Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[N:4][OH:5])[CH3:3].C(N(CC)CC)C.[CH3:13][C:14]1([CH3:27])[O:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:23]([C:24]#[CH:25])[C:17]=2[C:16](=[O:26])[O:15]1.P(=O)(O)(O)O>C(OC)(C)(C)C.O>[CH3:13][C:14]1([CH3:27])[O:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:23]([C:24]3[O:5][N:4]=[C:2]([CH3:3])[CH:25]=3)[C:17]=2[C:16](=[O:26])[O:15]1
Reactant: C#Cc1cccc2c1C(=O)OC(C)(C)O2
Reactant: CC(Cl)=NO
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: Cc1cc(-c2cccc3c2C(=O)OC(C)(C)O3)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
53 ml of the solution of 1-chloro-1-(N-hydroxyimino)ethane described above and 6.3 ml of triethylamine are added with stirring at 0° C. to a solution of 8.0 g of 2,2-dimethyl-5-(ethynyl)-4H-(1,3)benzodioxin-4-one in 400 ml of methyl tert-butyl ether, and the mixture is allowed to come to room temperature and is subsequently stirred overnight. A further 53 ml of the solution of 1-chloro-1-(N-hydroxyimino)ethane described above and 6.3 ml of triethylamine are added and the reaction solution is stirred at room temperature for 24 h. It is then poured into water containing phosphoric acid (pH 4) at 0° C. and extracted with methyl tert-butyl ether, and the combined organic phases are carefully washed with water, dried over sodium sulfate and concentrated. 8.8 g of crude product remain, which is chromatographed on silica gel using n-hexane/ethyl acetate. 4.1 g of colorless crystals are obtained, m.p. 74° C. (cf. Table 1, No. 1.020).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([I:13])[C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]([C:21](=[O:23])[CH3:22])[CH:18]=[CH:19][CH:20]=1.CCOC(C)=O>CC(O)C.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[I:13][C:7]1[C:8]([CH3:12])=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[N:4][N:3]=[C:2]2[NH:14][C:15]1[CH:16]=[C:17]([C:21](=[O:23])[CH3:22])[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccc2c(Cl)nncc2c1I
Reactant: CC(=O)c1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(=O)c1cccc(Nc2nncc3c(I)c(C)ccc23)c1
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 24.2 %

Procedure:
To a solution of 1-chloro-5-iodo-6-methylphthalazine (0.380 g, 1.25 mmol) in IPA (3.0 ml), charged to a 5 mL microwave reaction vessel, 3′-aminoacetophenone (0.253 g, 1.87 mmol) was added. The reaction mixture was stirred at 160° C. for 15 min. The reaction mixture was diluted with excess DCM and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The resulting residue was loaded on to silica and purified by column chromatography. (ISCO 40.0 g, 10-70% EtOAc in Hex., 25 min.) to give 1-(3-(5-iodo-6-methylphthalazin-1-ylamino)phenyl)ethanone (0.122 g, 24.2% yield). MS (M+H)+ 404.
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][C:29](ON3C(=O)CCC3=O)=[O:30])C3C(=CC=CC=3)C=2C=CC=1.[ClH:40].[NH2:41][C:42]1[CH:50]=[CH:49][CH:48]=[C:47]2[C:43]=1[C:44](=[O:65])[N:45]([C:52]1([CH2:60][CH2:61][CH2:62][CH2:63][NH2:64])[CH2:57][CH2:56][C:55](=[O:58])[NH:54][C:53]1=[O:59])[C:46]2=[O:51].C(N(CC)CC)C>CS(C)=O>[NH2:41][C:42]1[CH:50]=[CH:49][CH:48]=[C:47]2[C:43]=1[C:44](=[O:65])[N:45]([C:52]1([CH2:60][CH2:61][CH2:62][CH2:63][NH:64][C:29](=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][NH2:17])[CH2:57][CH2:56][C:55](=[O:58])[NH:54][C:53]1=[O:59])[C:46]2=[O:51].[ClH:40].[NH2:41][C:42]1[CH:50]=[CH:49][CH:48]=[C:47]2[C:43]=1[C:44](=[O:65])[N:45]([C:52]1([CH2:60][CH2:61][CH2:62][CH2:63][NH2:64])[CH2:57][CH2:56][C:55](=[O:58])[NH:54][C:53]1=[O:59])[C:46]2=[O:51]
Reactant: O=C(CCOCCOCCOCCNC(=O)OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: NCCCCC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: NCCOCCOCCOCCC(=O)NCCCCC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
To a solution of 23 (0.012 g, 0.022 mmol) in DMSO (2 mL) were added 7 (0.011 g, 0.0289 mmol) and triethylamine (0.01 mL, 0.071 mmol) under an atmosphere of argon, and the mixture was stirred at room temperature. After 16 h, the crude mixture was directly purified by preparative HPLC to afford 25 (0.005 g, 42%), 24 (0.0014 g, 8.2%) and unreacted 7 (0.0037 g, 48%). 1H NMR (400 MHz, DMSO) δ 8.39 (s, 2H), 7.86 (s, 1H), 7.49-7.37 (m, 1H), 7.04-6.82 (m, 2H), 6.53 (s, 2H), 3.59-3.36 (m, 11H), 3.03-2.93 (m, 2H), 2.84-2.76 (m, 2H), 2.33-2.16 (m, 5H), 2.05-1.96 (m, 2H), 1.44-1.31 (m, 3H), 1.25-1.16 (m, 3H). MS (ESI) m/z calcd for C26H38N5O8 [M+H]+ 548.6, found 548.5.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[S].[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[C:17](Cl)=[O:18].[H][H]>C1(C)C=CC=CC=1.[Pd].O>[F:12][C:13]([F:27])([F:28])[C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:22]=1)[CH:17]=[O:18]
Reactant: [H][H]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: [S]
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccc2ncccc2c1
Product: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 105 °C
Yield: 86.8 %

