Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]([C:11]1[CH:35]=[CH:34][C:14]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][C:24]3=[O:25])[CH2:19][CH2:18]2)=[O:16])=[CH:13][CH:12]=1)=O.Cl.[O:37]1C[CH2:40][CH2:39][CH2:38]1>>[OH:37][CH2:38][CH2:39][CH:40]=[CH:9][C:11]1[CH:35]=[CH:34][C:14]([C:15]([N:17]2[CH2:18][CH2:19][CH:20]([N:23]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][C:24]3=[O:25])[CH2:21][CH2:22]2)=[O:16])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Product: O=C(c1ccc(C=CCCO)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Hydroxypropyltriphenylphosphonium bromide (2.4 g) is dispersed into tetrahydrofuran (50 ml) and thereto is added dropwise lithium diisopropylamide (a solution in 1.99N tetrahydrofuran) (6.1 ml) at 0°-5° C. After adding, the mixture is stirred at 0°-5° C. for 1 hour and thereto is added 1-[1-(4-formylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (2 g). The mixture is stirred at room temperature overnight. The reaction mixture is poured into ice-water and adjusted to pH 4-5 by adding conc. hydrochloric acid. The mixture is extracted with ethyl acetate and dried with magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1→ethyl acetate:methanol=20:1) to give 1-{1-[4-(4-hydroxy-1-butenyl)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (1 g).
Reaction SMILES: [CH2:1]([C:3](=[CH:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2].[CH2:10]=[O:11].CO.[OH-:14].[Na+]>COCCOCCOC>[CH2:1]([C:3](=[CH:6][CH:7]([CH2:8][CH3:9])[CH2:10][OH:11])[CH:4]=[O:5])[CH3:2].[CH2:8]([C:7]1[CH:10]([OH:14])[O:11][CH2:4][CH:3]([CH2:1][CH3:2])[CH:6]=1)[CH3:9]
Reactant: C=O
Reactant: [OH-]
Reactant: CCCC=C(C=O)CC
Agent: [Na+]
Solvent: CO
Solvent: COCCOCCOC
Product: CCC(C=O)=CC(CC)CO
Product: CCC1=CC(CC)COC1O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a mixture of 726g of 2-ethyl-2-hexenal (purity: 99.0%, 5.7 mol), 308 g (3.8 mol) of 37% formalin, and 517 g of methanol heated to 50° C. was added dropwise with stirring 60.8 g (0.38 mol) of a 25% aqueous solution of sodium hydroxide over one hour. After the dropping was completed, the mixture was further stirred at 50° C. for 3 hours. The reaction mixture was analyzed by gas chromatography (the internal standard method with diethylene glycol dimethyl ether as an internal standard), and the yields of 2,4-diethyl-5-hydroxy-2-pentenal and 3,5-diethyl-5,6-dihydro-2H-2-pyranol based on the used formaldehyde and the consumed 2-ethyl-2-hexenal were found to be as follows.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].C([O:23][C:24](=O)[CH2:25][CH:26]([OH:30])[CH2:27][C:28]#[N:29])C>O1CCCC1>[C:28]([CH2:27][CH:26]([OH:30])[CH2:25][C:24](=[O:23])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])#[N:29]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)CC(O)CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)CC(=O)CC(O)CC#N
Temperature: -55 °C

Procedure:
To a vessel containing 265 kg of 16.8% n-butyllithium is added a mixture of 80 kg of diisopropylamine in 80 L of tetrahydrofuran maintaining the temperature at less than 20° C. The solution is cooled to −55° C., and 85 kg of tert-butyl acetate is added maintaining the temperature at −50°±5° C. A solution of 25 kg of R 4-cyano-3-hydroxybutanoic acid ethyl ester in 55 L of tetrahydrofuran is then added, and the temperature is allowed to warm to −20° C. for at least 20 minutes. The solution is then quenched by transferring to aqueous hydrochloric acid. The organic layer is separated and the aqueous layer re-extracted with ethyl acetate. The combined organic layers are concentrated by vacuum distillation to afford crude 5R 1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)=[C:5]([C:7](O)=[O:8])[CH:6]=1.[NH2:21][NH:22][C:23]([NH2:25])=[S:24]>O1CCCC1.N1C=CC=CC=1>[NH2:25][C:23](=[S:24])[NH:22][NH:21][C:7](=[O:8])[C:5]1[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=1[NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1
Reactant: O=C(O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Reactant: NNC(N)=S
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: NC(=S)NNC(=O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.9 %

