Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]Cl.[CH3:3][C:4]1[CH:8]([CH3:9])[C:7](=[O:10])[NH:6][N:5]=1>ClCCCl>[CH3:3][C:4]1[C:8]([CH3:9])([Cl:1])[C:7](=[O:10])[NH:6][N:5]=1
Reactant: CC1=NNC(=O)C1C
Reactant: ClCl
Solvent: ClCCCl
Product: CC1=NNC(=O)C1(C)Cl

Procedure:
A chlorine gas was introduced into a solution of 3,4-dimethyl-2-pyrazolin-5-one in 1,2-dichloroethane, followed by gradual refluxing. After the reaction, the reaction mixture was cooled and filtered. The solvent was then distilled off. The residue in the form of an oil was recrystallized from a 1:1 mixture of benzene and petroleum ether, whereby 3,4-dimethyl-4-chloro-2-pyrazolin-5-one was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[C@@H:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:20][CH:19]=3)[C:16]3[C:11](=[CH:12][C:13]([O:32]C)=[CH:14][CH:15]=3)[O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.N1C=CC=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[C@@H:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)=[CH:20][CH:19]=3)[C:16]3[C:11](=[CH:12][C:13]([OH:32])=[CH:14][CH:15]=3)[O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1cccc(F)c1)[C@H]2c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2c(c1)OC[C@@H](c1cccc(F)c1)[C@H]2c1ccc(OCCN2CCCC2)cc1

Procedure:
In an manner analogous to that described in step 5 for Example 10, (±)-cis-3-(3-fluorophenyl)-7-methoxy-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane (0.224 g, 0.50 mmol) was de-methylated by heating with pyridine hydrochloride to give the title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]\[C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(/C(C#N)=C/c2ccc(O)cc2)cc1OC
Solvent: CC#N
Product: COc1ccc(/C(C#N)=C\c2ccc(O)cc2)cc1OC
Yield: 41 %

Procedure:
Compound 1 (100 mg) was dissolved in acetonitrile, and the resultant solution was subjected to photoreaction by use of a high-pressure mercury lamp. The resultant reaction mixture was concentrated to dryness under reduced pressure, followed by purification by use of a silica gel column, to thereby produce the target product (41 mg, yield: 41%).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9](=[O:18])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[N:31]1([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:33][CH2:32]1>O1CCCC1.C(O)(C)(C)C.O>[CH2:37]([O:36][C:34]([NH:31][CH2:32][CH2:33][CH:10]([C:9](=[O:18])[CH2:8][CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:6][CH:5]=1)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:35])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(OCc1ccccc1)N1CC1
Reactant: CC(C)(C)OC(=O)CC(=O)CCc1ccc(-c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)C(CCNC(=O)OCc1ccccc1)C(=O)CCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 16.4 %

Procedure:
To a solution of the compound tert-butyl 5-biphenyl-4-yl-3-oxopentanoate (237 mg,) in tetrahydrofuran (4 ml) and tert-butyl alcohol (4 ml) at 0° C. under inert atmosphere was added potassium tert-butoxide (98 mg) and stirred for 20 minutes. To this at 0° C. was then added n-tetrabutylammonium iodide (27 mg) and benzyl aziridine-1-carboxylate (130 mg) and stirred the reaction mixture for 5 minutes. The resulting reaction mixture was warmed to room temperature and then further heated at 70° C. for 2 hours. The solvent was evaporated under reduced pressure and the residue thus obtained was taken in water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using 20% ethyl acetate in hexane as eluant to furnish the title compound (60 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[OH:11].[CH3:12][Li].Cl>CCOCC>[OH:11][C:3]1[C:2]([CH3:1])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](=[O:7])[CH3:12]
Reactant: [Li]C
Reactant: Cc1cccc(C(=O)O)c1O
Agent: Cl
Solvent: CCOCC
Product: CC(=O)c1cccc(C)c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a colorless solution of 3-methyl-salicylic acid (1 g, 6.57 mmol) in Et2O (50 mL) under argon and cooled down to 0° C. was added dropwise methyllithium 1.6M in Et2O (12.32 mL, 19.72 mmol) over 20 min. The resulting mixture was stirred at this temperature for 30 min then allowed to warm up and stir overnight at RT. The reaction mixture was slowly poured into a stirred mixture of 100 g of ice and HCl 4N (50 mL) and extracted twice with EtOAc. The combined organic layers were washed with 10% NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the title product (920 mg, 5.94 mmol, 90% yield) as a pale yellow oil. tR: 0.91 min (LC-MS 2); ESI-MS: 481/483 [M+H]+, ESI-MS: 479/501 [M−H]− (LC-MS 2); Rf=0.55 (hexane/EtOAc 3:1).
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].[CH2:5]([O:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[C:15]([O:26]C)[N:16]2[CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)=[C:12]([NH2:28])[N:11]=1)[CH2:6][CH2:7][CH3:8].CCN(C(C)C)C(C)C.CS(C)=O>CN(C=O)C>[NH2:28][C:12]1[N:11]=[C:10]([O:9][CH2:5][CH2:6][CH2:7][CH3:8])[N:18]=[C:17]2[C:13]=1[NH:14][C:15](=[O:26])[N:16]2[CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:2][CH2:3][CH3:4])[CH2:21]1
Reactant: CCCI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCCNC3)c2n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCCN(CCC)C3)c2n1
Reaction time: 18 h
Yield: 20.7 %

