Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:22]=1)=[N:7][C:8]1[CH2:9][CH2:10][N:11]([C:16]3[CH:21]=[N:20][CH:19]=[CH:18][N:17]=3)[CH2:12][C:13]=1[C:14]=2Cl.[C:23]1([NH:29][NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.C([O-])([O-])=[O:33].[Na+].[Na+]>CO.C(O)C>[OH2:33].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:13](=[CH:12][N:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:30]=3)[C:8]([CH2:9][CH2:10][NH:11][C:16]3[CH:21]=[N:20][CH:19]=[CH:18][N:17]=3)=[N:7][C:6]=2[CH:22]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:13](=[CH:12][N:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:30]=3)[C:8]([CH2:9][CH2:10][NH:11][C:16]3[CH:21]=[N:20][CH:19]=[CH:18][N:17]=3)=[N:7][C:6]=2[CH:22]=1
Reactant: Clc1ccc2c(Cl)c3c(nc2c1)CCN(c1cnccn1)C3
Reactant: NNc1ccccc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Clc1ccc2c(c1)nc(CCNc1cnccn1)c1cn(-c3ccccc3)nc12
Product: O
Yield: 43 %

Procedure:
A mixture of 1.5 g (4.53 mmol) of the compound of step B. above, 0.98 mol (9.96 mmol) of phenylhydrazine, 0.75 ml of conc. hydrochloric acid, and 30 ml of absolute ethanol is stirred under reflux for 6 hrs. The cooled precipitate is dissolved in methanol and treated with a Na2CO3 solution. The precipitate which forms is collected, washed with water, and dissolved in hot benzene-hexanes. On cooling the solid is collected. The filtrate, on standing forms a precipitate which is collected and purified by HPLC to furnish 0.788 g (43%) of title compound: m.p. 201°-203° C. (dec.); IR (KBr) 3250, 1585, and 1510 cm-1 ; NMR (DMSO-d6) δ 9.78 (s, 1H), 8.46 (d, 1H), 8.18 (d, 2H), 8.06 (s, 1H), 7.97 (s, 2H), 7.67 (m, 4H), 7.54 (m, 1H), 7.25 (m, 1H), 3.93 (m, 2H), 3.44 (t, 2H).
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].CCCCCC>C1(C)C=CC=CC=1>[Br-:8].[CH2:1]([P+:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:2]
Reactant: CCCCCBr
Reactant: CCP(CC)CC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCCC[P+](CC)(CC)CC
Product: [Br-]
Yield: 92 %

Procedure:
To 236 g (0.5 mol) of a commercially available 25% solution of triethylphosphine (product name: HISHICOLIN (registered trademark) P-2, manufactured by Nippon Chemical Industrial Co., Ltd.) in toluene, 77 g (0.5 mol) of 1-bromopentane (reagent, manufactured by Tokyo Chemical Industry Co., Ltd.) was added dropwise under a nitrogen atmosphere, and the mixture was reacted at 70 to 80° C. for 5 hours. After the reaction was completed, 100 ml of hexane was added to the reaction mixture to precipitate crystals. The resulting crystals were filtered and vacuum dried under a degree of vacuum of 0.5 kPa at 80° C. for 3 hours to obtain 124 g (yield 92%) of triethyl-n-pentylphosphonium bromide. To 54 g (0.2 mol) of the resulting triethyl-n-pentylphosphonium bromide, pure water was added to form a 50% aqueous solution. Thereto, was added 58 g (0.2 mol) of lithium bis(trifluoromethylsulfonyl)imide (reagent, manufactured by Kanto Chemical Co., Inc.) to allow them to react with each other, followed by stirring for 2 hours at room temperature for aging. After the completion of aging with stirring, the lower layer side (product) was separated from the mixture in the form of an upper and lower two-layer structure, washed four times with pure water, and then washed four times with n-hexane. After the completion of the washing, the product was vacuum dried under a degree of vacuum of 0.5 kPa at 80° C. for 3 hours. The structure of the product was examined by 1H-NMR, 13C-NMR, 19F-NMR, and 31P-NMR. The product was identified as triethyl-n-pentylphosphonium bis(trifluoromethylsulfonyl)imide (TEPP-TFSI), and it had a purity of 99%. The resulting TEPP-TFSI was a colorless transparent liquid at room temperature (25° C.), which had a moisture content determined by the Karl Fischer titration method of 28 ppm and a chlorine content determined by ion chromatography of 7 ppm. The amount of the product yielded was 82 g (yield 85%). The product had an electrical conductivity at 25° C. of 1.73 mS/cm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16]([NH:18][CH:19]3[CH2:21][CH2:20]3)=[O:17])[N:10]=[N:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:28][CH:29]([CH3:33])[C:30](Cl)=[O:31]>ClCCl>[CH:19]1([NH:18][C:16]([C:11]2[N:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:30](=[O:31])[CH:29]([CH3:33])[CH3:28])=[CH:3][CH:4]=3)[C:12]=2[CH2:13][CH2:14][CH3:15])=[O:17])[CH2:20][CH2:21]1
Reactant: CC(C)C(=O)Cl
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(N)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.29 g) obtained in Example 1d) and pyridine (0.09 ml) in dichloromethane (3 ml) was added 2-methylpropanoyl chloride (0.1 ml) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, and washed successively with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate), and the obtained product was washed with diisopropyl ether to give the title compound as a pale-yellow powder (0.21 g, 60%).