Procedure:
N,N'-Carbonyldiimidazole (4.56 g, 27.6 mmol) is added to a room temperature solution of flufenamic acid (5.07 g, 18.0 mmol) in 70 ml of tetrahydrofuran. The clear yellow solution is stirred at room temperature for three hours. The solution is then added via cannula to a suspension of thiosemicarbazide (3.41 g, 37.5 mmol) in 55 ml of pyridine. The suspension is heated at reflux overnight. The clear orange solution is concentrated in vacuo and the residue is partitioned between ethyl acetate and water. The organic layer is washed with water, dried over magnesium sulfate and concentrated. The resulting solid is slurried with a 1:3 mixture of ethyl acetate and hexane. The off-white solid is collected by filtration providing 2.80 g (44%) of 2-[(3-trifluoromethylphenyl)amino]-benzoic acid, 2-(aminothioxomethyl)hydrazide.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][S:21]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH2:8][CH2:9]1)(=[O:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
In 50 ml of methylene chloride was dissolved 2.5 g of 6-nitroindoline, and then 6.37 ml of triethylamine was added thereto. Under ice cooling, 3.51 g of methanesulfonyl chloride was added dropwise, the reaction solution was stirred at room temperature for 3 hours, and then ice-water was added thereto, followed by 1 hour of stirring. The reaction solvent was removed by evaporation under reduced pressure, a 1M aqueous hydrochloric acid solution was added to the residue, and precipitated was filtrated off, whereby 3.52 g of 1-methylsulfonyl-6-nitroindoline was obtained as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[C:17]([CH2:18][CH2:19][CH:20]=C)=[C:16]2[C:11]([CH2:12][CH2:13][C@H:14]([C:22]([CH3:30])([CH3:29])[O:23][SiH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[O:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:33].[Na+]>O1CCCC1.O.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[C:1]([O:5][C:6]([N:7]1[C:8]2[C:17](=[C:16]3[C:11](=[CH:10][CH:9]=2)[CH2:12][CH2:13][C@H:14]([C:22]([CH3:30])([CH3:29])[O:23][SiH2:24][C:25]([CH3:28])([CH3:26])[CH3:27])[O:15]3)[CH2:18][CH2:19][CH:20]1[OH:33])=[O:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCCc1c(NC(=O)OC(C)(C)C)ccc2c1O[C@@H](C(C)(C)O[SiH2]C(C)(C)C)CC2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1c2ccc3c(c2CCC1O)O[C@@H](C(C)(C)O[SiH2]C(C)(C)C)CC3
Reaction time: 6 h
Yield: 81.2 %

Procedure:
To a solution of (2R)-[8-but-3-enyl-2-(tert-butyl-dimethyl-silanyloxymethyl)-chroman-7-yl]-carbamic acid tert-butyl ester (3.6 g, 8.0 mmole) in tetrahydrofuran (150 mL) and water (15 mL) at 0° C. was added osmium tetroxide (0.4 mL, 5% in water), followed by sodium periodate (5.16 g, 24 mmole). The mixture was stirred for 6 hours. The solution was diluted with ethyl acetate and the organic layer was washed with water, dried over sodium sulfate, filtered, and the solvent evaporated in vacuum. Column chromatography on silica gel (10% ethyl acetate/hexane) afforded 2.92 g (81%) of the title compound as an oil, [α]25D=−36.75° (4.9, THF).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:8]([CH3:16])=[N:9][N:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[N:11]2)=O.[CH:18]1([NH:21][C:22]([NH2:24])=[NH:23])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:18]1([NH:21][C:22]2[N:24]=[C:5]([C:7]3[C:8]([CH3:16])=[N:9][N:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[N:11]4)[CH:4]=[CH:3][N:23]=2)[CH2:20][CH2:19]1
Reactant: Cc1nn2ncccc2c1C(=O)/C=C/N(C)C
Reactant: N=C(N)NC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn2ncccc2c1-c1ccnc(NC2CC2)n1
Temperature: 135 °C
Yield: 38 %