Procedure:
1-Iodopropane (0.1 mmol) was weighed into a vial and an aliquot (0.3 ml, 0.1 mmol) of a solution of 2-(butyloxy)-8-(methyloxy)-9-(3-piperidinylmethyl)-9H-purin-6-amine (802 mg, 2.398 mmol) suspended in DMF (7.2 ml) was added. DIPEA (40 μl, 0.229 mmol) was added and the tube was capped and shaken to aid dispersion then allowed to stand at room temperature (18 hours). An additional portion of 1-iodopropane (0.05 mmol) was added and the reaction allowed to stand for 18 hours. DMSO (400 uL) was added and the mixture purified by Mass Directed AutoPrep (Method A). The solvent was evaporated in vacuo using the Genevac. The residue was redissolved in 4M HCl/dioxane (0.5 ml), capped and stood at room temperature for 18 hours. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus. The material was redissolved in methanol (0.5 ml), and applied to a 0.5 g aminopropyl SPE (preconditioned with methanol, 2 CV). The cartridge was eluted with methanol (2 ml), the solvent was removed to give the title compound (7.5 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7]/[N:8]=[CH:9]/[CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[C:19]([F:35])=[C:20](/[CH:24]=[C:25](/[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)\[C:26]#[N:27])[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[C:19]=2[F:35])[C:25]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)([C:26]#[N:27])[CH:9]([CH2:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[NH:8]1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)C/N=C/CC1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1NC(CC2CCCC2)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1F
Yield: 25.8 %

Procedure:
In a manner similar to the method described in Example 1c, [2-cyclopentyl-eth-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 34a (1 g, 4.4 mmol) was vented with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (0.9 g, 3 mmol) prepared in Example 26a, AgF (1.3 g, 10 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (150 mL) at room temperature for 24 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.4 g, 26%).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(Cl)cc1Cl
Yield: 65.6 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 2,4-dichlorophenylboronic acid (available from Combi-Blocks Inc.; 76 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′,4′-dichloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (65 mg, 65%). 1H NMR (400 MHz, DMSO-d6) δ 13.15 (br s, 1H), 8.55 (s, 1H), 8.49 (s, 1H), 8.34 (s, 1H), 8.29 (d, J=7.8 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 7.70 (s, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.36-7.43 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7](Cl)=[O:8].[CH3:11][NH2:12]>C1COCC1>[CH3:11][NH:12][C:7]([CH:3]1[C:2]([CH3:10])([CH3:1])[C:4]1([CH3:6])[CH3:5])=[O:8]
Reactant: CN
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Solvent: C1CCOC1
Product: CNC(=O)C1C(C)(C)C1(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
A solution of 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (16.05 g, 0.1 mole) in the THF (50 ml) was added slowly to 35% aqueous methyl amine (200 ml). The reaction mixture was stirred for 24 hours at room temperature, and, after removal of THF under reduced pressure, was extracted with CH2Cl2 (2×50 ml). The CH2Cl2 extract was washed successively with H2O (2×100 ml), 0.3 N HCl (200 ml), 0.1 NaHCO3 (100 ml) and saturated NaCl (150 ml), dried over MgSO4 and evaporated to dryness under reduced pressure. The crude product was treated with hexane (100 ml) at room temperature for 30 minutes, filtered and dried to afford 10.5 g (68 mmole, 68%) of a white solid, m.p.: 98° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[C:9]([OH:11])=[N:10][C:5]2=[N:4][CH:3]=1.[CH3:20][S-:21].[Na+].CN1CCCC1=O>CCOC(C)=O>[CH3:20][S:21][C:2]1[N:7]=[C:6]2[N:8]([C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[C:9]([OH:11])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: C[C@@H](c1ccccc1)n1c(O)nc2ncc(Br)nc21
Reactant: C[S-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CSc1cnc2nc(O)n([C@@H](C)c3ccccc3)c2n1
Temperature: 180 °C
Yield: 24 %