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])#[C-:8].[C:14](=[S:16])=[S:15].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[C:18]1([CH2:17][S:15][C:14]2[S:16][CH:8]=[N:7][C:9]=2[C:10]([O:12][CH3:13])=[O:11])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: [C-]#[N+]CC(=O)OC
Reactant: S=C=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ncsc1SCc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 31.3 g of potassium t-butoxide in 280 ml of tetrahydrofuran was cooled to -50° and a solution of 27.7 g of methyl isocyanoacetate in 230 ml of tetrahydrofuran was added dropwise at -50° to -40°. The resulting brown suspension was stirred 15 minutes then cooled to -78°, then a solution of 16.8 ml of carbon disulfide in 225 ml tetrahydrofuran was added dropwise while maintaining the temperature below -50°. The pinkish-brown thick suspension was allowed to warm to -15° to 10° over 15 to 20 minutes. To the reaction mixture, a solution of 33.3 ml of benzyl bromide in 140 ml tetrahydrofuran was added dropwise at -15° to -5°. The reaction mixture was stirred at ambient temperature for 30 minutes, refluxed for 20 minutes, then cooled and the bulk of the solvent evaporated. To the oily residue, 1000 ml ice-water was added. After several minutes, the product soldified. The tan solid was collected, washed twice with water, follewed by hexane and dried giving 68.8 g of methyl 5-(phenylmethylthio)-4-thiazolecarboxylate, m.p. 90°-92°.
Reaction SMILES: C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[I:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([OH:40])=O)=[CH:33][CH:32]=1.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>CN(C=O)C>[I:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][C:38]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[O:40])=[CH:35][CH:36]=1
Reactant: C1COCCN1
Reactant: O=C(O)Cc1ccc(I)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(I)cc1)N1CCOCC1
Temperature: 0 °C
Yield: 62.3 %

Procedure:
Triethylamine (5.30 mL, 38.0 mmol), HOBt (3.96 g, 28.5 mmol) and EDC.HCl (5.47 g, 28.5 mmol) were added to a solution of (4-iodo-phenyl)-acetic acid (5.0 g, 19.0 mmol) in DMF (100 mL) and stirred. After 5 min morpholine (2.0 mL, 22.9 mmol) was added at RT. The reaction mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water (50 mL) and obtained solid was filtered, dried to get 3.92 g (Yield: 62.1%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6](=[O:17])[C:5]=2[NH:4][N:3]=1.[C:18](=[O:21])([O-])[O-].[K+].[K+].ClC[CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:36]=2[CH3:42])[CH2:31][CH2:30]1)=O>>[NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6](=[O:17])[C:5]=2[N:4]([C:18](=[O:21])[CH2:26][CH2:27][N:29]2[CH2:34][CH2:33][N:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:36]=3[CH3:42])[CH2:31][CH2:30]2)[N:3]=1
Reactant: Nc1n[nH]c2c1CCN(c1ccccc1)C2=O
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(N2CCN(C(=O)CCCl)CC2)c(C)c1
Agent: [K+]
Product: Cc1ccc(N2CCN(CCC(=O)n3nc(N)c4c3C(=O)N(c3ccccc3)CC4)CC2)c(C)c1

Procedure:
A target compound (152 mg, 0.321 mmol, 61.2%) was yielded in the same manner as Example 1 by reacting 3-amino-5,6-dihydro-6-phenyl-1H-pyrazolo[3,4-c]pyridin-7(4H)-one (120 mg, 0.525 mmol) with potassium carbonate (108.7 mg, 0.787 mmol) and 3-chloro-1-{4-(2,4-dimethylphenyl)piperazin-1-yl}propan-1-one (162 mg, 0.577 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][C:13](=O)CC)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:17]([O-])(=O)C.[NH4+].[C:22]([BH3-])#[N:23].[Na+]>CO>[Cl:1][C:2]1[C:3]([CH:12]([CH3:13])[CH:22]([NH2:23])[CH3:17])=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: CC(=O)[O-]
Reactant: CCC(=O)Cc1ncc(C(F)(F)F)cc1Cl
Reactant: [BH3-]C#N
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)C(C)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
