Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:7]2[C:8]([O:10][C:11](=O)[C:6]=12)=[O:9]>>[CH3:3][O:4][C:5]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:7]2[C:6]=1[CH2:11][O:10][C:8]2=[O:9]
Reactant: COc1ccc(OC)c2c1C(=O)OC2=O
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(OC)c2c1COC2=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of 1.7 g. of sodium borohydride in 100 ml. of dimethylformide is added 9.2 g. of 3,6-dimethoxyphthalic anhydride. The cold bath is removed and the mixture stirred for one hour. The mixture is cooled in ice and 20 ml. of hydrochloric acid is slowly added. The solvent is removed in vacuo and the residue is slurried in 100 ml. of water. The resulting solid is filtered, dissolved in chloroform and dried. After removal of solvent, the solid is recrystallized from toluene to yield 4,7-dimethoxyphthalide with a melting point of 168°-170° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14])[CH:8]=[O:9].O>O1CCCC1>[CH3:16][O:15][C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([O:4][CH3:3])[C:12]=1[O:13][CH3:14])[CH2:8][OH:9]
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CO)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94.4 %

Procedure:
To a 500 ml round-bottom flask under nitrogen were added 15.32 g (0.41 mol) of sodium borohydride and 100 ml of dry tetrahydrofuran. The mixture was stirred for 10 min., then 20 g (0.108 mol) of 3,4,5-trimethoxybenzaldehyde dissolved in 100 ml of tetrahydrofuran was added dropwise to the solution described above. After stirring at room temperature for 16 hr, the solution was cooled to 0° C., 5 ml of distilled water was added dropwise, and the ice-bath was removed. The mixture was stirred overnight. Tetrahydrofuran was concentrated. The mixture was then diluted with 200 ml of water, and extracted twice with 200 ml of diethyl ether. The extract was dried over magnesium sulfate, concentrated after filtration, and dried in vacuum overnight. 3,4,5-Trimethoxybenzyl alcohol (20.2 g, 100% yield) was obtained as a colorless oil, which can be used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=3[F:28])[CH:10]=2)=[N:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:35]1(=[O:41])[NH:39][C:38](=[O:40])[CH2:37][CH2:36]1.O>CN(C=O)C>[F:28][C:20]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[O:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:10]=[C:9]([C:6]3[N:7]=[CH:8][C:3]([CH2:2][N:39]4[C:35](=[O:41])[CH2:36][CH2:37][C:38]4=[O:40])=[CH:4][CH:5]=3)[S:17][C:16]=12
Reactant: O=C1CCC(=O)N1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CCl)cn4)sc23)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCC(=O)N1Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.5 %

Procedure:
To a solution of 102 (200 mg, 0.481 mmol, scheme 26) in DMF (5 mL) was added Cs2CO3 (313 mg, 0.962 mmol) and succinimide (95 mg, 0.962 mmol) and the reaction mixture was stirred at RT for 4 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated to afford title compound 138 (100 mg, 43% yield) that was triturated with Et2O and used with no additional purification. MS (m/z)=479.50 (M+H)
Reaction SMILES: C([Si](CC)(CC)[C:4]1[NH:16][C:7]2=[N:8][CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:6]2[C:5]=1[CH2:17][CH2:18][OH:19])C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[F:15][C:12]([F:13])([F:14])[C:10]1[CH:11]=[C:6]2[C:5]([CH2:17][CH2:18][OH:19])=[CH:4][NH:16][C:7]2=[N:8][CH:9]=1
Reactant: CC[Si](CC)(CC)c1[nH]c2ncc(C(F)(F)F)cc2c1CCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: OCCc1c[nH]c2ncc(C(F)(F)F)cc12
Reaction time: 10 h
Yield: 94.8 %

Procedure:
2-(2-(triethylsilyl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanol (3.8 g, 11.0 mmole) was stirred with TBAF (33.1 ml, 33.1 mmole; 1M solution in THF) for 6 hours at 50° C. and then for 10 hours at RT. The solvent was removed on a rotary evaporator. 2-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanol (2.4 g, 94.5%) was obtained.
Reaction SMILES: CN(C=O)C.I[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([NH2:16])=[N:10][NH:11]2.[C:17]([C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])#[CH:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[NH2:22][C:21]1[CH:20]=[C:19]([C:17]#[C:18][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[C:9]([NH2:16])=[N:10][NH:11]3)[CH:25]=[CH:24][CH:23]=1
Reactant: Nc1n[nH]c2cccc(I)c12
Reactant: C#Cc1cccc(N)c1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1cccc(C#Cc2cccc3[nH]nc(N)c23)c1
Temperature: 60 °C

