Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2.C([Sn](CCCC)(CCCC)[C:17]([O:19]CC)=[CH2:18])CCC>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.O1CCCC1>[C:17]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2)(=[O:19])[CH3:18]
Reactant: Brc1ccc2c(c1)CCCO2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)CCCO2

Procedure:
In accordance with this scheme a 6-bromochroman compound of Formula 2 (see Reaction Scheme 1) is reacted with by tributyl(1-ethoxyvinyl)tin in the presence dichlorobis(triphenylphosphine)palladium(II) under an inert gas (argon) atmosphere in an aprotic neutral solvent, such as tetrahydrofuran (THF), to provide a 6-acetylchroman derivative of Formula 25. The 6-acetylchroman derivative of Formula 25 is then reacted with iodine and silver(I)trifluoromethanesulfonate (AgOTf) to give a 6-acetyl-8-iodochroman derivative of Formula 26. The compound of Formula 26 is reacted with with trimethylsilyl acetylene in triethyl amine under argon atmosphere in the presence of copper(I)iodide and dichlorobis(triphenylphosphine)palladium(II) (Pd(PPh3)2Cl2) to give the 6-acetyl-8-trimethylsilanyl-ethynyl-chroman derivative of Formula 27. The latter reaction is analogous to the conversion of the 8-iodo-substituted chroman compounds of Formula 4 to the 8-trimethylsilanyl-ethynyl-chroman derivatives of Formula 5, as shown in Reaction Scheme 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([N+:16]([O-])=O)=[C:14]([F:19])[CH:13]=[C:12]([F:20])[C:11]=1[F:21].[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>C(Cl)Cl>[F:19][C:14]1[C:15]2[NH:16][C:22](=[O:23])[N:9]([C:3]3[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=3[F:1])[C:10]=2[C:11]([F:21])=[C:12]([F:20])[CH:13]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Solvent: ClCCl
Product: O=c1[nH]c2c(F)cc(F)c(F)c2n1-c1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.85 %

Procedure:
To the stirred solution of 3,4,6-trifluoro-N2-(2-Fluoro-4-iodo-phenyl)-benzene-1,2-diamine 3 (0.285 gm, 0.74 mmol) in CH2Cl2 (2 ml), 1,1′-carbonyldiimidazole (0.125 gm, 0.75 mmol) was added. This reaction mixture was kept stirring at room temperature for 16 hours when product precipitated out. The white solid was filtered and used further without any purification. (0.2 gm, yield: 65.85%): m/z=407 [M−1]−.
Reaction SMILES: Cl.[N:2]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][N:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.[F:23][CH2:24][CH2:25][N:26]1[C:35]2[C:30](=[CH:31][C:32]([F:38])=[C:33](F)[C:34]=2[F:36])[C:29](=[O:39])[C:28]([C:40]([OH:42])=[O:41])=[CH:27]1>C(#N)C>[F:38][C:32]1[CH:31]=[C:30]2[C:35](=[C:34]([F:36])[C:33]=1[N:9]1[CH2:10][CH2:11][CH:7]([N:2]3[CH:6]=[CH:5][N:4]=[N:3]3)[CH2:8]1)[N:26]([CH2:25][CH2:24][F:23])[CH:27]=[C:28]([C:40]([OH:42])=[O:41])[C:29]2=[O:39]
Reactant: c1cn(C2CCNC2)nn1
Reactant: O=C(O)c1cn(CCF)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(CCF)c2c(F)c(N3CCC(n4ccnn4)C3)c(F)cc2c1=O
Yield: 34.4 %

