Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:17])=[CH:10][C:11]([C:15]#[N:16])=[N:12]2)=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[N+:18]([C:21]1[CH:38]=[CH:37][C:24]([C:25]([O:27][C:28]([CH2:35][CH3:36])([C:31]([F:34])([F:33])[F:32])[C:29]#[CH:30])=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19].C(N(C(C)C)CC)(C)C>C1COCC1.C(OCC)(=O)C.[Cu](I)I>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][C@@:28]([C:29]2[N:3]=[N:2][N:1]([CH2:4][C:5]3[CH:14]=[C:13]4[C:8]([C:9]([Cl:17])=[CH:10][C:11]([C:15]#[N:16])=[N:12]4)=[CH:7][CH:6]=3)[CH:30]=2)([C:31]([F:32])([F:33])[F:34])[CH2:35][CH3:36])=[O:26])=[CH:37][CH:38]=1)([O-:20])=[O:19]
Reactant: N#Cc1cc(Cl)c2ccc(CN=[N+]=[N-])cc2n1
Reactant: C#CC(CC)(OC(=O)c1ccc([N+](=O)[O-])cc1)C(F)(F)F
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(Cl)cc(C#N)nc3c2)nn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-(azidomethyl)-4-chloroquinoline-2-carbonitrile (560 mg, 2.3 mmol) and 1-ethyl-1-(trifluoromethyl)prop-2-yn-1-yl 4-nitrobenzoate (S-isomer, 728 mg, 2.42 mmol) in THF (18 mL) was added diisopropylethylamine (2.0 mL, 11.5 mmol) followed by copper iodide (655 mg, 3.45 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with a sat. sol. of NH4Cl, Brine and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the resulting crude product was purified by flash chromatography (eluting solvent: 5% acetone in CH2Cl2) to afford the title compound. 1H NMR (400 MHz, acetone-d6): δ 8.55 (s, 1H), 8.45 (d, 2H), 8.37 (d, 1H), 8.30 (d, 2H), 8.22 (s, 1H), 8.07 (s, 1H), 7.90 (d, 1H), 6.05 (s, 2H), 3.05 (m, 1H), 2.85 (m, 1H), 1.15 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=C(O)c1ccccc1Br
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccccc1Br
Yield: 100 %

Procedure:
1.5 g (0.00745 mol) of 2-bromobenzoic acid were dissolved in 25 ml of thionyl chloride under argon and boiled under reflux for 2 hrs. The excess thionyl chloride was distilled off and the residue was taken up twice with 50 ml of toluene and concentrated each time. 1.63 g (100%) of 2-bromobenzoyl chloride were obtained as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:4][CH2:5][CH2:6][OH:7])[CH3:2].N1C=CC=CC=1.[S:24](Cl)([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25].C(OCC)(=O)C>C(Cl)Cl.O>[CH2:1]([N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:4][CH2:5][CH2:6][O:7][S:24]([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CCCO)C(=O)OCc1ccccc1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCN(CCCOS(=O)(=O)c1ccc(C)cc1)C(=O)OCc1ccccc1
Yield: 66.7 %

Procedure:
N-Ethyl 3-benzyloxycarbonylamino-1-propanol (4.0 g) was dissolved in methylene chloride (20 ml), and to the resulting solution were added pyridine (1.8 ml) and tosyl chloride (3.9 g). The resultant mixture was stirred at room temperature for 2 days. Ethyl acetate and water were added to the reaction solution obtained. The organic layer so separated was washed with an aqueous potassium hydrogen sulfate solution and then with water and then dried over magnesium sulfate. The solvent was evaporated off from the solution, and the residue was purified by a silica gel chromatography, thus affording the titled compound (4.4 g; 69%).
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7](Cl)=[N:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[NH4+:12].[OH-]>O1CCOCC1>[Br:1][C:2]1[C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1
Reactant: [NH4+]
Reactant: Clc1nccc2scc(Br)c12
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1nccc2scc(Br)c12
Temperature: 150 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
A mixture of 3-bromo-4-chlorothieno[3,2-c]pyridine (prepared according to the procedure described in Bull. Soc. Chim. Belges 1970, 79, 407-414, 3 g, 12 mmol), concentrated aqueous NH4OH (100 mL), and p-dioxane (100 mL) was sealed in a stainless steel, high-pressure reactor and stirred for 18 hours at 150° C. The mixture was concentrated to half its original volume, diluted with water, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated to provide 2.6 g (94%) of the desired product. 1H NMR (DMSO-d6, 400 MHz) δ 7.83 (d, 1H), 7.77 (s, 1H), 7.26 (d, 1H), 6.48 (br s, 2H); MS m/e 229 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[B-](F)(F)(F)[CH:11]=[CH2:12].[K+].C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(O)CC>[Cl:1][C:2]1[N:7]=[C:6]([CH:11]=[CH2:12])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: C=C[B-](F)(F)F
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: ClCCl
Solvent: CCCO
Product: C=Cc1nc(Cl)ncc1F
Temperature: 105 °C
Reaction time: 8 h

