Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Mg]Br.[CH2:4]([N:11]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.[CH2:18](OCC)C>O1CCCC1>[CH2:4]([N:11]1[CH2:15][CH2:14][C:13]([CH3:18])([OH:16])[CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOCC
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CC1(O)CCN(Cc2ccccc2)C1

Procedure:
Methylmagnesium bromide (4 ml of 3M solution in diethyl ether) was added dropwise to a solution of 1-benzylpyrrolidin-3-one (1.75 g) in tetrahydrofuran (50 ml) at 0° C. The mixture was stirred at 0° C. for 1 hour before water and diethyl ether were added and the layers separated. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by flash column chromatography (SiO2, 5% methanol/dichloromethane as eluent) to afford the subtitle compound as a pale brown oil (0.8 g).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:10]=1[C:11](Cl)=[O:12].[CH3:19][O:20][C:21](=[O:41])[CH:22]([NH2:40])[CH2:23][CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]([CH3:39])[C:33]2[N:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:19][O:20][C:21](=[O:41])[CH:22]([NH:40][C:11](=[O:12])[C:10]1[C:9]([F:8])=[CH:17][CH:16]=[CH:15][C:14]=1[F:18])[CH2:23]/[CH:24]=[CH:25]/[C:26]1[CH:27]=[CH:28][C:29]([N:32]([CH3:39])[C:33]2[N:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:30][CH:31]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: COC(=O)C(N)CC=Cc1ccc(N(C)c2ncccn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C/C=C/c1ccc(N(C)c2ncccn2)cc1)NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an argon atmosphere, triethylamine (0.028 ml) and 2,6-difluorobenzoyl chloride (0.015 ml) were added to a solution of 2-amino-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (31.7 mg) in dichloromethane (2 ml), and the resulting mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution and the resulting mixture was extracted with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by thin layer chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate=3/2) to obtain (E)-2-(2,6-difluorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (42 mg).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])C=C.[CH3:26][C:27]1C=CC=C[C:32]=1C>>[CH2:32]([C:6]1[C:5]([OH:4])=[C:14]([O:15][CH3:16])[CH:13]=[C:12]2[C:7]=1[C:8]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])=[N:9][CH:10]=[N:11]2)[CH:27]=[CH2:26]
Reactant: Cc1ccccc1C
Reactant: C=CCOc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OC
Product: C=CCc1c(O)c(OC)cc2ncnc(Nc3ccc(Br)cc3F)c12

Procedure:
A solution of (6-allyloxy-7-methoxy-quinazolin-4-yl)-(4-bromo-2-fluoro-phenyl)-amine (0.46 g, 1.13 mmol) (from Example 19, Step C, supra) in o-xylene (75 mL) was heated at 150° C. for 4 hours. At the end of this period, TLC analysis indicated almost complete consumption of the starting material and the formation of desired product as the major spot. The solution was concentrated to a small volume and filtered. The solid was collected and dried in vacuo to give the desired 5-allyl-4-(4-bromo-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-ol as an off white solid. (Yield 0.35 g, 76%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Cl:24])[CH3:2].[CH3:26][N:27](C=O)C>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.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.[Pd].[C-]#N.[Zn+2].[C-]#N>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:26]#[N:27])=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Cl:24])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)Cc1c(Cl)ccc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC(=O)Cc1c(Cl)ccc2cc(C#N)ccc12
Temperature: 125 °C
Reaction time: 1 h

Procedure:
(2-Chloro-6-trifluoromethanesulfonyloxy-naphthalen-1-yl)-acetic acid ethyl ester (3.59 g, 9.04 mmol) is dissolved in DMF (30 ml) under an atmosphere of argon. After addition of palladium(0) tetrakis(triphenylphosphane) (418 mg, 0.36 mmol) and zinc(II) cyanide (2.12 g, 18.09 mmol), the reaction mixture is heated to 125° C. After 1 h, TLC analysis indicates complete consumption of starting material. The suspension is cooled to RT and poured onto water. Extraction with EtOAc is followed by washing the organic layer with 1 M aqueous HCl, sat. aqueous NaHCO3 solution and brine. After drying over Na2SO4 and removal of solvent, purification by FCC (hexane/EtOAc 3:1) affords the title compound. 1H NMR (d6-DMSO, 400 MHz): δ 1.06 (t, J=8 Hz, 3H), 3.98 (q, J=8 Hz, 2H), 4.24 (s, 2H), 7.66 (d, J=10 Hz, 1H), 7.79 (d, J=10 Hz, 1H), 7.96 (d, J=10 Hz, 1H), 8.13 (d, J=10 Hz, 1H), 8.54 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[OH:26].C([O-])([O-])=O.[K+].[K+].Cl[CH:34]([CH3:38])[C:35](Cl)=[O:36]>CN(C=O)C>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:11]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[S:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:35](=[O:36])[CH:34]([CH3:38])[O:26][C:3]=3[CH:4]=2)(=[O:9])=[O:10])=[CH:19][CH:20]=1
Reactant: CC(Cl)C(=O)Cl
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(N)c(O)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OC(C)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
To a solution of 4-amino-3-hydroxy-N-(4-methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide (INTERMEDIATE AD) (2.0 g, 5.12 mmol) in DMF (15 mL) was added K2CO3 (2.1 g, 15.3 mmol, Quaigens). To the above suspension was added 2-chloropropanoyl chloride (0.780 g, 6.15 mmol) at 0° C. and reaction mixture was stirred at 25° C. for 30 min, then heated 60° C. for 3 h. The reaction mixture was cooled to 25° C. The organic compound was extracted with EtOAc, washed with water, dried over sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography using a gradient of 0-50% EtOAc in hexanes as the eluent to afford 1.45 g of N-(4-methoxybenzyl)-2-methyl-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide as off white solid in 63.6% yield. 1H-NMR (400 MHz, DMSO): δ 7.45-7.46 (m, 2H), 7.40-7.44 (m, 1H), 7.23-7.26 (m, 3H), 7.02 (d, J=8.4 Hz, 1H), 6.85 (d, J=8.8 Hz, 2H), 5.19 (s, 2H), 3.70 (s, 3H), 1.44 (t, J=6.8 Hz, 3H); m/z (ESI, positive ion) 445.9 (M+H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:20]([OH:30])(=[O:29])[C@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[OH:22]>C(OCC)C.C1(C)C(C)=CC=CC=1>[C:20]([OH:30])(=[O:29])[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[OH:22].[CH3:1][NH:2][CH2:3][CH2:4][CH:5]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)[C@@H](O)c1ccccc1
Agent: CNCCC(Oc1ccccc1C)c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: O=C(O)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 33.69 g (0.132 mol) of (+-)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine dissolved in 50 ml of diethyl ether was added a solution of 9.89 g (0.067 mol) of L-(+)-mandelic acid in 20 ml of warm xylene. The resulting mixture was refluxed gently for about 5 minutes and an additional 30 ml of diethyl ether was added thereto. The mixture was stirred at room temperature overnight and the resulting slurry was chilled in an ice bath. The mixture was filtered and the resulting solid was rinsed with 50 ml of diethyl ether. The solid was dissolved in 25 ml of methylene chloride and 50 ml of ethyl acetate and the resulting mixture was heated to reflux. The methylene chloride was removed by vacuum and 50 ml of diethyl ether was added to the residue. The mixture was seeded with a crystal of desired product and the resulting mixture was stirred for 2 hours while being chilled in an ice bath. The precipitated solid was collected by filtration and rinsed with 30 ml of a 1:1 (v:v) ethyl acetate/diethyl ether solvent solution. The resulting solid was dried overnight at 55° C. in a vacuum oven to provide 15.7 g of (-)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine mandelic acid as an off white solid. mp =119°-122° C. The resulting solid was recrystallized with 50 ml of methanol employing 3 g of decolorizing carbon. The resulting mixture was filtered through Celite and the filtrate was concentrated under vacuum to provide a white solid. This solid was dissolved in 50 ml of ethyl acetate with heating and the solution was allowed to cool. An additional 50 ml of diethyl ether was added and the precipitated solid was collected by filtration and rinsed with 50 ml of 1:1 (v:v) ethyl acetate/diethyl ether. The solid was dried in a vacuum oven at 50° C. for 1 hour to provide 13.2 g of (-)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine mandelic acid. mp=122°-123° C. Yield 49%.