Procedure:
3-(1,2,3-triazol-1-yl)pyrrolidinehydrochloride (87 mg) and DBU (76 mg) were added to a suspension of 1-(2-fluoroethyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (72 mg, 0.25 mmol) in acetonitrile (5 ml). The reaction mixture was refluxed for 21 hrs, concentrated and the residue was diluted with water. The separated solid was filtered, washed with water and acetonitrile to give 35 mg of the title product. m.p. 240°-243° C. (dec). 1H NMR (TFA) δ: 9.76 (s, 1H), 9.08 (s, 1H), 8.73 (s, 1H), 8.12 (d, 13.7Hz, 1H), 5.8-5.6 (m, 1H), 5.4-4.1 (m, 9H), 3.0-2.65 (m, 2H). Anal. Calcd. for C18H16F3N5O3 . 1/2 H2O; C, 51.93; H, 4.12; N, 16.32.Found: C, 51.77; H, 3.84; N, 15.6.
Reaction SMILES: C[O:2][C:3]1[CH:35]=[CH:34][C:6]2[C:7]3[CH:8]([C:19]4[CH:33]=[CH:32][C:22]([O:23][CH2:24][CH2:25][N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)=[CH:21][CH:20]=4)[O:9][CH2:10][C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[C:13]=3[S:14][C:5]=2[CH:4]=1>CN1C(=O)CCC1.C(Cl)Cl>[N:26]1([CH2:25][CH2:24][O:23][C:22]2[CH:21]=[CH:20][C:19]([CH:8]3[C:7]4[C:6]5[CH:34]=[CH:35][C:3]([OH:2])=[CH:4][C:5]=5[S:14][C:13]=4[C:12]4[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=4[CH2:10][O:9]3)=[CH:33][CH:32]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COc1ccc2c3c(sc2c1)-c1ccccc1COC3c1ccc(OCCN2CCCCC2)cc1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: Oc1ccc2c3c(sc2c1)-c1ccccc1COC3c1ccc(OCCN2CCCCC2)cc1
Temperature: 170 °C
Yield: 6.3 %

Procedure:
Add NaSEt (92 mg, 1.1 mmol) to a solution of 1-{2-[4-(10-methoxy-5H,7H-6-oxa-12-thia-dibenzo[a,e]azulen-7-yl)-phenoxy]-ethyl}-piperidine (266 mg, 0.55 mmol) in NMP (3 mL). Heat to 170° C. for 20 min. Add additional NaSEt (92 mg, 1.1 mmol) and continue heating for 1 h. Quench the reaction with water and dilute with CH2Cl2. Wash the organic phase with water and brine, dry over MgSO4, filter and concentrate. Purify the crude product by flash chromatography (0-10% (2M NH3 in MeOH)/CH2Cl2) followed by preparative HPLC to afford 7-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H,7H-6-oxa-12-thia-dibenzo[a,e]azulen-10-ol (16.3 mg, 6.3%)
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:23][CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[O:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:3]([C:5]2[N:6]([CH3:22])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:25][CH2:26]1
Reactant: NC1CCOCC1
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)n(C)n1
Product: CCCCc1noc(C)c1COc1cc(C(=O)NC2CCOCC2)n(C)n1
Yield: 95 %

Procedure:
As described for example 86, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (60 mg, 0.2 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (70 mg, 95%) which was obtained as a colorless oil. MS: m/e=377.2 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]#[N:13].Br[CH:15]([CH2:17][CH3:18])[CH3:16].C1C=CC=CC=1.[OH-].[Na+]>CCOCC.C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3>[CH:15]([CH:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:12]#[N:13])([CH2:17][CH3:18])[CH3:16]
Reactant: CCC(C)Br
Reactant: N#CCc1ccc2ccccc2c1
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCC(C)C(C#N)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.8 %