Procedure:
To a solution (2E)-3-(dimethylamino)-1-(2-methylpyrazolo[1,5-b]pyridazin-3-yl)-2-propen-1-one (50 mg, 0.22 mmol) in DMF (2.5 mL) was added N-cyclopropylguanidine.0.5H2SO4 (130 mg, 0.66 mmol) and potassium carbonate (152 mg, 1.10 mmol). The reaction was heated at an oil bath temperature of 135° C. for about 18 hours. The mixture was cooled to RT and the solvent was removed in vacuo. The residue was dissolved in chloroform and filtered. The filtrate was concentrated in vacuo then dissolved in CH2Cl2 and triturated with diethylether to give the title compound as a yellow solid (22 mg, 38%). 1H-NMR (300 MHz, CDCl3) δ 9.02 (d, 1H, J=8.8 Hz), 8.39 (d, 1H, J=5.2 Hz), 8.35 (dd, 1H, J=4.4, 2.0 Hz), 7.15 (dd, 1H, J=8.8, 4.4 Hz), 6.94 (d, 1H, J=5.3 Hz), 5.45 (s, 1H), 2.89 (m, 1H), 2.83 (s, 3H), 0.91 (m, 2H), 0.68 (m, 2H); MS (ESI) (M+H)+ 267.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([CH3:10])([O:8][CH3:9])[O:6][CH3:7].[NH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[CH3:10][Si:5]([O:8][CH3:9])([O:6][CH3:7])[CH2:4][CH2:3][CH2:2][NH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: CO[Si](C)(CCCCl)OC
Reactant: NCCN1CCNCC1
Product: CO[Si](C)(CCCNCCN1CCNCC1)OC
Yield: 44.5 %

Procedure:
Starting with 182.7 g of chloropropylmethyldimethoxysilane and 79 g of 2-aminoethylpiperazine, the procedure described in Example 2 was used to prepare 75 g of the title compound, boiling point range 90°-110° C. at 5 mm Hg (34 kPa).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](O)=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:58][C:59]1[C:67]([NH2:68])=[CH:66][CH:65]=[CH:64][C:60]=1[C:61]([NH2:63])=[O:62]>CN(C=O)C>[NH2:58][C:59]1[C:60]([C:61](=[O:62])[NH2:63])=[CH:64][CH:65]=[CH:66][C:67]=1[NH:68][C:18]([CH:17]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[CH:13][CH:14]=2)[CH2:9][N:8]1[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[O:19]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)CN(C(=O)OC(C)(C)C)C(C(=O)O)C2
Reactant: NC(=O)c1cccc(N)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)CN(C(=O)OC(C)(C)C)C(C(=O)Nc1cccc(C(N)=O)c1N)C2
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
Step-2: To a solution of 2-(tert-butoxycarbonyl)-7-((tert-butoxycarbonyl)amino)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (200 mg, 0.51 mmol) in anhydrous DMF (3 mL) was added EDC.HCl (293 mg, 1.53 mmol), HOAt (105 mg, 0.77 mmol) and triethylamine (0.107 ml, 0.77 mmol) at RT and the mixture was stirred for 10 min. To this reaction mixture, 2,3-diaminobenzamide (77 mg, 0.51 mmol) was added and heated to 80° C. over night. The reaction mixture was concentrated and purified by preparative TLC to afford tert-butyl 3-((2-amino-3-carbamoylphenyl)carbamoyl)-7-((tert-butoxycarbonyl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate. MS (ES+): m/z 526.30 [M+H]+
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:19])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH2:20][CH2:21][CH3:22])[CH3:2].[CH2:23]([Mg]Br)[CH3:24].[Cl-].[NH4+]>O1CCCC1.C(OCC)C.O>[CH2:1]([C:3]1[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH2:23][CH3:24])([OH:19])[CH2:17][CH3:18])=[CH:12][C:11]=2[CH2:20][CH2:21][CH3:22])=[CH:5][C:6]([OH:9])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CC[Mg]Br
Reactant: CCCc1cc(C(=O)CC)ccc1-c1cc(O)ccc1CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCc1cc(C(O)(CC)CC)ccc1-c1cc(O)ccc1CC
Temperature: -10 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
370 g (1.248 mol) of 1-(2′-ethyl-5′-hydroxy-2-propylbiphenyl-4-yl)propan-1-one in solution in 3.7 liters of tetrahydrofuran are placed in a reactor. 915 ml of a 3M solution of ethylmagnesium bromide in ethyl ether are slowly run into this solution cooled to −10° C. At the end of the addition, the reaction mixture is kept stirred for 1 hour and then transferred onto 5 liters of a 2.5 molar solution of ammonium chloride in water. The organic phase is separated by settling and washed twice with 800 ml of water. After evaporating under reduced vacuum, the residue is dissolved with 2.75 liters of methylene chloride at reflux. The medium is allowed to return to ambient temperature with stirring and is then cooled to 5° C. The crystals are filtered off and then dried under vacuum. 260 g (64%) of 6-ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-propylbiphenyl-3-ol are obtained. Melting point: 130° C. 1H NMR (d6-DMSO) (ppm): 0.67-0.74, m, 9H; 0.9, t, 3H; 1.38, m, 2H; 1.71-1.77, m, 4H; 2.13-2.35, m, 4H; 4.48, s, 1H; 6.45, d, 1H; 6.70, dd, 1H; 6.94, d, 1H; 7.07, d, 1H; 7.18, dd, 1H; 7.26, s, 1H; 9.16, s, 1H
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:25])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11](OS(O)(=O)=O)[C:10]([Cl:20])=[CH:9][C:8]=2[C:21]([F:24])([F:23])[F:22])(=[O:3])[CH3:2].[CH:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1>>[C:1]([C:4]1[C:5](=[O:25])[NH:6][C:7]2[C:12]([C:13]=1[NH:31][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[CH:11][C:10]([Cl:20])=[CH:9][C:8]=2[C:21]([F:22])([F:23])[F:24])(=[O:3])[CH3:2]
Reactant: NC1CCCC1
Reactant: CC(=O)c1c(C)c2c(OS(=O)(=O)O)c(Cl)cc(C(F)(F)F)c2[nH]c1=O
Product: CC(=O)c1c(NC2CCCC2)c2cc(Cl)cc(C(F)(F)F)c2[nH]c1=O
Yield: 67.1 %