Procedure:
60 g of freshly distilled quinoline and 10 g of sulfur were refluxed for 5 hours with stirring. The cooled mixture was diluted with 700 ml of toluene. This gave a solution of a quinoline-sulfur complex containing 100 mg of the complex per ml. 2.5 g of 5% palladium on barium sulfate, 0.25 ml of the solution of the complex and 250 g of 3,5-bis(trifluoromethyl)benzoyl chloride were placed in a reaction vessel at room temperature with exclusion of water. A gentle stream of hydrogen gas was then passed through the mixture at atmospheric pressure. The mixture was subsequently heated to 100-110° C. and hydrogen gas was continuously introduced at atmospheric pressure. After liberation of acidic offgases had ceased (12 hours), the mixture was cooled, the catalyst was separated off by filtration, and the filtrate was distilled at 27 mbar. A yield of 190.0 g of 3,5-bis(trifluoromethyl)benzaldehyde having a boiling point of 79° C. was obtained. This corresponds to a yield of 86% of theory. A small amount of a mixture of toluene and 3,5-bis(trifluoromethyl)benzene was obtained as first fraction during the distillation.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[I:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44]>ClCCCl.CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18](=[O:20])[NH:44][C:43]3[CH:45]=[CH:46][CH:47]=[C:41]([I:40])[CH:42]=3)=[CH:21][CH:22]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2]
Reactant: Nc1cccc(I)c1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(I)c4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 91 %

Procedure:
A 50 ml round bottomed flask was charged with 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 2) (1.466 g, 4.15 mmol), a drop of DMF, and 1,2-dichloroethane (10 ml). Oxalyl chloride (2M in dichloromethane) (2.283 ml, 4.565 mmol) was slowly added and the mixture became a clear solution. Gas evolution was observed. The mixture was stirred for 17 hours at ambient temperature. Triethylamine (1.157 ml, 8.30 mmol) and 3-iodoaniline (0.524 ml, 4.358 mmol) were added to the acid chloride solution. The mixture was stirred for 1 hour at ambient temperature. The crude mixture was purified on silica gel (EtOAc in hexanes gradient) to provide 2.094 g of the title compound as light brown solid (91%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][CH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH2:18][CH2:17]1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47]>>[ClH:1].[ClH:30].[ClH:1].[Cl:46][C:33]1[CH:34]=[C:35]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:17][CH2:18][C@H:19]([CH2:22][N:23]3[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]3)[CH2:20][CH2:21]2)[CH:36]=[C:31]([Cl:30])[C:32]=1[OH:47]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1NC1CCC(CN2CCN(C)CC2)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](CN2CCN(C)CC2)CC1
Product: Cl