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH:15]=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[C:17]([C:20]1[C:21]2[C:26]([CH:27]=[C:28]3[C:33]=1[CH:32]=[CH:31][CH:30]=[CH:29]3)=[CH:25][CH:24]=[CH:23][CH:22]=2)(=O)[CH3:18].CO[Na].CO>CN(C=O)C>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[C:15](=[O:16])[CH:18]=[CH:17][C:20]2[C:33]4[C:28]([CH:27]=[C:26]5[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]5)=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)c1c2ccccc2cc2ccccc12
Reactant: O=Cc1c2ccccc2cc2ccccc12
Agent: CO[Na]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(C=Cc1c2ccccc2cc2ccccc12)c1c2ccccc2cc2ccccc12
Reaction time: 8 h
Yield: 91.3 %

Procedure:
9-anthraldehyde (10 mmol, 2.06 g) and 9-acetylanthracene (10 mmol, 2.2 g) were combined in dry DMF under N2 and MeONa (28 mmol, 1.5 g) was added. The reaction mixture is stirred overnight. Then MeOH was added (60 mL) and the precipitate was filtered off and vacuum dried to afford 3.73 g of pure 1,3-di(anthracene-9-yl)-2-propene-1-one. Portion of it (2.5 mmol, 1 g) was suspended in a mixture of dioxane and MeOH (60 mL and 20 mL respectively) and heated to 75° C. at which point sodium borohydride (5.3 mmol, 200 mg) was added. The mixture was stirred for 5 min and 50 mL of water was added. After the mixture had cooled to ambient, the solids were filtered off, washed with water and vacuum dried affording 620 mg of the title product.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1)(=[O:19])=[O:18].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N:61]1[CH:66]=[CH:65][CH:64]=[C:63]([CH2:67][NH2:68])[CH:62]=1>CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:68][CH2:67][C:63]3[CH:62]=[N:61][CH:66]=[CH:65][CH:64]=3)=[O:13])=[CH:14][CH:15]=2)=[N:4][C:3]=1[CH2:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)=[CH:22][CH:21]=1)(=[O:18])=[O:19]
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(CN2CCOCC2)cc1
Reactant: NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(CN2CCOCC2)cc1
Yield: 68.4 %

Procedure:
To a solution of 4-(5-methyl-4-((4-(morpholinomethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoic acid (490 mg, 1.07 mmol, 1.00 equiv), EDCI (250 mg, 1.31 mmol, 1.22 equiv), HOBt (180 mg, 1.33 mmol, 1.24 equiv), triethylamine (330 mg, 3.27 mmol, 3.04 equiv) and pyridin-3-ylmethanamine (330 mg, 3.06 mmol, 2.84 equiv) in N,N-dimethylformamide (20 mL) was stirred overnight at room temperature. The product was precipitated by the addition of 60 mL ice/water. The solid was collected by filtration and washed with water (1×20 mL) and dried in an oven under reduced pressure to give 0.40 g (68%) of 4-(5-methyl-4-((4-(morpholinomethyl)phenylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide as a white solid. LC-MS: (ES, m/z): 547 [M+H]+. 1HNMR (400 MHz, DMSO-d6, ppm) δ 9.22 (s, 1H), 8.57 (s, 1H), 8.46 (s, 1H), 7.98 (d, J=7.6Hz, 2H), 7.86 (d, J=7.6Hz, 2H), 7.74-7.72 (m, 3H), 7.53 (d, J=7.6Hz, 2H), 7.36 (s, 1H), 4.67 (s, 2H), 4.51 (d, J=4.0Hz, 2H), 3.55 (s, 6H), 2.32 (s, 4H), 2.15 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:26])[C:11](=[O:25])[C:12]([CH3:24])=[CH:13][C:14]=2[C:15]([NH:17][O:18][CH2:19][CH2:20][O:21]C=C)=[O:16])=[C:4]([F:27])[CH:3]=1.Cl.[OH-].[Na+]>C(O)C.CCOC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:26])[C:11](=[O:25])[C:12]([CH3:24])=[CH:13][C:14]=2[C:15]([NH:17][O:18][CH2:19][CH2:20][OH:21])=[O:16])=[C:4]([F:27])[CH:3]=1
