS(=O)(=O)Nc1cc(Cl)ncc1I
Reactant: C#Cc1cnn(C(=O)OC(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: Clc1cc2[nH]c(-c3cn[nH]c3)cc2cn1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 71.1 %

Procedure:
Bis(triphenylphosphine)palladium dichloride (23.30 mg, 0.033 mmol) was added to a solution of N-(2-chloro-5-iodopyridin-4-yl)methanesulfonamide (14) (276.0 mg, 0.83 mmol), tert-butyl 4-ethynyl-1H-pyrazole-1-carboxylate (4) (239.0 mg, 1.24 mmol), triethylamine (521 μL, 3.73 mmol) and copper iodide (7.90 mg, 0.041 mmol) in anhydrous DMF (3.0 mL). The reaction mixture was heated at 60° C. for 1 h under microwave irradiation (absorption:normal). To this reaction mixture, DBU (0.51 mL, 3.36 mmol) was added and the microwave vial was placed in an oil-bath preheated at 100° C., and then stirred at this temperature for 2.5 h. More DBU (0.08 mL) was added and stirring was continued at this temperature for an additional 45 min. The reaction mixture was poured in to 1M aqueous NH4Cl (30 mL), extracted with EtOAc (3×50 mL). The combined organics were washed with brine (2×30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was triturated with dichloromethane (8.0 mL); the precipitate was collected by filtration and washed with dichloromethane to afford the product as a light brown solid, (0.129 g, 71%). 1H-NMR (500 MHz, DMSO-d6) 6.72 (dd, J=0.5, 1.5 Hz, 1H), 7.33 (t, J=0.85 Hz, 1H), 8.00 (br s, 1H), 8.24 (br s, 1H), 8.51 (s, 1H), 11.87 (s, 1H), 13.09 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[N:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:18]>C(Cl)(Cl)Cl.C(Cl)Cl>[F:1][C:2]1[CH:3]=[N+:4]([O-:18])[C:5]2[CH:6]=[CH:7][C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1
Reactant: O=c1ccc2ncc(F)cc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=c1ccc2c(cc(F)c[n+]2[O-])[nH]1

Procedure:
7-Fluoro-1,5-naphthyridin-2(1H)-one (1.280 g, 7.798 mmol) and m-chloroperoxybenzoic acid (2.123 g, ca. 1.2 eq. based on an mCPBA content of 75%) were stirred in chloroform (60 mL) at reflux overnight. Further mCPBA (0.420 g) was added and the mixture was stirred at reflux for an additional 6 hours. The mixture was diluted with DCM to a total volume of ca. 100 ml and filtered with suction. The solid collected was washed with DCM (2×20 mL) and air-dried to give 7-fluoro-1,5-naphthyridin-2(1H)-one 5-oxide as a tan solid (1.045 g, contaminated with ca. 12% starting material).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH3:15])=[N+:12]([O-])[CH:13]=1)#[N:7].C(N(CC)CC)C>ClCCl>[Cl:3][CH2:15][C:11]1[CH:10]=[CH:9][C:8]([C:6]#[N:7])=[CH:13][N:12]=1
Reactant: Cc1ccc(C#N)c[n+]1[O-]
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(CCl)nc1

Procedure:
A solution of phosphoryl chloride (6.5 g) in dichloromethane (20 ml) was added to a mixture of the above pyridine-1-oxide (4.4 g) and triethylamine (4.3 g) in dichloromethane (60 ml). After the addition was completed the reaction mixture was gently refluxed for 15 mins, cooled and washed with water (30 ml). The organic layer was separated, dried over anhydrous sodium sulphate and evaporated to dryness. The residue was purified by flash column chromatography on silica (K60) using ethyl acetate: toluene (1:9 by volume) as eluting solvent, to give 6-chloromethylnicotinonitrile.
Reaction SMILES: [C:1]([NH:4][C:5]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH:13]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:12]2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]>CO.CC(O)C.Cl>[C:25]1([CH2:24][CH:13]2[CH2:12][CH:11]([N:8]3[CH2:7][CH2:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:10][CH2:9]3)[CH2:16][CH2:15][NH:14]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)NC1(c2ccccc2)CCN(C2CCN(C(=O)OC(C)(C)C)C(Cc3ccccc3)C2)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: CC(=O)NC1(c2ccccc2)CCN(C2CCNC(Cc3ccccc3)C2)CC1
Yield: 7.9 %