Procedure:
A mixture of 2-naphthaleneacetonitrile (30.00 g, 0.179 mole), dicyclohexyl-18-crown-6 [1.60 g, 0.0043 mole (2.4 mole %)], 2-bromobutane (50.20 g, 0.366 mole), benzene (80 ml) and sodium hydroxide solution (50%, 80 ml) is stirred at room temperature for 16 hours. The organic layer is diluted with ether (250 ml), separated, washed successively with water, dilute hydrochloric acid and water and dried over sodium sulfate. Evaporation and distillation under vacuum gives α-sec-butyl-2-naphthaleneacetonitrile (34.3 g, 86%); b.p. 130° C. (0.1 mm).
Reaction SMILES: [Si]([N:8]1[C:22]2[C:23]3[C:10]([CH2:11][C@@H:12]4[C:17]([C:18]=3[CH:19]=[CH:20][CH:21]=2)=[CH:16][C@H:15]([NH:24][C:25](=[O:31])[N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH2:14][N:13]4[CH3:32])=[C:9]1[CH3:33])(C(C)(C)C)(C)C>CO.O1CCCC1.[Cl-].[Na+]>[CH3:33][C:9]1[NH:8][C:22]2[C:23]3[C:10]=1[CH2:11][C@@H:12]1[C:17]([C:18]=3[CH:19]=[CH:20][CH:21]=2)=[CH:16][C@H:15]([NH:24][C:25](=[O:31])[N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH2:14][N:13]1[CH3:32]
Reactant: CCN(CC)C(=O)N[C@H]1C=C2c3cccc4c3c(c(C)n4[Si](C)(C)C(C)(C)C)C[C@H]2N(C)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)C(=O)N[C@H]1C=C2c3cccc4[nH]c(C)c(c34)C[C@H]2N(C)C1
Yield: 68.4 %

Procedure:
Under argon, 183 mg (0.39 mmol) of 3-[1-(tert-butyldimethylsilyl)-9,10-didehydro-2,6-dimethyl-8α-ergolinyl]-1,1-diethylurea is dissolved in 5 ml of methanol with addition of 2 ml of tetrahydrofuran and stirred with 1 ml of 14N potassium hydroxide solution at room temperature for 17 hours. To work up the mixture, it is diluted with saturated sodium chloride solution and extracted with methylene chloride. The methylene chloride extracts are washed with saturated sodium chloride solution and water and dried over sodium sulfate. The crude product of 128 mg is chromatographed and crystallized as the tartrate, thus obtaining 94 mg (67% of theory) of 3-(9,10-didehydro-2,6-dimethyl-8α-ergolinyl)-1,1-diethylurea.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[NH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl>C1COCC1>[C:1]([NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCC(=O)Cl
Reactant: NCCc1ccc(O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCC(=O)NCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Procedure--Nonanoyl chloride (2.74 m, 14.6 mmol) was added dropwise to a cooled solution of tyramine (1 g, 7.29 mmol) and triethylamine (2.03 ml, 14.6 mmol) in THF (35 ml). The reaction mixture was stirred at room temperature for 48 hours. It was then poured into 10% HCl solution (70 ml) and the mixture was then extracted with ethyl acetate (3×50 ml). The ethyl acetate layer was separated, dried (MgSO4) and concentrated under reduced pressure to give crude N-nonanoyl tyramine. The product was purified by chromatography on a silica gel column eluted with methylene chloride/ethyl acetate (30:1). m.p. 65.9° to 66.7° C. IR (KBr) 3306, 2922, 2851, 1638; 1H NMR δ 6.65-6.98 (d of d, 4 H, aromatic), 7.78 (t, 1 H, NH), 9.15 (s, 1 H, OH). Analysis calculated for C17H27NO2 : C, 73.61; H, 9.81; N, 5.05. Found C, 73.49; H, 9.661; N, 5.31.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[CH2:4][O:3]1.[CH2:13](O)[CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[O:12]1[CH2:13][CH2:14][O:15][CH:11]1[C:7]1[N:6]=[C:5]2[CH2:4][O:3][C:2](=[O:1])[C:10]2=[CH:9][CH:8]=1
Reactant: OCCO
Reactant: O=Cc1ccc2c(n1)COC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: O=C1OCc2nc(C3OCCO3)ccc21
Temperature: 25 °C
Yield: 33.2 %