Reactant: C=COCCONC(=O)c1cc(C)c(=O)n(C)c1Nc1ccc(Br)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)NOCCO)c(Nc2ccc(Br)cc2F)n(C)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.6 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridine-3-carboxamide (0.067 g, 0.150 mmol) in ethanol (2 mL) was added aqueous 2 M HCl (0.380 mL, 0.760 mmol). The reaction mixture was stirred for 16 hours at room temperature. The pH of the reaction mixture was adjusted with 1 M NaOH. The reaction mixture was diluted with EtOAc and H2O. The organic layer was separated and washed with saturated NaCl. The combined aqueous layers were back extracted with EtOAc (1×). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to yield 0.060 g (94%) pure desired product as an off-white crystalline solid. MS ESI (+) m/z 414, 416 (M+, Br pattern detected); 1H NMR (400 MHz, CDCl3) δ 9.80 (s, 1H), 8.44 (s, 1H), 7.31 (d, 1H), 7.19 (d, 1H), 6.59 (t, 1H), 4.05 (m, 2H), 3.85 (m, 1H), 3.75 (m, 2H), 3.29 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[Br-].[Na+].BrBr.[F:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12].C(=O)([O-])[O-].[Na+].[Na+]>O.CO>[F:9][C:10]1[CH:16]=[C:15]([S:1][C:2]#[N:3])[CH:14]=[CH:13][C:11]=1[NH2:12]
Reactant: Nc1ccccc1F
Reactant: N#C[S-]
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CO
Solvent: O
Product: N#CSc1ccc(N)c(F)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a mixed liquid of 210.9 g of sodium thiocyanate and 200.9 g of methanol was dropped a solution composed of 60.2 g of sodium bromide, 166.6 g of methanol and 163.7 g of bromine over 90 minutes while internal temperature was controlled at −10 to −6° C. To the mixed liquid was dropped 100.0 g of 2-fluoroaniline over 50 minutes while internal temperature was controlled at −10 to −5° C. The resulting mixture was stirred at the same temperature for 3 hours and then was poured into 784 g of water cooled to 0° C. The resulting mixture was neutralized with sodium carbonate and then was extracted twice with 196 g of chloroform. The organic layer was dried over magnesium sulfate and then concentrated, so that 151.9 g of 2-fluoro-4-thiocyanoaniline (Compound S-4) was obtained.
Reaction SMILES: [NH2:1][CH:2]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[OH:19][C:20]1[C:25]([C:26](O)=[O:27])=[CH:24][N:23]=[C:22]([N:29]2[CH:33]=[CH:32][CH:31]=[N:30]2)[N:21]=1.OC1C(C(NC(C2C=CC=CC=2)C2C=CC(P(=O)(OCC)OCC)=CC=2)=O)=CN=C(N2C=CC=N2)N=1>>[OH:19][C:20]1[C:25]([C:26]([NH:1][CH:2]([P:11](=[O:18])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17])[C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=2)=[O:27])=[CH:24][N:23]=[C:22]([N:29]2[CH:33]=[CH:32][CH:31]=[N:30]2)[N:21]=1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Reactant: CCOP(=O)(OCC)C(N)c1ccc(OC)cc1
Agent: CCOP(=O)(OCC)c1ccc(C(NC(=O)c2cnc(-n3cccn3)nc2O)c2ccccc2)cc1
Product: CCOP(=O)(OCC)C(NC(=O)c1cnc(-n2cccn2)nc1O)c1ccc(OC)cc1

Procedure:
Compound 10-1 was prepared from compound 10-b and compound 8-b in a similar manner as the synthesis of compound 8-1. 1H NMR (300 MHz, DMSO-d6) δ1.09-1.20 (m, 6H), 3.73 (s, 3H), 3.84-4.04 (m, 4H), 5.44-5.54 (m, 1H), 6.71-6.73 (m, 1H), 6.92-6.94 (m, 2H), 7.30-7.33 (m, 2H), 8.06 (s, 1H), 8.41 (brs, 1H), 8.60-8.61 (m, 1H). LC-MS: (M+H)+ 462.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH2:10])=[C:8]([C:11]([NH2:13])=[O:12])[C:7]([CH3:14])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH2:21][C:22](OCC)=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O(C)[Na].C(O)C>C(O)(=O)C.O>[C:1]([N:5]1[C:9]2=[N:10][C:22]([CH2:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][C:11](=[O:12])[C:8]2=[C:7]([CH3:14])[NH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: Cc1nn(C(C)(C)C)c(N)c1C(N)=O
Agent: CO[Na]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]n(C(C)(C)C)c2nc(Cc3ccccc3)nc(=O)c1-2
Yield: 35.1 %

Procedure:
A mixture of 1-tert-butyl-3-methyl-5-amino-1H-pyrazole-4-carboxamide (1.0 g, 5.1 mmol), ethyl phenylacetate (1.67 g, 10.2 mmol), NaOCH3 (1.74 g, 31 mmol) and ethanol (50 mL) was refluxed for about 3 days. The reaction mixture was stripped to dryness and then the residue was treated with water and then acidified with acetic acid. The product was collected by filtration, washed with water and dried to afford 0.53 g (35%) of 1-tert-butyl-3-methyl-6-(phenylmethyl)pyrazolo[3,4-d]pyrimidin-4-one 1/5 hydrate, m.p. 196-197° C.