Procedure:
Following general procedure II, 1-(6-chloro-4-{4-[(4-methylpiperazin-1-yl)methyl]-cyclohexyl amino}-1,5-naphthyridin-3-yl)ethanone (32 mg, 0.076 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (26 mg, 0.092 mmol) followed by formation of the trihydrochloride salt to afford the desired product (31 mg, 67%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.14 (s, 1H), 8.46 (d, J=8.9 Hz, 1H), 8.33 (d, J=8.9 Hz, 1H), 8.10 (s, 2H), 5.73-5.68 (m, 1H), 3.75 (br s, 8H), 3.16 (br s, 2H), 3.02 (s, 3H), 2.76 (s, 3H), 2.46-2.42 (m, 2H), 2.22-2.14 (m, 2H), 2.10-2.00 (m, 1H), 1.72-1.63 (m, 2H), 1.46-1.37 (m, 2H); ESI MS m/z 542 [M+H]+; HPLC 96.7% (AUC), tR=9.37 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([OH:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([OH:29])([CH3:27])[CH3:28])=[CH:22][CH:21]=1)=[O:10]
Reactant: O=C(O)c1cccnc1Oc1cccc(F)c1
Reactant: CC(C)(O)c1ccc(CN)cc1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)c1ccc(CNC(=O)c2cccnc2Oc2cccc(F)c2)cc1
Yield: 98.3 %

Procedure:
To a stirred solution 2-(3-Fluoro-phenoxy)-nicotinic acid (0.250 g, 1.07 mmole), 2-(4-Aminomethyl-phenyl)-propan-2-ol (0.195 grams, 1.18 mmole) and 1-hydroxybenzotriazole hydrate (0.173 grams, 1.28 mmole) in dry dimethylformamide (15 ml) was added 1-(3-dimethylamino)-propyl)-3-ethylcarbodiimide hydrochloride (0.173 grams, 1.28 mmole) and stirred over night. The mixture was diluted with 300 ml water and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated to give an oil that was purified by chromatography on silica. Recrystalization from ethyl acetate/hexane gave a solid (0.400 g). M.P. 106-108° C.; Anal. calcd. for C22H21N2O3F: C, 69.46; H, 5.56; N, 7.36. Found: C, 69.05; H, 5.68; N, 7.25.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:21][C:22]([C:24]1[CH:25]=[C:26]2[CH2:32][C:31](=[O:33])[N:30]([CH3:34])[C:27]2=[N:28][CH:29]=1)=[O:23]>O1CCOCC1>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:21][C:22]([C:24]3[CH:25]=[C:26]4[CH2:32][C:31](=[O:33])[N:30]([CH3:34])[C:27]4=[N:28][CH:29]=3)=[O:23])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CN1C(=O)Cc2cc(C(=O)CBr)cnc21
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN1C(=O)Cc2cc(C(=O)CN3CCN(c4ccccc4)CC3)cnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Add 63 mg (3.9×10-4mol) of N-phenylpiperazine and then, very slowly, 0.08 ml (5.57'10-4 mol) of triethylamine to a previously prepared solution of 100 mg (3.72×10-4 mol) of 1,3-dihydro-5-bromoacetyl-1-methyl-2H-pyrrolo[2,3-b]pyridin-2-one (Preparation 19) in 3 ml of dioxane. After 30 minutes' stirring at room temperature, the resulting precipitate is removed by filtration and the filtrate is concentrated under reduced pressure to obtain the title product in a yield of 78%. ##STR75##
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[N:9]=[C:8]2[NH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:27]=[CH:26]2)(=O)C.CCN(C(C)C)C(C)C.[C:48](Cl)(=[O:52])[CH2:49][CH2:50][CH3:51].CCOCC>ClCCl>[C:48]([NH:21][C:17]1[CH:16]=[C:15]([C:10]2[N:9]=[C:8]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[N:27]=[CH:26]4)[C:7]3[C:12](=[CH:13][CH:14]=[C:5]([OH:4])[CH:6]=3)[N:11]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:52])[CH2:49][CH2:50][CH3:51]
Reactant: CC(=O)Oc1ccc2nc(-c3cccc(N)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2c1
Reactant: CCCC(=O)Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3cc(O)ccc3n2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.9 %

Procedure:
To a solution of tert-butyl 5-(6-acetoxy-2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.57 g, 1.12 mmol) and DIEA (0.65 g, 5.03 mmol) in dichloromethane (20 mL) was added butryl chloride (0.180 g, 1.69 mmol). The resulting reaction mixture was stirred at room temperature for 4 h. The volatiles were removed under reduced pressure and the residue was triturated with water causing formation of a precipitate. The solid was collected via filtration and dried under vacuum. The solid was suspended in anhydrous methanol (50 mL) and 28% ammonium hydroxide (0.9 mL) was added. The resulting reaction mixture was stirred at room temperature for 24 h. The volatiles were removed under reduced pressure and the residue upon trituration with ether gave tert-butyl 5-(2-(3-butyramidophenyl)-6-hydroxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.354 g, 0.66 mmol, 59% over two steps). HPLC retention time 6.342 min.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].OO.S([O-])([O-])(=[O:21])=S.[Na+].[Na+].[OH2:26]>CO.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH3:1][S:2]([CH:3]([C:8]1[CH:9]=[CH:10][C:11]([N:14]([CH3:16])[CH3:15])=[CH:12][CH:13]=1)[C:4]([O:6][CH3:7])=[O:5])(=[O:21])=[O:26]
Reactant: O
Reactant: O=S([O-])([O-])=S
Reactant: COC(=O)C(SC)c1ccc(N(C)C)cc1
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(c1ccc(N(C)C)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 60 h
Yield: 63.5 %