Procedure:
A mixture of intermediate 19 (0.081 mol) in CH3OH (300 ml) and 2-propanol in HCl (30 ml) was stirred and refluxed for 2 hours. The solvent was evaporated The residue was taken up in water/DIPE and the mixture was separated into its layers. The aqueous layer was alkalized with NaOH and CH2Cl2 was added. The combined organic layer was washed with water, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 95/5). Two pure fractions were collected and their solvents were evaporated, yielding 3 g of fraction 1, 2 g fraction 2 and 2.5 g of (±)-N-[1-[2-(phenylmethyl)-4-piperidinyl]-4-phenyl-4-piperidinyl]acetamide (intermediate 20). Fraction 1 was dissolved in 2-propanol and converted into the hydrochloric acid salt (1:2) with HCl/2-propanol. The precipitate was filtered off and dried, yielding 0.24 g (±)-cis-N-[1-[2-(phenylmethyl)-4-piperidinyl]-4-phenyl-4-piperidinyl]acetamide dihydrochloride. dihydrate (intermediate 21). Intermediate 20 was repurified by column chromatography oversilica gel (eluent: CH2Cl2/(CH3OH/NH3) 95/5). The pure fractions were collected and the solvent was evaporated The residue was dissolved in 2-propanol and converted into the hydrochloric acid salt (1:2) with HCl/2-propanol. The precipitate was filtered off and dried, yielding 0.44 g of (±)-trans-N-[4-phenyl-1-[2-(phenylmethyl)-4-piperidinyl]-4-piperidinyl]acetamide dihydrochloride.dihydrate (intermediate 22). Less pure fractions (20 g) were repurified by HPLC over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 95/5). Two pure fraction groups were collected and their solvent was evaporated, yielding 6.5 g (±)-cis-N-[4-phenyl-1-[2-(phenylmethyl)-4-piperidinyl]-4-piperidinyl]acetamide (intermediate 23) and 7.2 g (±)-trans-N-[1-[2-(phenylmethyl)-4-piperidinyl]-4-phenyl-4-piperidinyl]acetamide (intermediate 24).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O>O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:9][CH2:10][CH2:11][C:12]2=[O:14]
Reactant: O=C(O)CCCc1cccc(Cl)c1Cl
Solvent: O
Product: O=C1CCCc2c1ccc(Cl)c2Cl
Reaction time: 0.5 h

Procedure:
Polyphosphoric acid (35 g) was heated to melt at 120 C for 30 minutes. To this was added 1.2 g (5.1 mmol) 4-(2,3-dichlorophenyl)butanoic acid (PC68) and this mixture was heated further with stirring for 10 h at 130 C. LCMS analysis showed the formation of the product and the disappearance of starting material. The reaction mixture was then cooled and water (100 ml) was added. It was then extracted with ethylacetate (100 ml) and then was washed with Saturated Sodium bicarbonate (50 ml). The organic phase was dried and evaporated in vacuum. The oily residue was subjected to column chromatography with Hexane-ethylacetate (98:2) to obtain the tetralone as a yellow solid.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][CH3:16])[CH:9]=[C:8]2[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[O:28][CH3:29].Cl>O1CCCC1>[CH:3]([CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][CH3:16])[CH:9]=[C:8]2[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[O:28][CH3:29])=[O:2]
Reactant: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(CC(OC)OC)ccc21
Agent: Cl
Solvent: C1CCOC1
Product: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(CC=O)ccc21