Procedure:
3-Acetyl-6-chloro-8-trifluoromethyl-4-methylsulfoxy-2-quinolinone (3.5g, 0.01 mol) and cyclopentylamine (0.86g, 0.01 mol) were used, but the reaction was carried out as the above process of example 37 to obtain the desired product (2.5g, yield: 67 % ).
Reaction SMILES: C([Mg]Br)C.[CH:5]1([C:8]#[CH:9])[CH2:7][CH2:6]1.[N:10]([C:13]1[S:14][C:15]2[CH2:16][CH2:17][O:18][C:19]3[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:20]=3[C:21]=2[N:22]=1)=[N+:11]=[N-:12]>C1COCC1>[Br:27][C:25]1[CH:24]=[CH:23][C:20]2[C:21]3[N:22]=[C:13]([N:10]4[C:8]([CH:5]5[CH2:7][CH2:6]5)=[CH:9][N:12]=[N:11]4)[S:14][C:15]=3[CH2:16][CH2:17][O:18][C:19]=2[CH:26]=1
Reactant: C#CC1CC1
Reactant: [N-]=[N+]=Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)OCCc1sc(-n3nncc3C3CC3)nc1-2
Temperature: 50 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To a 1M solution of ethylmagnesium bromide in THF (1.3 mL, 1.3 mmol) under a nitrogen atmosphere, was added dropwise cyclopropylethyne (70% in toluene, 0.154 mL, 1.3 mmol). The reaction mixture was heated at 50° C. for 15 mins then allowed to cool down to RT. A solution of 2-azido-8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (425 mg, 1.3 mmol) in THF (1.5 mL) was then added dropwise. The reaction mixture was stirred at RT for 2 h, quenched with aqueous saturated ammonium chloride and diluted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was triturated with 20% ethyl acetate/cyclohexane and filtered to afford the title compound as a pale yellow solid (373 mg, 64%). LCMS 110142391 (Method B): RT=4.40 min, [M+H]+=390. 1H NMR (DMSO-d6): 8.20 (1H, d, J=8.6 Hz), 7.71 (1H, d, J=0.7 Hz), 7.36 (1H, dd, J=8.6, 2.1 Hz), 7.30 (1H, d, J=2.1 Hz), 4.40 (2H, t, J=5.0 Hz), 3.41 (2H, t, J=5.0 Hz), 2.70-2.63 (1H, m), 1.21-1.15 (2H, m), 0.91-0.86 (2H, m).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([PH:17](=[O:34])[C:18]2[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([O:28][CH3:29])=[C:20]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:19]=2)[CH:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(PCCCPC2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(O[C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][C:77]=1[Br:82])(=O)=O.C(N(CC)C(C)C)(C)C.Cl>C1(C)C=CC=CC=1>[C:24]([C:22]1[CH:23]=[C:18]([P:17](=[O:34])([C:7]2[CH:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([O:11][CH3:12])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=2)[C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][C:77]=2[Br:82])[CH:19]=[C:20]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:21]=1[O:28][CH3:29])([CH3:27])([CH3:26])[CH3:25]
Reactant: COc1c(C(C)(C)C)cc([PH](=O)c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)cc1C(C)(C)C
Reactant: O=S(=O)(Oc1ccccc1Br)C(F)(F)F
Agent: Cl
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: c1ccc(PCCCPc2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COc1c(C(C)(C)C)cc(P(=O)(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2ccccc2Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.7 %