Procedure:
A thick-walled microwave bottle equipped with a stirbar was charged with (S)-6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2-ol (1.0 equiv), sodium thiomethoxide (4.5 equiv), and N-methylpyrrolidone (10 volume equivalents). The bottle was fitted with a septum and cap and heated to 180° C. in a microwave for 30 min. The reaction mixture was then diluted with 100 volume equivalents of EtOAc and washed with 4×100 volume equivalents of water and 1×100 volume equivalents of brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Reverse-phase preparative HPLC (20%-80% MeCN/H2O) provided the title compound (24%) as a white solid. LCMS m/z (APCI)=287.1 (M+H).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].Cl.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][NH2:15])=[CH:10][CH:9]=1>O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][NH:15][C:2]([NH2:3])=[O:1])=[CH:10][CH:9]=1
Reactant: N#C[O-]
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: COc1ccc(NNC(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
Under ice-bath cooling, potassium cyanate (1.71 g, 21.1 mmol) was added to a suspension of 4-methoxyphenylhydrazine hydrochloride (3.35 g, 19.2 mmol) in water (40 mL). The mixture was stirred for 1 hour at the same temperature. And then the mixture was warmed to room temperature and stirred for 12 hours. An insoluble material was isolated by filtration, washed with water, and dried in vacuo to give 2-(4-methoxyphenyl)hydrazinecarboxamide (2.45 g, 70.5% yield).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1C=C(C2(C(N)C)CCC2)C=C[C:9]=1Cl.Cl.[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2([CH:31]([NH2:33])[CH3:32])[CH2:30][CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[Cl:26].[OH-].[Na+]>C(O)(=O)C>[ClH:3].[CH2:4]([NH:33][CH:31]([C:27]1([C:22]2[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([Cl:19])[CH:21]=2)[CH2:30][CH2:29][CH2:28]1)[CH3:32])[CH3:9]
Reactant: CC(N)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCNC(C)C1(c2ccc(Cl)c(Cl)c2)CCC1

Procedure:
Sodium borohydride (2.0 g) was added to solution of 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine (1.5 g prepared by treating the product of Example 1 with aqueous sodium hydroxide) in glacial acetic acid (30 ml). The mixture was heated at 95°-100° C. for sixteen hours and then cooled. Aqueous sodium hydroxide solution was added and the reaction mixture extracted with ether. The ther extract was shaken with 5N hydrochloric acid and the aqueous layer was washed with ether, basified and extracted with ether. Hydrogen chloride gas was passed into the ether extract which was evaporated to dryness. Trituration with acetone gave N-ethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine hydrochloride (m.p. 211°-212° C.). (Formula I R1 =Me, R2 =H; R3 =Et; R4 =H; R5 =4-Cl and R6 =3- Cl.)
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10](OC1C=CC([N+]([O-])=O)=CC=1)=[O:11].[NH2:22][C:23]([C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=1)([CH3:49])[CH2:24][NH:25][C:26](=[O:48])[CH2:27][N:28]1[C:32](=[O:33])[N:31]([CH2:34][C@H:35]([OH:40])[C:36]([F:39])([F:38])[F:37])[C:30]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)=[N:29]1.[OH-].[Li+].Cl>C1COCC1.O>[Cl:47][C:44]1[CH:45]=[CH:46][C:41]([C:30]2[N:31]([CH2:34][C@H:35]([OH:40])[C:36]([F:39])([F:38])[F:37])[C:32](=[O:33])[N:28]([CH2:27][C:26]([NH:25][CH2:24][C:23]([NH:22][CH:10]=[O:11])([C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=3)[CH3:49])=[O:48])[N:29]=2)=[CH:42][CH:43]=1
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Reactant: CC(N)(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)(NC=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At RT, 12 μl (68 μmol) of N,N-diisopropylethylamine and then 11 mg (65 μmol) of 4-nitrophenyl formate were added to a solution of 38 mg (62 μmol) of the compound of Example 53A in 1 ml of THF, and the mixture was stirred at RT. After 1 h, another 10 mg (62 μmol) of 4-nitrophenyl formate were added and stirring of the reaction mixture was continued overnight. Since LC/MS analysis indicated additional formation of an O-formylated byproduct, 248 μl of a 1 N solution of lithium hydroxide in water were added to the reaction mixture. After 1 h, the mixture was acidified with 1 N hydrochloric acid and separated by preparative HPLC [Method 8]. This gave 30 mg (81% of theory) of the title compound as a diastereomer mixture.
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[Br:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[CH:13][CH:12]=1
Reactant: Brc1ccc(I)cc1
Reactant: OC1CN2CCC1CC2
Product: Brc1ccc(OC2CN3CCC2CC3)cc1