Procedure:
A solution of methyl 4-[5-(2,2-dimethoxyethyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate (0.46 g) in tetrahydrofuran (7 ml) and b 1M hydrochloric acid (3.6 ml) was stirred at ambient temperature for 11 h, under a nitrogen atmosphere. The mixture was poured onto water, extracted with ethyl acetate (twice), and the extract washed with water (twice), brine, and then dried (MgSO4). The solvent was evaporated to give a dark oil which was used in the next step without further purification.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:4][CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[C:28]([O:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:6][CH2:7]1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CCCCCC[C@H]1CC[C@H](O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)O[C@H]1CC[C@H](CCCCCCC(=O)O)CC1
Reaction time: 72 h

Procedure:
trans-7-(4-Hydroxycyclohexyl)heptanoic acid (6.5 g) and p-toluenesulfonic acid (15 mg) are stirred in acetic anhydride (32.5 ml) at 60°-70° C. for 1.5 hours. The excess acetic anhydride is distilled off under reduced pressure, followed by addition of water (90 ml), and the mixture is stirred for 3 days. The resulting crystalline precipitate is collected by filtration and recrystallized from ethyl acetate-hexane to give 6.5 g of trans-7-(4-acetoxycyclohexyl)heptanoic acid as colorless needless, m.p. 66°-68° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[C:6]#[N:7].[BH4-].[Na+]>[Co](Cl)Cl>[CH3:14][O:13][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:10]=1[O:11][CH3:12])[CH2:6][NH2:7]
Reactant: COc1cc(C#N)cc(OC)c1OC
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Product: COc1cc(CN)cc(OC)c1OC

Procedure:
The starting material 3,4,5-trimethoxybenzylamine was prepared by reduction of 3,4,5-trimethoxybenzonitrile with cobalt chloride and sodium borohydride, according to the general method described by L. S. Heinzman in J. Am. Chem. Soc., 104, p. 6801 (1980).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[NH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH2:19][C:20]1[CH:25]=[C:24]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=3)[N:4]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[N:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: Nc1cccc(B(O)O)c1
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Yield: 87 %

Procedure:
The title compound was prepared as described in Example 161, using 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.300 g, 0.98 mmol), in ethylene glycol dimethyl ether (10 mL), 3-aminophenyl boronic acid (0.227 g, 1.46 mmol), [1,1′-bis(diphenylphosphino)-ferrocene] complex with dichloromethane (1:1) (0.113 g, 0.098 mmol), and potassium phosphate (1.03 g, 4.9 mmol): (0.273 g, 87% yield): ES-MS (m/z) 319 [M+1]+.
Reaction SMILES: [CH:1]([CH:5]1[CH2:10][C:9](=[O:11])[CH2:8][C:7](=[O:12])[CH2:6]1)([CH2:3][CH3:4])[CH3:2].[C:13]1([CH3:25])[CH:18]=[CH:17][C:16]([S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])=[CH:15][CH:14]=1>C1C=CC=CC=1>[CH:1]([CH:5]1[CH2:6][C:7](=[O:12])[CH:8]([C:23](=[O:24])[NH:22][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:25])=[CH:14][CH:15]=2)(=[O:20])=[O:21])[C:9](=[O:11])[CH2:10]1)([CH2:3][CH3:4])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CCC(C)C1CC(=O)CC(=O)C1
Solvent: c1ccccc1
Product: CCC(C)C1CC(=O)C(C(=O)NS(=O)(=O)c2ccc(C)cc2)C(=O)C1

Procedure:
Reaction of equimolar amounts of 5-sec.-butyl-1,3-cyclohexanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-sec.-BUTYL-2-(N-p-TOLUENESULFONYLCARBAMOYL)-1,3-CYCLOHEXANEDIONE, m.p. 92°-93° C. (corr.).