Procedure:
Methyl α-methylthio(p-dimethylaminophenyl)acetate (105 mg) was dissolved in 10 ml of methanol, and 8.2 mg of sodium tungstate dihydrate and 0.6 ml of a 30% aqueous solution of hydrogen peroxide were added. The mixture was stirred at room temperature for 60 hours. The remaining hydrogen peroxide was decomposed with sodium thiosulfate, and 20 ml of water was added to the mixture. It was then extracted three times with 10 ml of methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Recrystallization of the residue from methanol afforded 76 mg of methyl α-methylsulfonyl(p-dimethylaminophenyl)acetate in a yield of 63.5%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[CH2:24]([CH:31]1[CH2:36][NH:35][CH2:34][CH2:33][NH:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CS(C)=O>[CH2:24]([CH:31]1[NH:32][CH2:33][CH2:34][N:35]([C:18]2[C:19]([F:21])=[CH:20][C:10]3[C:11]([CH:17]=2)=[N:12][C:13]2[N:14]([CH3:16])[CH:15]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:7](=[O:23])[C:8]=2[CH:9]=3)[CH2:36]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: c1ccc(CC2CNCCN2)cc1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C)c2nc3cc(N4CCNC(Cc5ccccc5)C4)c(F)cc3cc2c1=O
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 82.6 %

Procedure:
A suspension of 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.3 g) and (RS)-2-benzylpiperazine (1.3 g) in dimethyl sulphoxide (25 cc) is heated to approximately 90° C. with stirring for 1 hour 45 minutes. After cooling to a temperature in the region of 20° C., the reaction mixture is treated with water (100 cc) and extracted with trichloromethane (3×30 cc). The combined organic extracts are washed with water (3×30 cc), dried over magnesium sulphate, filtered and concentrated to dryness at approximately 50° C. under reduced pressure (20 kPa). After 1 recrystallization in a mixture of dimethylformamide (4 cc) and ethanol (1 cc), (RS)-8-(3-benzyl-1-piperazinyl)-3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.6 g) is obtained in the form of a yellow solid, m.p. 190° C.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH:9]([OH:15])[CH:10]=[CH:11][CH:12]=[CH:13][CH3:14])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:16]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:10]([C@H:9]1[O:15][C:16]2([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[O:1][C@@H:2]([CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH2:8]1)=[CH:11][CH:12]=[CH:13][CH3:14]
Reactant: O=C1CCCCC1
Reactant: CC=CC=CC(O)CC(O)CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC=CC=C[C@@H]1C[C@H](CC(=O)OC)OC2(CCCCC2)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.7 %

Procedure:
Methyl 3,5-dihydroxy-6,8-decadienoate (7.6 g, 35.5 mmol) and p-toluenesulfonic acid (0.1 g) was added to cyclohexanone (10 g, 100 mmol) and stirred for 16 hours at ambient temperature. The yellow solution was loaded directly onto a silica gel column and the product eluted with diethyl ether:hexane (1:4). The appropriate fractions were combined to give 3.52 g (33.6%) of the title compound as a colorless oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][SiH2:2]1.[C:6]1([Mg]Br)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:14]1[CH2:18]O[CH2:16][CH2:15]1>C(OCC)C>[OH:1][CH2:5][C:4]1[CH:18]=[CH:14][CH:15]=[CH:16][C:3]=1[Si:2]([CH:9]([CH3:10])[CH3:8])([CH:6]([CH3:11])[CH3:7])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C1CCOC1
Reactant: Br[Mg]c1ccccc1
Reactant: C1CO[SiH2]C1
Solvent: CCOCC
Product: CC(C)[Si](c1ccccc1)(c1ccccc1CO)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The resultant oxasilacyclopentane (11.0 g, 50.0 mmol) was dissolved in THF (125 ml), and a 1.07M solution of phenylmagnesium bromide in THF (51 ml, 55 mmol) was slowly added thereto at 0° C. After finishing dropping the solution, the resultant was stirred at room temperature for 16 hours. The reaction solution was diluted with diethyl ether and was washed with a saturated NH4Cl aqueous solution, water, and brine, and then was dried over anhydrous MgSO4. After removal of the solvents, the residue was purified by column chromatography on silica gel, thereby obtaining [2-(hydroxymethyl)phenyl]diisopropylphenylsilane (13.5 g, 90%) as colorless crystal.
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:6][C:7](=[O:23])[C:8]2[N:9]=[CH:10][N:11]([C:21]=2[N:22]=1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)(=[O:3])[CH3:2].[C:24]([O:32][C@@H:33]1[C@H:37]([F:38])[C@@H:36]([CH2:39][CH:40]([P:48]([O:53][CH2:54][CH3:55])([O:50][CH2:51][CH3:52])=[O:49])[S:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:35][C@H:34]1OC(=O)C)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl.ClCCCl>[C:24]([O:32][C@@H:33]1[C@H:37]([F:38])[C@@H:36]([CH2:39][CH:40]([P:48]([O:53][CH2:54][CH3:55])([O:50][CH2:51][CH3:52])=[O:49])[S:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:35][C@H:34]1[N:11]1[CH:10]=[N:9][C:8]2[C:7](=[O:23])[NH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:22][C:21]1=2)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: CCOP(=O)(OCC)C(C[C@H]1O[C@@H](OC(C)=O)[C@H](OC(=O)c2ccccc2)[C@@H]1F)Sc1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(C[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(NC(C)=O)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1F)Sc1ccccc1
Temperature: 25 °C
Yield: 29.3 %