Procedure:
3-Hydroxy quinuclidine (Aldrich, 1.27 g, 10 mmol) was treated with 4-bromo-iodobenzene (Aldrich, 2.82 g, 10 mmol) according to the procedure of Example 14A. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.20) as oil (0.85 g, yield, 30%). 1H NMR (MeOH-d4, 300 MHz) δ 1.40–1.56 (m, 1H), 1.64–1.80 (m, 2H), 1.90–2.08 (m, 1H), 2.10–2.21 (m, 1H), 2.60–3.00 (m, 5H), 3.34–3.40 (m, 1H), 4.46 (m, 1H), 6.83 (d, J=9.5 Hz, 2H) 7.37 (d, J=9.2, Hz, 2H), ppm. MS (DCl/NH3) m/z 282 (M+H)+, 284 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[C:9]([CH3:28])=[C:10]([NH:14][C:15](=[O:27])[CH2:16][C:17]23[CH2:26][CH:21]4[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]4)[CH2:18]2)[CH2:24]3)[CH:11]=[CH:12][CH:13]=1.I[CH2:30][CH2:31][CH2:32][N:33](C)[C:34](=O)OC(C)(C)C.[ClH:42]>C(#N)C.CO>[ClH:42].[CH3:34][NH:33][CH2:32][CH2:31][CH2:30][O:7][C:8]1[C:9]([CH3:28])=[C:10]([NH:14][C:15](=[O:27])[CH2:16][C:17]23[CH2:26][CH:21]4[CH2:20][CH:19]([CH2:25][CH:23]([CH2:22]4)[CH2:24]2)[CH2:18]3)[CH:11]=[CH:12][CH:13]=1
Reactant: CN(CCCI)C(=O)OC(C)(C)C
Reactant: Cc1c(O)cccc1NC(=O)CC12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CC#N
Product: CNCCCOc1cccc(NC(=O)CC23CC4CC(CC(C4)C2)C3)c1C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Dry dichloromethane (40 ml), triphenylphosphine (3.28 g), imidazole (1.05 g) and iodine (3.85 g) were combined in that order. A solution of tert-butyl N-(3-hydroxypropyl)-N-methylcarbamate (1.90 g, J. Org. Chem., 1988, 53(10), 2229) in dichloromethane (10 ml) was added and the resulting reaction mixture stirred at room temperature for 1 hour. An aqueous solution of sodium hydrogen sulphite (6 g in 100 ml of water) was then added and the organic layer separated. The latter was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with iso-hexane:ether (7:3) to give tert-butyl N-(3-iodopropyl)-N-methylcarbamate (2.54 g) which was used immediately. Caesium carbonate (0.655 g) was added to a suspension of N-(3-hydroxy-2-methylphenyl)-tricyclo[3.3.1.13,7]decane-1-acetamide (0.453 g, Example 26) in acetonitrile (35 ml) and the mixture heated at 100° C. for 10 minutes. After cooling to room temperature a solution of tert-butyl N-(3-iodopropyl)-N-methylcarbamate (0.600 g) in acetonitrile (5 ml) was added and the reaction heated at reflux for 90 minutes. The reaction was concentrated under reduced pressure and the residue partitioned between dichloromethane (100 ml) and water (100 ml). The organic layer was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane:ethyl acetate (9:1) to give a solid that was dissolved in methanol (10 ml). A solution of hydrogen chloride (generated by slow addition of acetyl chloride (12 ml) to methanol (15 ml) at 0° C. CARE—Very Exothermic) was then added to the latter solution and the reaction stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to give a gum that was scratched under ether:hexane (1:1) (20 ml) to give the title compound as a pale yellow powder (0.477 g).
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:8]=[C:9]([O:15][CH3:16])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1.C1(S([CH:26]2[CH2:30][CH2:29][CH:28]([O:31][CH3:32])[O:27]2)(=O)=O)C=CC=CC=1>C1COCC1.[Zn+2].[Br-].[Br-]>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([CH:26]2[CH2:30][CH2:29][CH:28]([O:31][CH3:32])[O:27]2)[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: COc1ccc(Br)cc1OC
Reactant: COC1CCC(S(=O)(=O)c2ccccc2)O1
Agent: [Br-]
Agent: [Mg]
Agent: [Zn+2]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COc1ccc(C2CCC(OC)O2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
Magnesium (2.18 g, 0.091 M) was placed in a 3-necked flask containing dry THF (10 ml) and 1,2-dibromoethane (0.2 ml). A solution of 4-bromoveratrole (18.0 g, 0.086 M) in THF (50 ml) was added dropwise, warming to initiate reaction. The resulting solution was heated at reflux for 0.75 h then cooled to room temperature and cannulated into a 1M solution of ZnBr2 in THF (50 ml, 0.05 M) and stirred for 0.5 h at room temperature. A solution of 2-benzenesulphonyl-5-methoxytetrahydrofuran (10.0 g, 0.041 M) in THF (50 ml) was added dropwise to the pale yellow suspension and the mixture allowed to stir at room temperature for 20 h. Reaction was quenched by addition of 1N HCl (50 ml), and extracted with ether (2×100 ml). The organics were combined washed with water (50 ml) dried (Na2SO4) and evaporated. Flash column chromatography (flash silica gel, hexane:ethyl acetate (3:2)) gave 2-(3,4-dimethoxyphenyl)-5-methoxytetrahydrofuran (8.0 g, 82%) as a yellow oil (rf 0.28).
Reaction SMILES: CO[C:3](=[O:25])[C@H:4]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])[NH:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C[CH:27]1[CH2:32][CH2:31][CH2:30]CC1(C)C.CC1(CC)CCCCC1.C(C1(CC)CCCCC1)C.N#N.[CH2:56]([NH2:60])[CH2:57][CH2:58][CH3:59]>CO.C1CCCCC1>[CH2:56]([N:60]([CH2:30][CH2:31][CH2:32][CH3:27])[C:3](=[O:25])[C@H:4]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[NH:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:57][CH2:58][CH3:59].[CH2:4]([NH2:5])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCC(=O)N[C@@H](CCC(=O)OC)C(=O)OC
Reactant: CC1CCCCC1(C)C
Agent: CCC1(C)CCCCC1
Agent: CCC1(CC)CCCCC1
Agent: N#N
Solvent: C1CCCCC1
Solvent: CO
Solvent: CCCCN
Product: CCCCCCCCCCCC(=O)N[C@@H](CCC(=O)O)C(=O)N(CCCC)CCCC