Procedure:
2,4-Dichloro-5-fluoropyrimidine (111 g, 661.47 mmol, 1.00 equiv., 99.5%), potassium trifluoro(vinyl)borate (98 g, 716.72 mmol, 1.08 equiv., 98%), TEA (67 g, 98%), 1-propanol (1100 mL), PdCl2(dppf).CH2Cl2 (27 g, 33.06 mmol, 0.05 equiv) were added into five 2000-mL pressure tank reactors which purged and maintained with an inert atmosphere of nitrogen. The resulting solution was stirred overnight at 105° C. The reaction mixture of five batches was combined and then cooled to room temperature with a water bath. The solid was filtered out. The filtrate was concentrated under reduced vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20) to afford 2-chloro-4-ethenyl-5-fluoropyrimidin as a highly volatile yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccccc1OCc1ccccc1

Procedure:
A stirred mixture of 2-nitrophenol (13.9 g, 0.10 mol), benzyl bromide (12.0 ml, 0.10 mol) and anhydrous potassium carbonate (30 g, 0.22 mol) in acetone (200 ml) was heated under reflux for 16 hours, cooled, poured onto ice-dilute hydrochloric acid, and extracted with dichloromethane. The extract was dried and evaporated and the residue was crystallised from ether-hexane as pale crystals, m.p. <50° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[NH:14]C(=O)C)([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+]>Br.CCOC(C)=O>[C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[NH2:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1C(C)(C)C
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc([N+](=O)[O-])ccc1N
Temperature: 110 °C
Yield: 102.4 %

Procedure:
N-(2-tert-butyl-4-nitrophenyl)acetamide (840 mg, 3.57 mmol) was dissolved in concentrated HBr (48%, 20 mL). The resulting solution was heated at 110° C. for 3 h. The reaction mixture was cooled to rt, diluted with EtOAc, and poured into sat. NaHCO3 solution. The organic phase was extracted with sat. NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated to give the desired product as a yellow-green oil (710 mg, >100%). 1H NMR (400 MHz, CD3OD) δ: 7.52 (d, 1H), 7.40 (dd, 1H), 7.33 (d, 1H), and 1.42 (s, 9H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[N:20]1[CH2:21][CH2:22][N:23]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[CH:7]2)[CH2:24][CH2:25]1
Reactant: ClCCCCn1cnc2ccccc21
Reactant: c1coc(N2CCNCC2)c1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1coc(N2CCN(CCCCn3cnc4ccccc43)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.6 %

Procedure:
1-(4-chlorobutyl)-1H-benzimidazole (7.51 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(2-furyl) piperazine (4.6 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 6.0 g compound (I-12) with a yield of 61.5%. ESI-MS [M+H]+: m/z 325.2.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[CH:11][C:10]=2[CH:22]=1)=[O:5].[CH:24]1([Mg]Br)[CH2:26][CH2:25]1>>[CH:24]1([C:4]([C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH2:14][CH2:15][N:16]4[CH2:20][CH2:19][CH2:18][C@H:17]4[CH3:21])=[CH:11][C:10]=3[CH:22]=2)=[O:5])[CH2:26][CH2:25]1
Reactant: CON(C)C(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Reactant: Br[Mg]C1CC1
Product: C[C@@H]1CCCN1CCc1cc2cc(C(=O)C3CC3)ccc2o1