Procedure:
To 8 ml of DMF was added 4-iodo-1H-indazol-3-amine (690 mg, 2.65 mmol) and 3-ethynylaniline (480 mg, 1.5 eq., 4.1 mmol). Following that, Bis(triphenylphosphine) palladium(II) dichloride (180 mg, 0.25 mmol, 10 mol %), Copper Iodide (100 mg, 0.52 mmol, 20 mol %), Triphenylphosphine (18 mg, 0.07 mmol, 3 mol %) and 8 ml of triethylamine was added. Nitrogen was bubbled through the reaction mixture for 15 minutes. The reaction was then set with a reflux condenser, set under nitrogen atmosphere, and heated at 60° C. for 2 hours. After that, the reaction was cooled to room temperature and 40 ml of ethyl acetate was added. The organic layer was extracted with aqueous sodium bicarbonate (3×40 ml), brine (3×40 ml), dried using anhydrous sodium sulfate, loaded onto silica and columned to give 4-((3-aminophenyl)ethynyl)-1H-indazol-3-amine.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][CH:11]([C:17](=[O:23])[NH:18][CH2:19][CH2:20][CH:21]=O)[CH:12]([OH:16])[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C@H:26]([C@@H:32]([OH:54])[C@H:33]1[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@@H:36]([O:42][C:43](=[O:45])[CH3:44])[C@H:35]([N:46]2[CH:51]=[CH:50][C:49](=[O:52])[NH:48][C:47]2=[O:53])[O:34]1)[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[C:39]([O:38][C@H:37]1[C@@H:36]([O:42][C:43](=[O:45])[CH3:44])[C@H:35]([N:46]2[CH:51]=[CH:50][C:49](=[O:52])[NH:48][C:47]2=[O:53])[O:34][C@@H:33]1[C@H:32]([OH:54])[CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[NH:25][CH2:21][CH2:20][CH2:19][NH:18][C:17](=[O:23])[C@H:11]([C@@H:12]([OH:16])[CH:13]([CH3:15])[CH3:14])[NH:10][C:9](=[O:24])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:41])[CH3:40]
Reactant: CC(C)C(O)C(NC(=O)OCc1ccccc1)C(=O)NCCC=O
Reactant: CCOC(=O)[C@H](N)[C@@H](O)[C@@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C(NCCCNC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](O)C(C)C)[C@@H](O)[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 3 h

Procedure:
A solution of [2-hydroxy-3-methyl-1-(3-oxo-propylcarbamoyl)-butyl]-carbamic acid benzyl ester (313 mg, 0.93 mmol, obtained from Reference Example 14) and ethyl (2R,3R)-2-amino-3-hydroxy-3-[(2S,3R,4R,5R)-3,4-bis(acetyloxy)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]propanoate [400 mg, 0.93 mmol, obtained by hydrogenation of ethyl (2R,3R)-2-{[(benzyloxy)carbonyl]amino}-3-{[(benzyloxy)carbonyl]oxy}-3-[(2S,3R,4R,5R)-3,4-bis(acetyloxy)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]propanoate (from Reference Example 41)] in anhydrous tetrahydrofuran (7 ml) was stirred at room temperature under a nitrogen atmosphere for 15 minutes. Acetic acid (53 μl) and sodium triacetoxyborohydride (395 mg, 1.86 mmol) were added, and the resulting solution was stirred for 3 hours. The reaction mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate solution and the aqueous layer was separated and extracted with ethyl acetate (2×75 ml). The combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (250×21 mm Phenomenex Prodigy ODS3 column eluted with 10-90% acetonitrile in water containing 0.02% trifluoroacetic acid over 72 minutes) to provide ethyl (5S)-12-[(R)-[(2R,3R,4R,5R)-3,4-bis(acetyloxy)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[(1S)-1-hydroxy-2-methylpropyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate as white amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1.CO>C(O)C>[CH:29]1([C:32]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:11])[N:8]([CH:12]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=2)[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:7]3)=[O:33])[CH2:31][CH2:30]1
Reactant: O=C(Cl)C1CC1
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)ccc1OC
Solvent: CO
Solvent: CCO
Product: CCOc1cc(C(CS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A stirred mixture of 7-amino-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindolin-1-one (1.0 g, 2.5 mmol) and cyclopropane carbonyl chloride (1 mL) was heated to reflux for 7 min. To the cooled mixture was added methanol (3 mL) at 0° C. and the mixture was stirred for 30 min. To the suspension was added ethanol (5 mL). The suspension was filtered and washed with ethanol to give cyclopropyl-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindolin-4-yl}carboxamide as an off-white solid (1.0 g, 86% yield); mp, 115-117° C.; 1H NMR (CDCl3) δ 0.86-0.93 (m, 2H, 2CHH), 1.07-1.14 (m, 2H, 2CHH), 1.46 (t, J=6.9 Hz, 3H, CH3), 1.63-1.73 (m, 1H, CH), 2.95 (s, 3H, CH3), 3.68 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.07 (q, J=7.1 Hz, 2H, CH2), 4.20 (d, J=16.7 Hz, 1H, CHH), 4.21 (dd, J=9.9, 14.3 Hz, 1H, CHH), 4.44 (d, J=16.7 Hz, 1H, CHH), 5.73 (dd, J=4.3, 9.9 Hz, 1H, NCH), 6.84-7.02 (m, 4H, Ar), 7.44 (t, J=7.8 Hz, 1H, Ar), 8.43 (d, J=8.3 Hz, 1H, Ar), 10.46 (s, 1H, NH); 13C NMR (CDCl3) δ 8.24, 14.61, 16.10, 41.43, 47.81, 51.55, 55.75, 55.88, 64.56, 111.46, 112.09, 116.69, 116.99, 117.76, 119.17, 129.27, 133.54, 138.06, 141.22, 148.84, 149.67, 169.96, 172.59; Anal Calcd for C24H28N2O6S+0.9H2O: C, 58.98; H, 6.15; N, 5.73; H2O, 3.32. Found: C, 58.62; H, 5.99; N, 5.53; H2O, 3.15.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:7](=[O:18])[N:6]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)[C:5]2=[O:30].CCOC(C)=O.[CH3:37][N:38](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[O:26][CH3:27])[CH2:19][N:6]1[C:5](=[O:30])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:37]#[N:38])[CH:3]=2)[N:8]([CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[C:7]1=[O:18]
Reactant: COc1ccc(Cn2c(=O)c3cc(Br)ccc3n(C3CCOCC3)c2=O)cc1OC
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2c(=O)c3cc(C#N)ccc3n(C3CCOCC3)c2=O)cc1OC