Procedure:
To a solution of 5-oxo-5,7-dihydro-furo[3,4-b]pyridine-2-carbaldehyde (100 mg, 0.61 mmol) in anhydrous benzene (5 mL) is added ethylene glycol (0.1 mL, 1.77 mmol), a catalytic amount p-toluenesulfonic acid monohydrate and 4 Å mole sieves. The reaction mixture is heated at a reflux temperature for 20 h. The reaction mixture is allowed to cool to room temperature and saturated aqueous NaHCO3 solution is added. The resulting mixture is filtered through celite, washed with saturated aqueous NaHCO3 and EtOAc. The isolated organic layer is washed with brine (1×), dried with anhydrous Na2SO4, and concentrated. The residue is treated with EtOAc-Hexane (1:4) and the light brown solid which forms is collected by filtration and dried to give the title compound (42 mg, 33%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:24])[CH2:18][CH2:19][C:20]([O:22]C)=[O:21])=[CH:13][CH:12]=1>>[C:1]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:24])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)c2ccccc2)cc1
Yield: 53.8 %

Procedure:
In a manner similar to that described in Example 3, benzoyl chloride (0.047 g, 0.00033 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.040 g of 4-[4-(benzoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+332.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH2:28])=[CH:22][CH:21]=1>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:28][CH2:27][CH2:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2cccs2)c1C#N
Reactant: COc1ccc(CCN)cc1
Solvent: C1COCCO1
Product: COc1ccc(CCNc2nc(N)nc(-c3cccs3)c2C#N)cc1

Procedure:
From 2-amino-4-methanesulfinyl-6-thiophen-2-yl-pyrimidine-5-carbonitrile and 2-(4-methoxyphenyl)ethylamine in dioxane. ES-MS m/e (%): 352 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[N:10][C:9]([SH:12])=[N:8][C:7]=1[OH:13])=[O:5])[CH3:2].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[N:10][C:9]([S:12][CH3:14])=[N:8][C:7]=1[OH:13])=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1nnc(S)nc1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1nnc(SC)nc1O
Reaction time: 1 h

Procedure:
To a 0° C. solution of 29.0 g (144.1 mmol) of 5-hydroxy-3-mercapto-1,2,4-triazine-6-carboxylic acid ethyl ester in 75 mL of DMF was added 14.4 g (144.1 mmol) of potassium carbonate. The reaction mixture was stirred for 1 hour, and 24.2 mL (389.2 mmol) of methyl iodide was added as fast as the effervescence would allow. The ice bath was removed, and the reaction was covered with a nitrogen filled balloon and stirred at room temperature overnight.
Reaction SMILES: I[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH3:16])[N:10]=2)=[CH:4][C:3]=1[CH3:17].[F:18][C:19]1[CH:20]=[CH:21][C:22](B2OC(C)(C)C(C)(C)O2)=[C:23]2[C:27]=1[C@H:26]([O:28][C:29]1[CH:42]=[CH:41][C:32]3[C@H:33]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH2:34][O:35][C:31]=3[CH:30]=1)[CH2:25][CH2:24]2.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH3:16])[N:10]=3)=[CH:4][C:3]=2[CH3:17])=[C:23]2[C:27]=1[C@H:26]([O:28][C:29]1[CH:42]=[CH:41][C:32]3[C@H:33]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH2:34][O:35][C:31]=3[CH:30]=1)[CH2:25][CH2:24]2
Reactant: COc1nccc(-c2cc(C)c(I)c(C)c2)n1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ccnc(OC)n6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from 4-(4-iodo-3,5-dimethylphenyl)-2-methoxypyrimidine and methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.82 min; Mass spectrum (ESI+): m/z=555 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][NH2:11])[CH:5]=[CH:6][CH:7]=1.Cl.[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[C:15](=O)[CH2:14]2.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[CH:15]([NH:11][CH2:10][CH2:9][NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:14]2
Reactant: NCCNc1cccc(Cl)c1
Reactant: O=C1CN2CCC1CC2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Clc1cccc(NCCNC2CN3CCC2CC3)c1
Yield: 3.7 %