Procedure:
The product from Example 71E and cyclopropylmagnesium bromide were processed as described in Example 71F to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 1.10 (m, 5H), 1.28 (d, 3H), 1.78 (m, 1H), 2.10 (m, 2H), 2.38 (m, 1H), 2.9 (m, 1H), 3.2-3.8(m, 6H), 6.85 (s, 1H), 7.58 (d, 1H), 8.05 (dd, 1H), 8.33 (d, 1H); MS (ESI) m/z 298 (M+H)+.
Reaction SMILES: Br[C:2]1[C:6]2[C:7]([NH2:11])=[N:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:22][CH:21]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.CO.O.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>[NH2:11][C:7]1[C:6]2[C:2]([C:20]3[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:24][CH:25]=3)=[CH:3][S:4][C:5]=2[CH:10]=[CH:9][N:8]=1
Reactant: Nc1nccc2scc(Br)c12
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
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: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2csc3ccnc(N)c23)cc1
Temperature: 25 °C

Procedure:
A suspension of 3-bromothieno[3,2-c]pyridin-4-amine (13.7 g, 59.7 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (20 g, 62.7 mmol), tetrakis(triphenylphosphine)palladium(0) (2.5 g, 2.1 mmol) and Na2CO3 (13.3 g, 125 mmol) in tetrahydrofuran (150 mL), methanol (40 mL) and water (80 mL) was degassed, then stirred at reflux overnight. The reaction mixture was cooled to room temperature, then partitioned between ethyl acetate and water. The aqueous layer was extracted with additional ethyl acetate and the combined organics were dried (using MgSO4), filtered and the filtrate was concentrated. The residue was purified via silica gel chromatography eluting with 50 to 70% ethyl acetate-hexanes to give crude tert-butyl 4-(4-aminothieno[3,2-c]pyridin-3-yl)phenylcarbamate. A solution of the crude product (59.7 mmol based on 100% yield) in N,N-dimethylformamide (80 mL) was treated with N-iodosuccinimide (13.5 g, 59.7 mol-added in portions) and the resulting dark solution was stirred at room temperature for 2 hours, then partitioned between water (500 mL) and ethyl acetate (100 mL) with NaCl added to facilitate layer separation. The aqueous layer was extracted with additional ethyl acetate (2×75 mL) and the combined organics were washed with sodium thiosulfate (3×20 mL) and brine (50 mL), and then dried (using MgSO4), filtered, and concentrated. The crude material was treated with TFA (20 mL) and CH2Cl2 (5 mL), stirred at room temperature for 2 hours, concentrated under a stream of nitrogen, then concentrated in vacuo. The solid was dissolved in water (100 mL), carefully treated with solid Na2CO3 until gas evolution ceased and filtered, washing with additional water. The solid collected was dried to provide the title compound as a solid (contaminated by ca. 10% mole PPh3).
Reaction SMILES: C([O:4][C:5]([CH3:33])([CH2:7][CH2:8][CH2:9][N:10]1[CH2:19][C@@H:18]2[CH2:20][O:21][CH2:22][CH2:23][N:17]2[C:16]2[N:15]=[C:14]([C:24]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:25]=3[CH:26]=[CH:27][NH:28]4)[N:13]=[CH:12][C:11]1=2)[CH3:6])(=O)C.[OH-].[Na+]>CO>[NH:28]1[C:29]2[C:25](=[C:24]([C:14]3[N:13]=[CH:12][C:11]4[N:10]([CH2:9][CH2:8][CH2:7][C:5]([CH3:33])([OH:4])[CH3:6])[CH2:19][C@@H:18]5[CH2:20][O:21][CH2:22][CH2:23][N:17]5[C:16]=4[N:15]=3)[CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: CC(=O)OC(C)(C)CCCN1C[C@@H]2COCCN2c2nc(-c3cccc4[nH]ccc34)ncc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(O)CCCN1C[C@@H]2COCCN2c2nc(-c3cccc4[nH]ccc34)ncc21
Temperature: 50 °C
Reaction time: 4 h
Yield: 71.1 %

