Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[N:2]12[CH2:8][C:5]([C:9]([O:11]CC)=O)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Cl.[O:15]([NH2:17])[CH3:16]>C(N(CC)CC)C>[N:2]12[CH2:8][C:5]([C:9]([NH:17][O:15][CH3:16])=[O:11])([CH2:4][CH2:3]1)[CH2:6][CH2:7]2
Reactant: CCOC(=O)C12CCN(CC1)C2
Reactant: CON
Agent: Br
Agent: Cl
Solvent: CCN(CC)CC
Product: CONC(=O)C12CCN(CC1)C2

Procedure:
Ethyl 1-azabicyclo[2.2.1]hept-4-ylcarboxylate hydrobromide salt (D17, 16.85 g, 0.067 mole) was converted to the acid chloride hydrochloride salt and treated with methoxylamine hydrochloride (6.19 g, 0.074 mole) and triethylamine as in the method of Description 8 to give the title compound (D18) as a pale brown crystalline solid (4.60 g, 40%) m.p. 129°-134° C.
Reaction SMILES: [Cl-].[Na+].O.CS(C)=O.C([CH:12]1[CH2:17][C:16]([C:32]#[N:33])([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:19]=2)[CH2:15][CH2:14][C:13]1=[O:34])(OC)=O>C(O)(C)C>[C:32]([C:16]1([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:19]=2)[CH2:17][CH2:12][C:13](=[O:34])[CH2:14][CH2:15]1)#[N:33]
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC)c(OC3CCCC3)c2)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: CS(C)=O
Product: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC1CCCC1
Temperature: 155 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium chloride (315 g, 5.39 mol) and deionized water (315 mL) was added the dimethyl sulfoxide (4.2 L) solution of 2-carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-one (323 g, 0.87 mol) and the resulting suspension was heated to 155° C. for 1.75 h. The reaction was cooled to 40° C., was quenched into 8 L of iced water (2° C.) and was extracted with ethyl acetate (3.5 L). The aqueous layer was isolated and re-extracted with 2.5 L of ethyl acetate. The combined organic extract (6 L) was washed two times with deionized water (2×1 L) and once with brine (1 L). The organic layer was isolated and concentrated in vacuo to afford a residue. This residue was dissolved in refluxing isopropanol (500 mL), was cooled to 0° C. and held at this temperature for 1 hour. The crystals were isolated by filtration, were washed with 250 mL of isopropanol (0° C.), and were dried in a vacuum oven (45° C. at 20 inches) to produce 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one. m.p. 111-112° C.; Anal. (C19H23NO3) calcd: C 72.82, H 7.40, N 4.47; found: C 72.72, H 7.39, N 4.48.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[CH2:18]([Sn](=O)CCCC)[CH2:19][CH2:20]C.C([C@@]1(O)[C@H](OCCCC)[C@@H](C(=[SnH2])O)O[C@H]1N1C=CC(=O)NC1=O)CCC.ICCC>>[CH2:18]([O:3][C@@H:2]1[C@H:4]([OH:5])[C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12])[CH2:19][CH3:20]
Reactant: CCCC[Sn](=O)CCCC
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: CCCCO[C@@H]1[C@@H](C(O)=[SnH2])O[C@@H](n2ccc(=O)[nH]c2=O)[C@@]1(O)CCCC
Solvent: CCCI
Product: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O

Procedure:
As per the procedure of Example 49, uridine (10 g) was treated with dibutyl tin oxide (10.2 g, 1 eq). The resulting 2',3'-O-dibutylstannylene uridine was treated with iodopropane (8 ml, 2 eq.) at 110° C. as per Example 50 to give a mixture of the 2' and 3' isomers (5.5 g) as a foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[Cl:11][C:12]([Cl:16])([CH3:15])[CH:13]=O.[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:17]1([CH:13]([NH:7][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[C:12]([Cl:16])([Cl:11])[CH3:15])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC(Cl)(Cl)C=O
Reactant: NC(=O)c1cccc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(Cl)(Cl)C(NC(=O)c1cccc(F)c1)n1nnc2ccccc21