0.64 g of 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]butan-2-one (Int-12) (0.0025 mol) were diluted in 5 mL of methanol. 7.0 g of molecular sieves 3 Å, 1.90 g (0.025 mol) of ammonium acetate and 0.39 g (0.0052 mol) of sodium cyanoborohydride were added. The reaction medium was stirred overnight at room temperature. After filtration, the pH was adjusted to 9 with an aqueous solution of 1 N sodium hydroxide. The reaction mixture was concentrated to dryness and 30 mL of ethyl acetate were added. The organic phase was washed with an aqueous solution of 1 N sodium hydroxide, brine and water; dried over magnesium sulfate, filtered and concentrated to dryness. The crude material was dissolved in 15 mL of 1 N hydrochloric acid and extracted with 15 mL of ethyl acetate. An aqueous solution of 1 N sodium hydroxide was added to the aqueous phase, which was subsequently extracted twice with 15 mL of ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated to dryness. 0.21 g (32%) of desired product 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]butan-2-amine (IIa-16) were obtained, [M+1]=253.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][NH:7]1.Br[CH2:29][C:30](Br)=[O:31].[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:29][C:30]([NH:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]
Reactant: O=C(Br)CBr
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(OC)c(OC)c1OC)NCC2
Reactant: NCc1ccccc1
Product: COc1cc2c(cc1OC)C(Cc1ccc(OC)c(OC)c1OC)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with benzylamine
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:19]=2)=[CH:12][C:11]=1[NH:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O>O>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:19]=2)=[CH:12][C:11]=1[NH:31][C:32](=[O:40])[C:33]1[CH:34]=[CH:35][C:36]([O:39][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=2)=[CH:37][CH:38]=1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1ccc(O)cc1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1ccc(Oc2cc(Cl)ncn2)cc1
Yield: 53.2 %

Procedure:
4,6-Dichloropyrimidine (0.103 g) was added to a stirred mixture of N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-4-hydroxybenzamide (0.3 g), caesium carbonate (0.453 g) and DMA (7.5 ml) and the resultant solution was stirred at ambient temperature for 18 hours. The mixture was poured into water (200 ml) and extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. The material so obtained was triturated under diethyl ether. The resultant solid was isolated, washed with diethyl ether and dried under vacuum at 60° C. There was thus obtained the title compound (0.2 g); NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 3.2 (t, 4H), 3.74 (t, 4H), 7.12 (m, 1H), 7.23 (m, 1H), 7.41 (m, 6H), 7.58 (m, 1H), 7.82 (d , 3H); 8.06 (d, 2H), 8.67 (s, 1H), 9.93 (s, 1H), 10.12 (s, 1H); Mass Spectrum: M+H+ 544.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C)C=O.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([F:42])=[C:26]([CH:41]=1)[O:27][C:28]1[N:33]=[C:32]2[S:34][C:35]([NH:37][C:38](=[O:40])[CH3:39])=[N:36][C:31]2=[CH:30][CH:29]=1.O>C(Cl)(=O)C(Cl)=O.CN(C)C(=O)C>[C:38]([NH:37][C:35]1[S:34][C:32]2[C:31]([N:36]=1)=[CH:30][CH:29]=[C:28]([O:27][C:26]1[CH:41]=[C:22]([NH:21][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])[C:2]=3[Cl:1])[CH:23]=[CH:24][C:25]=1[F:42])[N:33]=2)(=[O:40])[CH3:39]