Procedure:
To a 25 mL pear flask was added (R)-5-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-methylpentan-2-yl acetate (PREPARATION x82, 48 mg, 0.107 mmol) in methanol (3 mL) to give a yellow solution. Aqueous NaOH (3N, 0.4 mL) was added and the mixture was stirred at 50° C. for 4 hours, before being cooled to room temperature. The reaction mixture was partitioned between saturated NaHCO3 and ethyl acetate, and the aqueous layer was extracted a second time with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated. After trituration with Et2O, the solid product was dried in vacuo to give the title compound as an off-white solid (31 mg, 71%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (s, 6H), 1.32-1.48 (m, 2H), 1.53-1.73 (m, 2H), 2.95-3.10 (m, 2H), 3.11-3.25 (m, 2H), 3.26-3.40 (m, 2H), 3.50-3.64 (m, 2H), 3.93 (dd, J=10.99, 3.16 Hz, 1H), 4.06 (dd, J=11.49, 3.16 Hz, 1H), 4.19 (s, 1H), 4.52 (d, J=11.62 Hz, 1H), 7.11 (t, J=7.71 Hz, 1H), 7.29-7.44 (m, 3H), 7.77 (s, 1H), 7.93 (dd, J=7.45, 0.88 Hz, 1H), 11.11 (br s, 1H); ESI-MS m/z [M+H]+ calc'd for C23H29N5O2, 408.24. found 408.3.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1>CC(C)=O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:3][C:2](=[O:1])[CH3:9])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Solvent: CC(C)=O
Product: CC(=O)C=Cc1ccc(O)cc1

Procedure:
It has also been disclosed that 4-hydroxy-benzaldehyde can be condensed with acetone to give 4-hydroxy-benzalacetone, which is then hydrogenated to 4-(4-hydroxy-phenyl)-butan-2-one (cf. J. Am. Chem. Soc. 70 (1948), 3360). The 4-hydroxy-benzaldehyde required as the starting compound for this two-stage process is, however, difficult to prepare and therefore very expensive. Furthermore, the overall yield of 1-(4-hydroxy-phenyl)-butan-3-one obtained by this process is unsatisfactory.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[N:28]1[C:37]2[C:32](=[CH:33][C:34]([C:38](O)=[O:39])=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38]([C:34]5[CH:33]=[C:32]6[C:37](=[CH:36][CH:35]=5)[N:28]=[CH:29][CH:30]=[CH:31]6)=[O:39])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc2ncccc2c1

Procedure:
The title compound, white solid (80 mg, 66%), MS (ISP) m/z=486.5 [(M+H)+], mp 211.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and quinoline-6-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C:8]([NH2:10])=[O:9].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C:8]([NH:10][C:20]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1)=[O:21])=[O:9]
Reactant: NC(=O)c1c(Cl)cncc1Cl
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1C
Product: O=C(NC(=O)c1c(Cl)cncc1Cl)Nc1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
A reaction vessel was charged with sixty-eight grams (0.36 mole) of 3,5-dichloro-4-pyridinecarboxamide, 55.5 grams (0.36 mole) of p-chlorophenyl isocyanate, and 1200 milliliters of xylene. The solution was heated under reflux with stirring for three hours. A small amount of impurity was removed by filtering the hot reaction mixture. On cooling in an ice water bath, a solid precipitated. The precipitated product was collected by suction filtration, washed with cold xylene and dried in a vacuum oven at about 70° C. The dried crude product was purified by recrystallization from 90 percent aqueous acetic acid. The yield was 81 grams (66 percent of theoretical) of white needles melting at 225°-227° C. Nuclear magnetic resonance spectral data confirmed the structure as being ##STR12##
Reaction SMILES: [Cl-].[Li+].[N-:3]=[N+:4]=[N-:5].[Na+].[C:7]([C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1)#[N:8]>COC(O)C>[NH:3]1[C:7]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)=[N:8][N:5]=[N:4]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(C=O)cc1
Agent: COC(C)O
Agent: [Cl-]
Agent: [Li+]
Product: O=Cc1ccc(-c2nnn[nH]2)cc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
20.0 g (0.47 mol) of lithium chloride and 20.5 g (0.315 mol) of sodium azide are added to 41.2 g (0.315 mol) of 4-cyano-benzaldehyde (Fluka, Buchs, Switzerland) in 310 ml of methoxyethanol (Fluka, Buchs, Switzerland) and the mixture is heated at boiling for 6 hours (argon atmosphere). The cooled reaction mixture is poured into 1 liter of ice/37% HCl 10:1 and stirred thoroughly to complete the reaction. Filtration and washing with water yield the title compound: m.p.: 180-182° C.; 1H-NMR (DMSO-d6) δ 10.11 (s, HCO), 8.29 and 8.14 (2d, J=8, each 2H).
Reaction SMILES: O1C=CC(CS[CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH:17]=3)[NH:12][C:11]([CH3:28])([CH3:27])[CH:10]=2)=C1.BrCC1[C:40]2[C:35](=[CH:36][CH:37]=[C:38](C3C=CC=CC=3OC)[CH:39]=2)[NH:34]C(C)(C)C=1.C(=O)([O-])[O-].[K+].[K+].C(S)C1OC=CC=1>>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:27])([CH3:28])[CH:10]=[C:9]2[CH2:8][NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CSCc1ccoc1)=CC(C)(C)N2
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: SCc1ccco1
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
4-(Furan-3-ylmethylsulfanylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline 80 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 69 mg of potassium carbonate, and 45 μL of furfuryl mercaptan reacted to give 9 mg of the title compound as a foam.
Reaction SMILES: Br[CH2:2][CH:3]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[K].[CH2:21]([O:23][C:24]([O:26][NH:27][C:28](=[O:32])[O:29][CH2:30][CH3:31])=[O:25])[CH3:22]>CN(C)C=O>[CH2:30]([O:29][C:28]([N:27]([CH2:2][CH:3]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])[O:26][C:24]([O:23][CH2:21][CH3:22])=[O:25])=[O:32])[CH3:31]
Reactant: CCOC(=O)NOC(=O)OCC
Reactant: CCOP(=O)(CC(CBr)OC1CCCCO1)OCC
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)ON(CC(CP(=O)(OCC)OCC)OC1CCCCO1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2.4 h
Yield: 36.7 %