Procedure:
A suspension of 3-fluorobenzamide, 2,2-dichloropropionaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 53A to provide the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][CH2:5][C:6]([NH2:8])=[O:7].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[N:43]1([C:48]2[CH:53]=[CH:52][C:51]([S:54]([O:57][C:58]3[CH:67]=[CH:66][C:61]4[NH:62][C:63](N)=[N:64][C:60]=4[CH:59]=3)(=[O:56])=[O:55])=[CH:50][CH:49]=2)[CH:47]=[CH:46][N:45]=[CH:44]1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:9])[CH2:4][CH2:5][C:6]([NH:8][C:63]1[NH:62][C:61]2[CH:66]=[CH:67][C:58]([O:57][S:54]([C:51]3[CH:52]=[CH:53][C:48]([N:43]4[CH:47]=[CH:46][N:45]=[CH:44]4)=[CH:49][CH:50]=3)(=[O:56])=[O:55])=[CH:59][C:60]=2[N:64]=1)=[O:7]
Reactant: COC(=O)CCC(N)=O
Reactant: Nc1nc2cc(OS(=O)(=O)c3ccc(-n4ccnc4)cc3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCC(=O)Nc1nc2cc(OS(=O)(=O)c3ccc(-n4ccnc4)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8.9 mg of succinamic acid methyl ester, 25 mg of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and 12 μl diisopropyl-ethylamine were taken up in 0.4 ml dimethylformamide. Reaction mixture was stirred at room temperature for one hour and 5-(4-[1-imidazolyl]-phenylsulfonyloxy)-1H-benzimidazole-2-ylamine was added in 0.2 ml dimethylformamide. Reaction mixture was then stirred at room temperature for 24 hours. Solvent was evaporated in a Jouan model RC 10.10 centrifuge evaporator and title compound was solubilised in 0.5 ml dimethylsulfoxide for LCMS trigged purification yielding 3.9 mg of N-[5-(4-[1-imidazolyl]-phenylsulfonyloxy)-1H-benzimidazole-2-yl]-succinamic-acid-methyl ester. (LC/MS analysis: retention time=2.70 min., mass spectrum: 470.34, [M+H]+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OCC)=O.[CH:52]([C:54]1[C:59](=[O:60])[N:58]([CH2:61][CH2:62][CH3:63])[C:57](=[O:64])[N:56]2[CH2:65][CH2:66][S:67][C:55]=12)=O>C(Cl)Cl>[O:64]=[C:57]1[N:56]2[CH2:65][CH2:66][S:67][C:55]2=[C:54](/[CH:52]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:59](=[O:60])[N:58]1[CH2:61][CH2:62][CH3:63]
Reactant: CCOC(=O)CBr
Reactant: CCCn1c(=O)c(C=O)c2n(c1=O)CCS2
Agent: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCn1c(=O)c(/C=C/C(=O)OCC)c2n(c1=O)CCS2
Yield: 78.7 %

Procedure:
A solution of the Wittig reagent prepared from triphenylphosphine (5.3 g) and ethyl bromoacetate (3.4 g), (carboethoxymethylene)triphenylphosphorane (6 g) and 8-formyl-6-propyl-2,3-dihydro-5H-thiazolo[3,2-c]pyrimidine-5,7(6H)-dione (3.76 g) in methylene chloride (15 ml) was refluxed in for 7 hours. The reaction solution was concentrated to dryness. The resulting residue was purified by column chromatography on silica gel. The resulting crude crystals were recrystallized from methylene chloride -isopropyl ether to give colorless needles (3.82 g, 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[NH:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[O:13].C(CN)O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[C:17]1[NH:11][C:12](=[O:13])[NH:14][C:15]1=[O:16]
Reactant: O=C1CNC(=O)N1
Reactant: COc1cccc(C=O)c1
Solvent: NCCO
Solvent: O
Product: COc1cccc(C=C2NC(=O)NC2=O)c1
Yield: 79.9 %