Procedure:
Into a four-neck flask were weighed 28.71 g (59.0 mmol) of bis(3,5-di-t-butyl-4-methoxyphenyl)phosphine oxide, 1.27 g (2.5 mmol) of Pd2(dba)3CHCl3 (dba represents dibenzylideneacetone), and 1.01 g (2.5 mmol) of 1,3-diphenylphosphinopropane. The atmosphere of the reaction vessel which was fitted with a thermometer, a condenser tube, and a dropping funnel with a pressure-equalizing tube was completely replaced with nitrogen. Thereto were added 150 mL of toluene, 15.00 g (49.2 mmol) of the 2-(trifluoromethanesulfonyl)oxy-bromobenzene (5), and 9.53 g (73.8 mmol) of N,N-diisopropylethylamine, followed by 16 hours of heating at reflux. After the completion of the reaction, the reaction mixture was cooled to room temperature and poured into 150 mL of 5% hydrochloric acid aqueous solution. After 30 minutes of stirring, the layers were separated from each other. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. Toluene was removed by evaporation and the residue was purified by silica gel column chromatography to obtain the title compound (30.83 g, a white viscous solid). Yield 97.7%.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.N[C:23]1[C:24]([CH3:29])=[CH:25][CH:26]=[N:27][CH:28]=1.CC[N:32](C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]([NH:32][C:26]4[CH:25]=[C:24]([CH3:29])[CH:23]=[CH:28][N:27]=4)=[O:18])=[CH:20][CH:21]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: Cc1ccncc1N
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccnc(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Temperature: 25 °C
Yield: 51.6 %

Procedure:
To solution of (4-adamantan-1-yl-phenoxy)-acetic acid (50 mg, 0.17 mmol), 5-amino-4-picoline (28.32 mg, 0.26 mmol) and DIPEA (33.85 mg, 0.26 mmol) in DMF 1 mL was added EDC (50.2 mg, 0.26 mmol) and HOBt (35.39 mg, 0.26 mmol) at room temperature. Reaction mixture was stirred at room temperature. Resulting mixture poured onto ice cold water, was extracted with ethyl acetate, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (EtoAC:Hexane=1:9˜2:8) to give 2-(4-adamantan-1-yl-phenoxy)-N-(4-methyl-pyridine-2-yl)-acetamide as a colorless solid (0.033 g, 50% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.[CH:10]1(B(O)O)[CH2:12][CH2:11]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1>[CH:10]1([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=2)[CH2:12][CH2:11]1
Reactant: OB(O)C1CC1
Reactant: N#Cc1cc(Br)ccn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1cc(C2CC2)ccn1
Yield: 63.1 %