Procedure:
To a stirred solution of N-(3-chlorophenyl)-1,2-diaminoethane (1 g; 0,00586 moles) in 25 ml of anhydrous methanol kept under nitrogen atmosphere, 3-quinuclidinone hydrochloride (1.01 g, 0.0062? moles) is added. The pH is adjusted to pH 6 by addition of glacial acetic acid. Sodium cyanoborohydride (0.74 g; 0.0117 moles) is added in two portions. The reaction mixture is refluxed for 10 hours, cooled and then filtered. After evaporation to dryness the residue is taken up with water, basified with 20% sodium hydroxide solution and extracted three times with ethyl acetate. The organic layer is washed with brine, dried over anhydrous sodium sulfate and, after filtration, evaporated to dryness. The residue is purified by silica gel flash-chromatography (methylene chloride--methanol--30% ammonium hydroxide, 150:50:5 as eluant) to give the desired product as a clear oil (0.06 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[Mg].[C:16]1([CH3:24])[C:17]([CH:22]=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1>O1CCCC1>[CH3:24][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[CH:4][CH:3]=1)[OH:23]
Reactant: Cc1ccccc1C=O
Reactant: CC1(C)COC(c2ccc(Br)cc2)=N1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccccc1C(O)c1ccc(C2=NC(C)(C)CO2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-bromophenyl)-4,4-dimethyl-2-oxazoline (1 g) in dry tetrahydrofuran (10 ml) are added dropwise magnesium (526 mg) and dry tetrahydrofuran (50 ml) under refluxing. The heating of the mixture is stopped, and thereto is added 2-(4-bromphenyl)-4,4-dimethyl-2-oxazoline (4 g) at a slowly refluxing rate, during which the mixture is stirred for 30 minutes, and then thereto is added o-tolualdehyde (2.16 ml) under ice-cooling. The mixture is stirred under ice-cooling for one hour, and stirred at room temperature for two hours, and the reaction is quenched with adding thereto a saturated aqueous ammonium chloride solution. The mixture is extracted with ethyl acetate, and the organic layer is washed successively with 1N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=4~2:1) to give 2-{4-[1-(2-methylphenyl)-1-hydroxymethyl]phenyl}-4,4-dimethyl-2-oxazoline (3.07 g) as white powder.
Reaction SMILES: CO.Cl.Cl.Cl.[S:6]([C:10]1[CH:35]=[CH:34][C:13]([CH2:14][NH:15][C:16]([NH:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[NH:20])=[NH:17])=[CH:12][CH:11]=1)(=[O:9])(=[O:8])[NH2:7].[CH3:36][C:37]([CH3:39])=O>>[CH3:36][C:37]1([CH3:39])[N:17]=[C:16]([NH:15][CH2:14][C:13]2[CH:12]=[CH:11][C:10]([S:6](=[O:8])(=[O:9])[NH2:7])=[CH:35][CH:34]=2)[NH:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[N:20]1
Reactant: CCCCCCCCCCCCNC(=N)NC(=N)NCc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)=O
Agent: Cl
Solvent: CO
Product: CCCCCCCCCCCCNC1=NC(C)(C)N=C(NCc2ccc(S(N)(=O)=O)cc2)N1