Procedure:
A mixture of m-methoxybenzaldehyde (2.00 g., 14.7 mmoles) and hydantoin (1.47 g.) in water (12 ml) was heated to 70°; monoethanolamine (1.35 g., 1.5 molar ratio) was then added and the mixture was heated in an oil bath at 90°-92° for 4 hours with magnetic stirring. Isolation in the usual manner gave the title compound as a beige solid (2.56 g.), m.p. 229°-231°.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[CH2:13][Si:14]1(C2C=CC=CC=2)[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH2:16][CH2:15]1>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:13][Si@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH2:16][CH2:15]2)=[CH:7][CH:8]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: COCCCCCC1CC[Si](CBr)(c2ccccc2)CC1
Product: COCCCCC[C@H]1CC[Si@H](COc2ccc(C(F)(F)F)cc2)CC1

Procedure:
The general procedure of Example 9 was repeated using 4-trifluoromethylphenol and 4-bromomethyl-1-(5-methoxypentyl)-4-phenyl-4-silacyclohexane, thereby obtaining the intended compound.
Reaction SMILES: [F:1][C:2]1([CH:8]([OH:11])C#N)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[BH4-].[Na+].CC(C)=O>C(O)(C)(C)C.O>[F:1][C:2]1([CH2:8][OH:11])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: N#CC(O)C1(F)CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CC(C)=O
Product: OCC1(F)CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
2-(4-Fluorotetrahydro-2H-pyran-4-yl)-2-hydroxyacetonitrile (2.06 g, 12.9 mmol) was dissolved in tert-butanol (20 mL) and water (5.0 mL). To this, sodium borohydride (537 mg, 14.2 mmol) was added and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, ice and acetone were added and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated off under reduced pressure, brine was added to the residue, and extraction with chloroform was performed, followed by drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/7) to give 4-fluorotetrahydro-2H-pyran-4-ylmethanol (1.59 g, yield: 92%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:13][C:12]=2[F:24])[CH2:7][CH2:6]1)[CH3:2].[Cl:26]N1C(=O)CCC1=O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:25])[CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[C:12]([F:24])=[CH:13][C:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[CH:15][C:16]=2[Cl:26])[CH2:9][CH2:10]1)[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)OC(C)(C)C)cc2F)CC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2c(F)cc(C(=O)OC(C)(C)C)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.9 %

Procedure:
To a solution of 0.50 g of N-(4-tert-butoxycarbonyl-2-fluorophenyl)isonipecotic acid ethyl ester in 5 ml of DMF, 0.21 g of N-chlorosuccinimide was added, and the mixture was stirred at room temperature for 1 day. After the evaporation of the solvent, the residue was purified by silica gel column chromatography (eluent:hexane-EtOAc=5:1˜1:1) to obtain 0.51 g of N-(4-tert-butoxycarbonyl-2-chloro-6-fluorophenyl)isonipecotic acid ethyl ester.
Reaction SMILES: [C:1]12([C:11]3[CH:22]=[CH:21][C:14]([O:15][CH2:16][CH2:17]C(O)=O)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([OH:33])[CH:27]=1.ClCCl.[OH-].[Na+]>C[Si](OP(=O)=O)(C)C>[CH3:23][O:24][C:25]([C:26]1[CH:31]=[CH:30][C:29]2[N:32]=[C:17]([CH2:16][O:15][C:14]3[CH:13]=[CH:12][C:11]([C:1]45[CH2:10][CH:5]6[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]6)[CH2:2]4)[CH2:8]5)=[CH:22][CH:21]=3)[O:33][C:28]=2[CH:27]=1)=[O:34]
Reactant: O=C(O)CCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: COC(=O)c1ccc(N)c(O)c1
Agent: C[Si](C)(C)OP(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)oc2c1
Temperature: 140 °C
Yield: 63 %