Procedure:
In a 1 I Quickfit flask with a glass-jacketed thermosensor, gas inlet, stainless steel anchor stirrer and heatable (67°-70° C.) pre-column with an attached Claisen bridge and subsequent cold trap, 110 g of N-lauroyl-L-glutamic acid dimethyl ester (LGA-DME) and 100 g of a mixture of cyclohexane derivatives (trimethylcyclohexane, methylethylcyclohexane and diethylcyclohexane in an approximate ratio of 45:25:10) are initially introduced under a gentle stream of N2. 110 g of n-butylamine are metered in over a period of 30 minutes and the mixture is heated under reflux. During the reaction, portions of the methanol liberated during the amidation are separated off, with a little n-butylamine, via the temperature-controlled pre-column. After refluxing for about 8 hours, monitoring by TLC indicates quantitative conversion. The excess n-butylamine is distilled off, first under normal pressure and then in vacuo, and the product is precipitated by addition of acetone. The precipitate formed is filtered off with suction, washed with acetone, dried and comminuted. The target product N-lauroyl-L-glutamic acid di-n-butylamide is obtained in a good yield of about 80% and in excellent purity (LGB 99% (HPLC), nBuNH2 50 ppm (GC), other impurities<1%) in the form of a colorless powder of melting point 150°-152° C.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][N:12]=[C:13]=[S:14])[C:4]2=[CH:3][CH:2]=1.[NH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CO.C(Cl)(Cl)Cl>CO.C1COCC1>[C:10]1([CH2:11][NH:12][C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[S:14])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: S=C=NCc1cccc2ccccc12
Reactant: NCC1CCNCC1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: S=C(NCc1cccc2ccccc12)NCC1CCNCC1
Yield: 54 %

Procedure:
To a solution of 1-naphthalenemethylisothiocyanate (2.8 g, 13.6 mmol) in 100 ml of MeOH-THF solution (1:1 mixture) was added 4-aminomethylpiperidine (3.1 ml, 27.0 mmol) in a portion and the resulting solution was stirred at reflux for 12 h. The reaction mixture was concentrated in vacuo, yielding oily mixture which was subjected to column chromatography (10% MeOH/CHCl3) to yield 2.3 g (48%) of the desired product as an oil.