Procedure:
100 ml of methanol, 80 ml of acetone and 0.3 ml of concentrated hydrochloric acid were added to 5.5 g (10.0 mmol) of N1-(4-sulfamoylbenzyl)-N5-dodecyl-biguanide dihydrochloride. The mixture was refluxed for 22 hours, and the solvent was distilled off under reduced pressure. To the residue were added 60 ml of ethanol, 40 ml of water and 6.2 ml of 5N sodium hydroxide, and the mixture was refluxed for 1 hour, concentrated under reduced pressure, and extracted with ethyl acetate. The extract was washed with 10% aqueous sodium acetate, washed with water, and concentrated under reduced pressure to remove the solvent. The residue was recrystallized repeatedly from a mixture of methyl ethyl ketone and ethanol (8:2) and then from ethanol to obtain 1.4 g of colorless crystals having a melting point of 188 to 191° C.
Reaction SMILES: [C:1]([O-:7])([O-])([O:3][CH2:4][CH3:5])[CH3:2].[CH:8]#[C:9][CH:10](O)[CH2:11][CH3:12].C(O)(=O)CCC>C(O)C>[C:1]([O:3][CH2:4][CH3:5])(=[O:7])[CH2:2][CH:8]=[C:9]=[CH:10][CH2:11][CH3:12]
Reactant: C#CC(O)CC
Reactant: CCOC(C)([O-])[O-]
Solvent: CCO
Solvent: CCCC(=O)O
Product: CCC=C=CCC(=O)OCC
Yield: 97 %

Procedure:
A 200 ml- capacity three-necked flask was charged with 78 g of ethyl ortho-acetate, 20 g of 1-pentyn-3-ol and 2.0 g of butyric acid and was heated at 117° to 122°C. and ethanol formed as a by-product was distilled off. Even after completion of the distillation of the ethanol, the mixture was agitated at the above temperature for several hours. After complete extinction of the starting alcohol was confirmed by the gas chromatography, the reaction mixture was subjected to distillation under reduced pressure, and a fraction boiling at 87° to 89.5°C. under 16 mm Hg was collected. The intended ethyl 3,4-heptadienoate was obtained in a yield of 97%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11]CBr)=[CH:7][CH:6]=1)[CH3:2].[CH2:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[CH3:16]>C1COCC1.O>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:20]2[CH2:21][CH2:22][N:17]([CH2:15][CH3:16])[CH2:18][CH2:19]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCN1CCNCC1
Reactant: CCOC(=O)c1ccc(CCBr)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CN2CCN(CC)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.3 %

Procedure:
To a solution of 4-bromoethyl-benzoic acid ethyl ester (4.0 g, 16.46 mmol) in THF (30 mL), N-ethyl piperazine (3.76 g, 32.92 mmol) was added and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried over Na2SO4. The solvent was removed to give 4.61 g of crude 4-(4-ethyl piperazin-1-ylmethyl)-benzoic acid ethyl ester (100% yield). LAH (0.792 g, 20.86 mmol) was taken up in a 3-neck dry flask and THF (60 mL) was added on cooling. A solution of 4-(4-ethyl piperazin-1-ylmethyl)-benzoic acid ethyl ester (4.61 g, 16.69 mmol) in THF (10 mL) was added slowly on cooling. After completion of addition, the reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled to 0° C., 10% NaOH solution was added, and then water was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was removed to give 2.78 g of crude (4-(4-ethyl piperazin-1-ylmethyl)phenyl)-methanol in 78% yield. To a 3-neck flask containing anhydrous CH2Cl2 (100 mL) cooled to the −78° C. oxalyl chloride (1.8 g, 14.25 mmol) and DMSO (1.85 g, 23.76 mmol) were added and the mixture was stirred for 15 min at −78° C. The solution of (4-(4-ethyl piperazin-1-ylmethyl)phenyl)-methanol (2.78 g, 11.88 mmol) in CH2Cl2 (10 mL) was added at −78° C. and stirred at −78° C. for 1 h. Then Et3N (4.8 g, 47.52 mmol) was added at −78° C. The reaction mixture was allowed to come to room temperature. Water was added and the organic layer was separated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, brine and dried over Na2SO4. Then, solvent was removed to give crude 4-(4-ethyl piperazin-1-ylmethyl)benzaldehyde (2.5 g, 91%).