Procedure:
A mixture of (4-adamantan-1-yl-phenoxymethyl)acetic acid (200.0 mg, 0.70 mmol) and 4-amino-3-hydroxy-benzoic acid methyl ester (164.3 mg, 0.98 mmol) in PPSE (3 mL) was heated at 140° C. for 2 h. At the end of the reaction period, the mixture was taken to dichloromethane and neutralized with 1 N NaOH solution. The organic layer was separated and the aqueous solution extracted with dichloromethane. The combined extracts were dried over anhydrous MgSO4, filtered and the solvent was removed with rotary evaporator under reduced pressure. The residue was purified by flash chromatography (n-Hexane:EtoAc:MeOH=6:3:1) to afford 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-6-carboxylic acid methyl ester as a white solid (184.0 mg, 63.0% yield).
Reaction SMILES: [CH:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[CH2:2].[CH2:8]([Br:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CO>C(OCC)C>[Br-:24].[CH:1]([N+:3]1[CH:7]=[CH:6][N:5]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8])[CH:4]=1)=[CH2:2]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: C=Cn1ccnc1
Solvent: CO
Solvent: CCOCC
Product: C=C[n+]1ccn(CCCCCCCCCCCCCCCC)c1
Product: [Br-]
Temperature: 60 °C
Reaction time: 15 h

Procedure:
(From Yuan & Antonietti, DOI: 10.1021/ma102858b.) A solution/suspension comprising 0.1 mol of 1-vinylimidazole, 0.1 mol of n-hexadecyl bromide and 30 mL of methanol were loaded into a 100 mL reactor. The mixture was stirred at 60° C. for 15 h. After cooling the reaction mixture was added dropwise into 1 L of diethyl ether. The white precipitate was filtered off and dried at room temperature to yield a powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][CH:16]=2)[NH:13][CH2:12][CH2:11][CH2:10]3)[CH:2]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][CH:16]=2)[N:13]([C:23](=[O:25])[CH3:24])[CH2:12][CH2:11][CH2:10]3)[CH:2]=1
Reactant: c1cncc(-c2cnc3c(c2)CCCN3)c1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1CCCc2cc(-c3cccnc3)cnc21
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
6-Pyridin-3-yl-1,2,3,4-tetrahydro-[1,8]naphthyridine (41 mg, 0.19 mmol) is dissolved in 2 mL of DCM and pyridine (0.19 mL, 2.3 mmol) is added into the solution. Then acetyl chloride (0.08 mL, 1.2 mmol) is added. The mixture is stirred for 0.5 hrs and saturated aqueous NaHCO3 (2 mL) is added along with water (3 mL). The mixture is extracted with EtOAc (3×10 mL) and the organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography affords 37 mg of the titled product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[NH:16]1[CH:20]=C[C:18]([CH2:21][OH:22])=[CH:17]1.C([O-])([O-])=O.[Na+].[Na+].C[N:30](C=O)C>>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:16]1[CH:17]=[C:18]([CH2:21][OH:22])[N:30]=[CH:20]1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: OCc1cc[nH]c1
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1-n1cnc(CO)c1
Temperature: 70 °C