Procedure:
A mixture of 1.22 g of 6-bromo-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-quinazoline-2,4(1H,3H)-dione, 0.3 g of zinc cyanide and 0.089 g of tetrakis(triphenylphosphine)palladium(0) in 10 ml of DMF is irradiated in a microwave field for 3 minutes at 170° C. EtOAc is added and the mixture is washed six times with water. The resulting solution is dried over Na2SO4, filtered and evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture from (100/0, v/v) to (80/20, v/v) to give 0.804 g of the expected product.
Reaction SMILES: [Br:1][C:2]1[CH: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]2Cl.Cl.[CH3:17][N:18]([CH2:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)[CH3:19]>>[Br:1][C:2]1[CH: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:25][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:18]([CH3:19])[CH3:17])=[CH:27][CH:26]=1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CN(C)Cc1ccc(N)cc1
Agent: Cl
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN(C)C)cc1
Yield: 70 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (500 mg, 1.76 mmol) was reacted with 4-((dimethylamino)methyl)aniline hydrochloride (479 mg, 2.56 mmol) to afford the desired product (491 mg, 70%) as a yellow solid. ESI MS m/z 398 [C20H20BrN3O+H]+
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][C@H:7]([CH3:14])[CH2:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12].C1(C)C=CC(S(O[CH2:25][C@@H:26]([CH3:33])[CH2:27][O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=O)=O)=CC=1.OS(O)(=O)=O>O1CCCC1>[C:29]([O:28][CH2:27][C@H:26]([CH3:33])[CH2:25][CH2:5][CH2:6][C@H:7]([CH3:14])[CH2:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](C)COC(C)(C)C)cc1
Reactant: CC(C)CCC[C@@H](C)CCBr
Agent: II
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)COC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2.33 g. (0.097 mole) of powdered magnesium and a few iodine crystals in 23 ml. of dry tetrahydrofuran was stirred at reflux temperature while a solution of 17.9 g. (0.08 mole) of (R)-(-)-1-bromo-3,7-dimethyloctane in 51 ml. of dry tetrahydrofuran was added dropwise over 1 hour. The mixture was stirred at reflux for an additional 1 hour then cooled to room temperature. To a solution of 19.5 g. (0.065 mole) of (S)-(+)-3-tert. butoxy-2-methyl-1-propyl p-toluenesulfonate in 56 ml. of dry tetrahydrofuran, stirring at -78° C. was added the R-3,7-dimethyl-1-octyl magnesium bromide solution dropwise, followed by 3.3 ml. of a 0.1 M Li2CuCl4 solution in dry tetrahydrofuran. The resulting mixture was stirred at -78° C. for 10 minutes, for 2 hours at 0°-5° C. (ice bath) and finally for 18 hours at room temperature. At the end of this time, the reaction mixture was treated with 1 N aqueous H2SO4 and work up was carried out by extraction with ether in the manner of Example 1. The crude product was chromatographed on 450 g. of silica gel. Elution with 19:1 parts by volume hexane-ether gave the desired product which was distilled under high vacuum yielding 12.5 g. of (2R,6R)-(+)-1-tert. butoxy-2,6,10-trimethylundecane as a colorless oil, b.p. 91°-95° C. (0.3 mm Hg); [α]25D+0.94° (c 2.01, hexane).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH3:12][N:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15]>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:14](=[O:15])[N:13]([CH3:12])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][CH:6]=1
Reactant: COCCc1ccc(O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: COCCc1ccc(OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title product was prepared from 4-(2-methoxyethyl)phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (4%, light yellow oil). HPLC-MS: m/z=286.1 (M+1); Rt: 4.01 min.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH:5]1[CH2:10][N:9]([C:11](=[O:24])[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:8][CH2:7][NH:6]1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[S:32][CH:33]=[C:34]([C:36](O)=[O:37])[N:35]=2)[CH:26]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O>[CH3:2][O:3][CH2:4][CH:5]1[CH2:10][N:9]([C:11](=[O:24])[C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)[CH2:8][CH2:7][N:6]1[C:36]([C:34]1[N:35]=[C:31]([C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)[S:32][CH:33]=1)=[O:37]
Reactant: O=C(O)c1csc(-c2cccnc2)n1
Reactant: COCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1C(=O)c1csc(-c2cccnc2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-methoxymethyl-4-(3,4,5trimethoxybenzoyl)piperazine hydrochloride obtained in Reference Example 6 (0.52 g), 2-(3-pyridyl)thiazol-4-carboxylic acid (0.3 g), triethylamine (0.46 g) and N,N-dimethylformamide (3 ml) is added dropwise, while stirring under icecooling, diethyl cyanophosphonate (0.47 g). The reaction mixture is stirred at 0° C. for one hour, and then poured into ice-water, followed by extraction with ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is purified by means of a silica gel column chromatography (eluent:AcOEt-CH2Cl2 --CH3OH=10:9:1) to give 2-methoxymethyl-1-[2-(3-pyridyl) thiazol-4-ylcarbonyl]-4-(3,4,5-trimethoxybenzoyl) piperazine. Recrystallization from ethanol gives colorless needles m.p. 149-150° C.
Reaction SMILES: [CH3:1][O:2][P:3](CC(CC(C)C)C(O)=O)([CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])=[O:4].NC1CCCCCCCCCCC(=O)N1>>[CH3:1][O:2][PH:3]([CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])=[O:4]
Reactant: COP(=O)(CC(CC(C)C)C(=O)O)CN1C(=O)c2ccccc2C1=O
Agent: NC1CCCCCCCCCCC(=O)N1
Product: CO[PH](=O)CN1C(=O)c2ccccc2C1=O