Procedure:
N-Acetyl Guanosine (108 mg, 0.56 mmol) was suspended in 10 mL anhydrous CH2Cl2. With stirring under nitrogen, BSA (345 mg, 1.4 mmol) was added to the suspension. The mixture was stirred at 80° C. for 2 h and cooled to r.t. Compound 35.14 (200 mg, 0.37 mmol) in 5 mL anhydrous DCE was added to the mixture, followed by SnCl4 (64 mL, 0.55 mmol). The mixture was heated to 65° C. for 6 h and then cooled to r.t., diluted with 50 mL CH2Cl2 and poured onto a mixture of 50 g ice/50 mL saturated Rochelles Salt. The mixture was stirred for another 1 h. The organic layer was separated and the aqueous layer was extracted with 100 mL additional CH2Cl2. The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with 5% MeOH in CH2Cl2 to give compound 35.15 (73 mg, 30% yield).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:17](=O)[CH:16]3[NH:19][CH:12]([CH2:13][CH2:14][CH2:15]3)[C:11]2=O)=[CH:6][CH:5]=1.S(C)C.FC(F)(F)C1C=CC(C2CCNCC=2)=CC=1.[OH-].[Na+]>C1COCC1>[F:22][C:2]([F:1])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:17][CH:16]3[NH:19][CH:12]([CH2:13][CH2:14][CH2:15]3)[CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=C1C2CCCC(N2)C(=O)N1c1ccc(OC(F)(F)F)cc1
Agent: FC(F)(F)c1ccc(C2=CCNCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CSC
Product: FC(F)(F)Oc1ccc(N2CC3CCCC(C2)N3)cc1
Reaction time: 0.67 h

Procedure:
A solution of 3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-2,4-dione (80 mg, 0.25 mmol) and THF (4 mL) was heated at 70° C. under N2. A solution of BH3.SMe2 (2M in THF, 0.4 mL, 0.8 mmol) was added dropwise. After 40 min, 6N HCl (1.0 mL) was added dropwise (Caution: H2 evolution). After an additional 30 min, the reaction was poured into 1N NaOH (8 mL) and extracted with dichloromethane (30 mL×2). The combined organic extracts were dried, filtered and concentrated to give 3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane: MS (ESI): 287.5 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C1(C)C=CC=CC=1>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Clc1nccc2ccccc12
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(-c2nccc3ccccc23)c1
Temperature: 25 °C

Procedure:
1-chloroisoquinoline (7 g, 42.8 mmol), (3-methoxyphenyl)boronic acid (8.78 g, 57.8 mmol), Tris(dibenzylideneacetone)palladium(0) (0.783 g, 0.856 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos) (1.403 g, 3.42 mmol) were charged into the reaction vessel with 250 mL of toluene. Lastly, potassium phosphate tribasic monohydrate (29.5 g, 128 mmol) was dissolved in 60 mL of water and was charged into the reaction mixture. The reaction was degassed with nitrogen gas then was heated to reflux for 18 h. The reaction mixture was cooled to room temperature and the toluene layer was separated and dried over magnesium sulfate. The organics were filtered and stripped under vacuum. The crude residue was purified by silica gel chromatography using 25-35% ethyl acetate/hexanes yielding 9.4 g (93%) of 1-(3-methoxyphenyl)isoquinoline as a viscous yellow oil.