Procedure:
To a solution of 4-bromopicolinonitrile (0.2 g, 1.1 mmol) in tetrahydrofuran were added cyclopropyl boronic acid (0.093 g, 1.1 mmol), and potassium phosphate tribasic (0.694 g, 3.2 mmol). The resulting reaction mixture was degassed with nitrogen for 10 minutes and then added Pd(OAc)2 and S-phos were added. The reaction mixture was heated at reflux for 16 h, then was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue was purified via flash chromatography (10% ethyl acetate in petroleum ether) to afford 4-cyclopropylpicolinonitrile (0.1 g, 70%). MS (ES+APCI) (M+H) 145.2; LCMS retention time 3.02 min (Method J).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([O:23]C3CCCCO3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1.C1CCCCC=1>[OH-].[Pd+2].[OH-].C(O)C>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[CH:11][CH:10]=1
Reactant: OCCCCCCOc1ccc(/C=C/c2ccc(OC3CCCCO3)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: OCCCCCCOc1ccc(CCc2ccc(O)cc2)cc1
Yield: 84.1 %

Procedure:
A mixture of 3.3 g of (E)-4-(6-hydroxyhexyloxy)-4′-(tetrahydropyran-2-yloxy)stilbene (C), 0.6 g of palladium hydroxide, 34 ml of cyclohexene and 50 ml of ethanol was refluxed for 16 hours. The cooled mixture was filtered over celite and evaporated. 2.2 g of 4-{2-[4-(6-Hydroxy-hexyloxy)-phenyl]-ethyl}-phenol (L, 86%) was obtained after dissolution in 600 ml of dichloromethane, two extractions with 50 ml of water, drying over magnesium sulphate and evaporation. Apparently, deprotection of (K) had occurred under the reaction conditions.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:9]2[NH:8][CH:7]=[N:6][C:5]=2[C:4](=S)[NH:3]1.[CH3:12][NH:13][NH2:14]>>[CH3:12][N:13]([C:4]1[C:5]2[N:6]=[CH:7][NH:8][C:9]=2[NH:10][C:2](=[O:1])[N:3]=1)[NH2:14]
Reactant: CNN
Reactant: O=c1[nH]c(=S)c2nc[nH]c2[nH]1
Product: CN(N)c1nc(=O)[nH]c2[nH]cnc12
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
2-Oxo-6-thioxo-1,2,3,6-tetrahydro-9H-purine (1.0 g, 5.9 mmol) were added to methylhydrazine (20 ml), and the mixture was stirred in a sealed tube for 30 minutes at 120° C. After completion of reaction, the mixture was concentrated under reduced pressure. The residual crystals were washed with 50% ethanol, and crystals collected by filtration were recrystallized from ethanol to obtain 0.64 g (yield 60%) of colorless powdery crystals (m.p.=247° C. (decomposed)).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[N:22]=[CH:21][CH:20]=3)[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.C(=O)C(C)C.C(N(CC)CC)C.[BH4-].[Na+]>O>[CH2:4]([NH:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)[CH2:13][CH2:14]1)[CH:1]([CH3:3])[CH3:2]
Reactant: Clc1ccc2c(NCCCN3CCN(CCCNCC4CC4)CC3)ccnc2c1
Agent: CC(C)C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)CNCCCN1CCN(CCCNc2ccnc3cc(Cl)ccc23)CC1
Reaction time: 3 h

Procedure:
To a solution of N4-3-[4(3-aminopropyl)piperazine]propyl-7-chloroquinolin-4-amine (Intermediate of example 12) (150 mg, 0.41 mmol) in CH2C2 (4 mL) isobutyraldehyde (62 μL, 0.46 mmol), triethylamine (26 μL, 0.16 mmol) and 3 Å molecular sieves are added. The reaction media is stirred for 3 h and cooled before NaBH4 (78 mg, 2.05 mmol) is added portionwise over 30 min. Stirring is left for 1.5 h, water (10 mL) is added and the media is filtered. Compound is extracted with CH2Cl2 (3×20 mL). Combined organic layers are dried over MgSO4. Crude compound is purified by thick-layer chromatography (CH2Cl2/MeOH/NH4OH:90/10/1.4).