Procedure:
In an analogous manner to that described in Example 1(A)(iv), from 0.347 g of 2(RS)-[[(RS)-(methoxy)(phthalimidomethyl)phosphinyl]methyl]-4 -methylvaleric acid and 0.2 g of (-)-3-amino-2-azacyclotridecanone there was obtained 0.21 g of [(RS)-4-methyl-2-[[(R or S)-2-oxoazacyclotridecyl]carbamoyl]pentyl](phthalimidomethyl)phosphinic acid methyl ester in the form of a white solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[NH:15][NH2:16].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:19]([O:18][C:14]([NH:15][N:16]=[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=1)[CH3:10])=[O:17])[CH3:20]
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)NN=C(C)c1cccc(C(F)(F)F)c1
Yield: 99 %

Procedure:
m-Trifluoromethylacetophenone (74 g, 0.394 mole), ethyl carbazate (43 g, 0.413 mole), and catalytic p-toluenesulfonic acid (20 mg) were refluxed under N2 over a Dean-Stark trap in toluene (1.2 L) until the theoretical amount of water of reaction was removed (7.1 mL, 6 h). The solvent was then removed in vacuo and 2-(1-(3-(trifluoromethyl)phenyl)ethylidene)hydrazinecarboxylic acid ethyl ester (107 g, 100% yield) was obtained as a white solid which was recrystallized from cyclohexane, mp=94°-96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2([CH3:13])OCC[O:9]2)[CH:5]=[C:4]([Cl:14])[C:3]=1[NH:15][C:16]1[C:25]2[CH:26]=[CH:27][N:28]=[C:29]([O:30]CC)[C:24]=2[C:23]2[C:18](=[CH:19][CH:20]=[N:21][CH:22]=2)[N:17]=1.ClC1C=C(C2(C)OCCO2)C=C(Cl)C=1NC1C2C=CN=C(OC)C=2C2C(=CC=NC=2)N=1.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[C:8]([C:6]1[CH:5]=[C:4]([Cl:14])[C:3]([NH:15][C:16]2[C:25]3[CH:26]=[CH:27][NH:28][C:29](=[O:30])[C:24]=3[C:23]3[C:18](=[CH:19][CH:20]=[N:21][CH:22]=3)[N:17]=2)=[C:2]([Cl:1])[CH:7]=1)(=[O:9])[CH3:13]
Reactant: CCOc1nccc2c(Nc3c(Cl)cc(C4(C)OCCO4)cc3Cl)nc3ccncc3c12
Agent: COc1nccc2c(Nc3c(Cl)cc(C4(C)OCCO4)cc3Cl)nc3ccncc3c12
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c(Nc2nc3ccncc3c3c(=O)[nH]ccc23)c(Cl)c1
Temperature: 85 °C

Procedure:
To a solution of N-[2,6-dichloro-4-(2-methyl-1,3-dioxolan-2-yl)phenyl]-10-ethoxypyrido[4,3-c]-1,6-naphthyridin-6-amine and N-[2,6-dichloro-4-(2-methyl-1,3-dioxolan-2-yl)phenyl]-10-methoxypyrido[4,3-c]-1,6-naphthyridin-6-amine (3.0 g) in THF (30 mL) was added 6 N HCl (20 mL) and the mixture was heated to 85° C. for 3.5 hr. After cooling to room temperature, the mixture was neutralized with saturated NaHCO3 and extracted with 1:1 THF/EtOAc. The precipitate between the organic and aqueous layers were collected and determined to be pure by LCMS. The organic layer was concentrated and purified by column chromatography (100% CH2Cl2 to 30% MeOH).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O)(C)C.[NH2:15][C:16]1[CH:17]=[C:18]([C:29]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[C:40]([NH2:51])[CH:39]=2)([C:34]([F:37])([F:36])[F:35])[C:30]([F:33])([F:32])[F:31])[CH:19]=[CH:20][C:21]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(O)C.O.C(O)C.Cl>[F:31][C:30]([F:32])([F:33])[C:29]([C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10]([C:9]3[CH:12]=[CH:13][CH:14]=[C:7]([C:6]#[CH:5])[CH:8]=3)=[N:15][C:16]=2[CH:17]=1)([C:38]1[CH:43]=[CH:42][C:41]2[N:44]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:10]([C:9]3[CH:12]=[CH:13][CH:14]=[C:7]([C:6]#[CH:5])[CH:8]=3)=[N:51][C:40]=2[CH:39]=1)[C:34]([F:35])([F:36])[F:37]
Reactant: Nc1cc(C(c2ccc(Nc3ccccc3)c(N)c2)(C(F)(F)F)C(F)(F)F)ccc1Nc1ccccc1
Reactant: C[Si](C)(C)C#Cc1cccc(C=O)c1
Agent: Cl
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C#Cc1cccc(-c2nc3cc(C(c4ccc5c(c4)nc(-c4cccc(C#C)c4)n5-c4ccccc4)(C(F)(F)F)C(F)(F)F)ccc3n2-c2ccccc2)c1
Temperature: 100 °C

Procedure:
Compound VIII was synthesized from compounds (VI) and (V) as follows. A mixture of 2.00 g of sodium metabisulfite and 0.76 g (4.26 mmol) of 3-(trimethylsilylethynyl)benzaldehyde (VI) in 50 ml of 1:1 ethanol-water was deaerated with argon and heated at 75°-80° C. for 30 minutes. The yellow solution was then treated with a slurry of 1.00 g (1.94 mmol) of 2,2-bis(3-amino-4-anilinophenyl)hexafluoropropane (V) in 50 ml of ethanol. The mixture was heated at a gentle reflux (oil bath temperature about 100° C.) for 7 hours, cooled, diluted with 100 ml of 10% hydrochloric acid. The bright yellow solid was filtered, then washed with 50 ml of 10% hydrochloric acid, 50 ml of water and 50 ml of cold hexane. The powdery product (VII), after thorough drying, weighed 1.67 g (1.90 mmol, 97.8%) and showed characteristic trimethylsilylethynyl absorptions in its infrared spectrum.