Procedure:
To a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (1.04 mL, 7.43 mmol) and (1H-pyrrol-3-yl)methanol hydrochloride salt (1.0 g, 7.43 mmol) in DMF (10 mL) was added Na2CO3 (2.36 g, 22.3 mmol). The resulting mixture was heated at 70° C. overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was reconstituted in EtOAc (50 mL) and washed with 9% aq. Na2CO3 (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (1-(2-nitro-4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)methanol.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:29])=[C:24]([CH:28]=1)[C:25](O)=[O:26])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.[NH2:41][CH2:42][CH2:43][OH:44].CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH2:1]([O:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:29])=[C:24]([CH:28]=1)[C:25]([NH:41][CH2:42][CH2:43][OH:44])=[O:26])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(CNc2ccccc2C(=O)NOCc2ccccc2)ccc1F
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCCO)c1cc(CNc2ccccc2C(=O)NOCc2ccccc2)ccc1F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
5-[(2-Benzyloxycarbamoyl-phenylamino)-methyl]-2-fluoro-benzoic acid (Example 498, 96.5 mg) and 1-hydroxybenzotriazole hydrate (36 mg) was dissolved in DMF (1.0 ml). 2-Amino-ethanol (15 μl), N-methylmorpholine (28 μl), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (50.1 mg) was added in that order. The reaction mixture was shaken at room temperature for 15 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane and evaporated onto silica gel. Purification by column chromatography on silica gel (elution with 50-100% EtOAc in petroleum ether) gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]([C:6]1[CH:24]=[CH:23][C:9]2[C:10]3(OCC[O:19]3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH:13]=[CH:14][C:8]=2[CH:7]=1)[CH3:5].CC(C)=O>O>[CH3:1][O:2][C:3](=[O:25])[CH:4]([C:6]1[CH:24]=[CH:23][C:9]2[C:10](=[O:19])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH:13]=[CH:14][C:8]=2[CH:7]=1)[CH3:5]
Reactant: COC(=O)C(C)c1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)C(C)c1ccc2c(=O)c3ccccc3ccc2c1
Yield: 75 %

Procedure:
1.0 Gm. of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d] cyclohepten-2-yl)propionic acid methyl ester is dissolved in 10 ml. of acetone and to the solution is added 5 ml. of N-hydrochloric acid. The mixture is refluxed for one hour, then cooled, diluted with water, and extracted with ethyl acetate. The extract is washed with aqueous sodium carbonate and water, then dried and evaporated to afford a 75% yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid methyl ester, as an oil which slowly crystallized, m.p. 37°-39°C., NMR: δCDCl 3 1.55(d), 3.67(s), 3.83(g), 7.04(s) ppm. Use of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d] cyclohepten-2-yl)acetic acid methyl ester gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetic acid methyl ester, m.p. 67°-69°C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18](O)=[O:19])[CH:8]=1)=[O:5].C([N:39]1[CH2:44][CH2:43][O:42][C@H:41]([CH2:45][NH2:46])[CH2:40]1)C1C=CC=CC=1>>[Cl:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([NH:46][CH2:45][C@H:41]2[O:42][CH2:43][CH2:44][NH:39][CH2:40]2)=[O:19])[CH:8]=1)=[O:5]
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Reactant: NC[C@@H]1CN(Cc2ccccc2)CCO1
Product: O=C(NC[C@@H]1CNCCO1)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1