Reactant: CC(=O)Nc1nc2ccc(Oc3cc(N)ccc3F)nc2s1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1nc2ccc(Oc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4Cl)ccc3F)nc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethyl)benzoic acid (0.11 g, 0.5 mmol) produced in Example C61(v) in oxalyl chloride (0.5 mi) was added N,N-dimethylformamide (40 μL), and the mixture was stirred at room temperature for 30 min, and concentrated to dryness under reduced pressure. This was dissolved in a mixture of N,N-dimethylacetamide (1 mL) and tetrahydrofuran (1 mL), and the solution was added dropwise to a solution of N-[5-(5-amino-2-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]acetamide (0.11 g, 0.33 mmol) in N,N-dimethylacetamide (1 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hr, and poured into water (100 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (52 mg, 30%) as colorless crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C@@H:11]([OH:14])[CH2:12][OH:13])=[CH:7][CH:6]=1.CO[C:19](OC)([CH3:21])[CH3:20].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C>[CH3:20][C:19]1([CH3:21])[O:14][C@H:11]([CH2:10][O:9][C:8]2[CH:15]=[CH:16][C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=2)[CH2:12][O:13]1
Reactant: OCCCc1ccc(OC[C@@H](O)CO)cc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](COc2ccc(CCCO)cc2)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-3-[4-(3-hydroxy-propyl)-phenoxy]-propane-1,2-diol (6.5 g, 28.7 mmol) in anhydrous DMF (100 mL) is added 2,2-dimethoxypropane (15.0 mL, 122.0 mmol) and pyridinium p-toluenesulfonate (0.75 g, 2.98 mmol). The reaction mixture is stirred at RT for 16 h and then concentrated in vacuo. The residue is dissolved in EtOAc and the organic portion is washed with 10% aqueous NaHCO3 solution, water, brine and dried over Na2SO4. The solvent is removed in vacuo and the crude product is purified by column chromatography (SiO2, EtOAc in petroleum ether, gradient 0-30% EtOAc) to obtain the title compound as a colourless oil. [M+H]+ 267.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:14])[CH3:13])[CH:2]([CH3:4])[CH3:3].Cl[Si:16]([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([O:14][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH2:13])[CH:2]([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)c1ccccc1OCC(C)C
Solvent: C1CCOC1
Product: C=C(O[Si](C)(C)C)c1ccccc1OCC(C)C
Reaction time: 0.25 h

Procedure:
A solution of commercially available 1-(2-isobutoxyphenyl)ethanone (10.0 g, 56.5 mmol) in THF (30 mL) was added dropwise to a stirred solution of lithium hexamethylsilylamide (1M in hexanes, 62 mL) in THF (200 mL) over a period of 30 min at 0° C. The resulting solution was stirred for an additional 15 min, and a solution of chlorotrimethylsilane (7.1 mL) in THF (8 mL) was added. The reaction mixture was stirred for 4 hours at room temperature. The mixture was concentrated. To the residue was added dichloromethane (60 mL), the mixture was filtered. The filtrate was concentrated to give (1-(2-isobutoxyphenyl)vinyloxy)trimethylsilane, that was submitted to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:22][CH3:23])[C:5]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12].O=[C:25]([CH3:40])[CH2:26][CH2:27][CH2:28][N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39].[BH4-].[Na+].[OH-].[Na+].[C:45](O)(=O)C>>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[Cl:20])[O:13][C:5]1[C:4]([O:22][CH3:23])=[CH:3][C:2]([NH:1][CH:25]([CH3:40])[CH2:26][CH2:27][CH2:28][N:29]2[C:33](=[O:34])[C:32]3=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]3[C:30]2=[O:39])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH2:9][N:10]2[CH3:45].[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[Cl:20])[O:13][C:5]1[C:4]([O:22][CH3:23])=[CH:3][C:2]([NH:1][CH:25]([CH3:40])[CH2:26][CH2:27][CH2:28][N:29]2[C:33](=[O:34])[C:32]3=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]3[C:30]2=[O:39])=[C:11]2[C:6]=1[C:7]([CH3:12])=[CH:8][CH:9]=[N:10]2
Reactant: CC(=O)CCCN1C(=O)c2ccccc2C1=O
Reactant: CC(=O)O
Reactant: COc1cc(N)c2nccc(C)c2c1Oc1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(NC(C)CCCN2C(=O)c3ccccc3C2=O)c2c(c1Oc1ccc(Cl)c(Cl)c1)C=CCN2C