Procedure:
To a solution of diethyl 3-bromo-2-(tetrahydro-2H-pyran-2-yloxy)propylphosphonate (134.4 g.) in N,N-dimethylformamide (880 ml.) was added potassium salt of ethyl N-ethoxycarbonyloxycarbamate (88.45 g.) under ice-cooling, and the mixture was stirred at ambient temperature for half an hour, and then for additional 2.4 hours at 50° to 60° C. The solvent was distilled off under reduced pressure. The residue was dissolved in water (1300 ml.) and then extracted twice with ethyl acetate (1000 ml. and 800 ml.). The combined extracts were washed twice with a saturated aqueous sodium chloride solution (500 ml. and 300 ml.), dried over magnesium sulfate and evaporated to dryness under reduced pressure to give an oily residue (143.2 g.), which was subjected to column chromatography on silica gel (700 g.) and fractionated by elution with a mixture of chloroform and ethyl acetate (the ratio was gradually changed from 9:1 to 1:1 v/v respectively) and then ethyl acetate. The fractions containing an object compound were combined and evaporated to dryness under reduced pressure to give oily diethyl 3-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)-2-(tetrahydro-2H-pyran-2-yloxy)propylphosphonate (62.6 g.).
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.[CH2:12]([O:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH2:17]1)[C:13]#[CH:14]>O>[CH:12]([O:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH2:21]1)=[C:13]=[CH2:14]
Reactant: C#CCOC1(c2ccccc2)C=CC=CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C=COC1(c2ccccc2)C=CC=CC1
Yield: 63.2 %

Procedure:
Into a similar reaction vessel, as used in the abovementioned reaction, were placed 1.342 parts of t-BuOK and 7.607 parts of THF and to this, a mixture of 10.000 parts of 1propargyloxybiphenyl and 23.333 parts of THF was added dropwise. The content was reacted at 50° C. for 60 minutes and then a deionized water was added to stop the reaction. THF layer and water layer were removed by using an evaporator, and the residue was subjected to a column chromatography (silica gel 200 mesh) to obtain a purified 1-allenyloxy biphenyl as colorless oily product. This compound was identified by FT-NMR(H) and IR spectrum. The reaction yield was 63.2%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:13]([CH2:15][CH3:16])[CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:17][CH:18]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19]1>>[CH2:23]([N:20]1[CH2:21][CH2:22][CH:18]([NH:17][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[C:3]([N:13]([CH2:15][CH3:16])[CH3:14])=[CH:4][C:5]=2[O:11][CH3:12])[CH2:19]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCN(C)c1cc(OC)c(C(=O)O)cc1Cl
Reactant: NC1CCN(Cc2ccccc2)C1
Product: CCN(C)c1cc(OC)c(C(=O)NC2CCN(Cc3ccccc3)C2)cc1Cl

Procedure:
Following the procedure set forth in general method A supra using 1.22 g. of 5-chloro-4-(N-ethyl-N-methylamino)-2-methoxybenzoic acid and 0.97 g. of 3-amino-1-benzyl-pyrrolidine, 1.31 g. of N-(1-benzyl-3-pyrrolidinyl)-5-chloro-4-(N-ethyl-N-methylamino)-2-methoxybenzamide was obtained.