Procedure:
The title compound was prepared according to the method described for Example 52 using 5-(2-chloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 105) and (R)-(4-benzylmorpholin-2-yl)methanamine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH2:14][C:15]#N)=[CH:12][N:11]([CH3:17])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:18].[Na+].[O:20]1[CH2:24]CCC1.Cl>C(O)C>[CH2:1]([O:8][C:9]1[C:13]([CH2:14][C:15]([O:20][CH3:24])=[O:18])=[CH:12][N:11]([CH3:17])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: Cn1cc(CC#N)c(OCc2ccccc2)n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COC(=O)Cc1cn(C)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A mixture of 3-benzyloxy-1-methyl-1H-pyrazol-4-ylacetonitrile (12.0 g), 4N aqueous sodium hydroxide solution (100 ml), tetrahydrofuran (100 ml) and ethanol (100 ml) was refluxed for 21 hrs. After cooling, the mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. A mixture of the residue, methyl iodide (4.95 ml), potassium carbonate (14.7 g) and N,N-dimethylformamide (100 ml) was stirred overnight at room temperature. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-benzyloxy-1-methyl-1H-pyrazol-4-ylacetate (12.2 g, yield 88%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[H-].[Na+].Br[CH:15]([CH2:25][CH3:26])[C:16]([NH:18][C:19]([CH3:24])([CH3:23])[C:20]#[C:21][CH3:22])=[O:17].O>CN(C)C=O.C(OCC)C>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][CH:15]([CH2:25][CH3:26])[C:16]([NH:18][C:19]([CH3:24])([CH3:23])[C:20]#[C:21][CH3:22])=[O:17])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC#CC(C)(C)NC(=O)C(Br)CC
Reactant: Oc1ccc2ncccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC#CC(C)(C)NC(=O)C(CC)Oc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Hydroxyquinoline (0.46 g) in dry N,N-dimethylformamide (10 ml) was added dropwise to a stirred suspension of sodium hydride (0.10 g, 80% dispersion in mineral oil) in dry N,N-dimethylformamide under an atmosphere of nitrogen at ambient temperature. The green solution was stirred at ambient temperature for 1 hour and a solution of 2-bromo-N-(4-methylpent-2-yn-4-yl) butyramide (0.74 g) in dry N,N-dimethylformamide (10 ml) was added. The mixture was stirred at ambient temperature for 18 hours, poured into water and extracted into diethyl ether (three times). The organic extracts were combined, washed with dilute aqueous sodium hydroxide, water (twice), dried over magnesium sulphate and evaporated under reduced pressure to give a gum. The gum was fractionated by chromatography (silica; diethyl ether) to give the required product, 0.44 g, as a colourless gum.
Reaction SMILES: [CH2:1]([C:3]1([CH2:21][CH3:22])[CH2:8][CH:7]([OH:9])[CH2:6][C:5]([CH3:11])([CH3:10])[N:4]1[O:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[CH3:2].C(N([CH2:28][CH3:29])CC)C.[C:30]1([CH3:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:21]([C:3]1([CH2:1][CH3:2])[CH2:8][CH:7]([O:9][C:7](=[O:9])[CH2:6][CH2:5][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:30][CH2:36][CH2:28][CH3:29])[CH2:6][C:5]([CH3:11])([CH3:10])[N:4]1[O:12][CH:13]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:14])[CH3:22]
Reactant: CCN(CC)CC
Reactant: CCC1(CC)CC(O)CC(C)(C)N1OC(C)c1ccccc1
Reactant: Cc1ccccc1
Product: CCCCCCCCCCCC(=O)OC1CC(C)(C)N(OC(C)c2ccccc2)C(CC)(CC)C1
Yield: 91 %

Procedure:
In analogy to example 1 were reacted 6.1 g (2 mmol) of 2,2-diethyl-6,6-dimethyl-1-(1-phenyl-ethoxy)-piperidin-4-ol (prepared as described in GB 2335190, compound 110) with 4.38 g (2 mmol) of lauroyl chloride chloride and 2.02 g (2 mmol) of triethylamine in toluene to give 8.9 g (91%) dodecanoic acid 2,2-diethyl-6,6-dimethyl-1-(1-phenyl-ethoxy)-piperidin-4-yl ester as yellowish liquid.
Reaction SMILES: [Cl:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[CH:6]1([P:12]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C(OCC)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH:19]1([PH+:12]([CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: CCOCC
Product: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Product: [O-][Cl+3]([O-])([O-])[O-]
Yield: 74.4 %

Procedure:
1.1 ml (12 mmol) perchloric acid is added to 25 ml of a solution of 12 mmol tricyclohexyl phosphine in diethylether prepared as in comparative example 3. Under a slight heat development a crystalline solid precipitates immediately, which is filtered off, and washed with diethylether. 3.4 g of a colorless solid is obtained. This solid is an explosive due to a shock sensitivity at an impact energy of 25 J.