Product: COc1cc(NC(C)CCCN2C(=O)c3ccccc3C2=O)c2nccc(C)c2c1Oc1ccc(Cl)c(Cl)c1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
A mixture of 12.4 g of 8-amino-5-(3,4-dichlorophenoxy)-6-methoxy-4-methylquinoline (36 mM) and 11.6 g of 4-oxo-1-phthalimidopentane (50 mM), in glacial acetic acid was stirred for 15 min under nitrogen and 2.6 g of sodium borohydride (70 mM) was added portionwise maintaining the temperature 25-35° C. After the addition, the reaction mixture was stirred for 30 min and then poured into ice cold solution of concentrated sodium hydroxide. The resulting precipitate was filtered and chromatographed over silica gel. Elution with hexanes:ethyl acetate 90:10 yielded the expected product of 5-(3,4-dichlorophenoxy)-6-methoxy-4-methyl-8-[(4-phthalimido-1-methylbutyl)amino]quino line which was crystallized from ether to give 12.4 g (22 mM) of yellow crystalline product.
Reaction SMILES: [CH3:1][C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH3:1][C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH3:20]
Reactant: CC1(c2ccccc2)NCCc2ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2ccccc2C1(C)c1ccccc1
Temperature: 0 °C

Procedure:
To a solution of (+)-1-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline (1.0 g) in N,N-dimethylformamide (10 ml) was added sodium hydride (0.19 g) in ice-bath with stirring. After stirring for 30 minutes at room temperature, to the mixture was added methyl iodide (0.31 ml). And after stirring for an hour at room temperature, the mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with water, sodium chloride aqueous solution, dried over magnesium sulfate and evaporated in vacuo to give (+)-1,2-dimethyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline (0.6 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11]>C(N(CC)CC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:8][C:4]1[CH:3]=[C:2]([C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9])[CH:7]=[CH:6][N:5]=1
Reactant: Clc1cc(Br)ccn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
A mixture of 2.5 g of 4-bromo-2-chloropyridine (12.6 mmol), 2.2 ml of (trimethylsilyl)acetylene (15.1 mmol), 153 mg of copper(I)iodide (0.79 mmol) and 287 mg of bis(triphenylphosphine)palladium(II)chloride (0.41 mmol) in triethylamine (15 ml) was stirred at RT for 1 h. The triethylamine was then removed in vacuo, water was added and the mixture was extracted with diethylether. The combined organic extracts were then washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo to give a residue which was purified by column chromatography (heptane/EtOAc 100:0 to 98:2) to give 2-chloro-4-trimethylsilanylethynyl-pyridine (2.394 g, 91%) as a light yellow liquid. MS (ISP) 210.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].C(O)=O.[C:15]([OH:21])(=[O:20])[CH2:16]C(O)=O.C([O-])=O.[NH4+:25].Cl>O>[NH2:25][CH:6]([C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:16][C:15]([OH:21])=[O:20]
Reactant: O=C(O)CC(=O)O
Reactant: [NH4+]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C[O-]
Solvent: O=CO
Solvent: O
Product: NC(CC(=O)O)c1ccccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
o-Nitrobenzaldehyde (20.4 g, 0.135 mol), formic acid (20.3 mL, 0.539 mol) and malonic acid (18.3 g, 0.176 mol) were stirred at 45° C. for half an hour. Then ammonium formate (21.3 g, 0.338 mol) was added thereto, the reaction temperature was raised to 70° C. and stirred for 1 hour, and then stirred at 95° C. for another 4 hours. Then concentrated hydrochloric acid (50 mL) was added and further stirred maintaining this temperature for another 1 hour. It was cooled. 25 mL water was added, and washed twice with ethyl acetate (2×25 mL). The aqueous phase was adjusted to pH 4.2 with 50% potassium hydroxide solution. A solid precipitated. It was pumping filtered, and dried in vacuum to obtain a yellow solid 18.33 g, at a yield of 64.6%.