Reaction SMILES: B(Br)(Br)Br.O1C2C=CC=CC=2C=N1.[CH2:14]([O:16][C:17]1[C:21]2[CH:22]=[CH:23][C:24]([O:26]C)=[CH:25][C:20]=2[O:19][N:18]=1)[CH3:15].C([O-])(O)=O.[Na+].[Na+].[Cl-]>ClCCl.O.CCCCCC.C(OCC)(=O)C>[CH2:14]([O:16][C:17]1[C:21]2[CH:22]=[CH:23][C:24]([OH:26])=[CH:25][C:20]=2[O:19][N:18]=1)[CH3:15]
Reactant: CCOc1noc2cc(OC)ccc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOc1noc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Boron tribromide (1.0M solution in dichloromethane; 1.39 ml, 1.39 mmol) was added to a stirred, −78° cooled solution of benzisoxazole from part (c) (179 mg, 928 μmol) in dichloromethane (4 ml) under an argon atmosphere. The reaction mixture was gradually warmed to room temperature over approx. 2 hours, and stirred overnight. Tlc (silica, 2:1 hexane/ethyl acetate) showed new polar material as well as unreacted starting material. The reaction was worked up by adding water (5 ml) and ice. The aqueous phase was neutralized by addition of saturated NaHCO3 solution, and saturated with NaCl. The aqueous phase was extracted into dichloromethane (3×60 ml), then the organic extracts combined and washed with brine (10 ml) and dried (NaSO4). The product was purified by chromatography on silica (18 g; eluent 2.5%, 5%, then 15% ethyl acetate/hexane). The first compound to elute was unreacted 3-ethoxy-6-methoxy-1,2-benzisoxazole, (46 mg), followed by 3-ethoxy-6-hydroxy-1,2-benzisoxazole 108 mg (65%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]([F:19])([F:18])[C:10](=O)[CH2:11][C:12](OCC)=[O:13]>>[OH:13][C:12]1[CH:11]=[C:10]([C:9]([F:19])([F:18])[F:8])[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Product: Oc1cc(C(F)(F)F)c2ccccc2n1

Procedure:
Aniline (ex Aldrich) and ethyl trifluoroacetoacetate (ex Lancaster) were reacted together according to Westland et al, J. Med. Chem., 16, 326 (1973), to give 2-hydroxy-4-trifluoromethylquinoline. The latter (2.5 g), was treated for 30 minutes at 90°-100° C. with phosphorous oxychloride (20 ml) and resublimed phosphorous pentachloride (2.45 g). The reaction mixture was allowed to cool and poured onto ice-water and neutralised with aqueous ammonium hydroxide. Extraction into diethyl ether yielded 2-chloro-4-trifluoromethyl quinoline, which after conventional work-up was used directly in Stage a.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[OH:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:18]2[C:19]([O:21][C:22](=O)[C:17]=12)=[O:20]>>[OH:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:18]2[C:17]=1[C:22](=[O:21])[N:1]([CH2:2][CH:3]([C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:19]2=[O:20]
Reactant: CCOC(=O)C(CN)C1(C)OCCO1
Reactant: O=C1OC(=O)c2c(O)cccc21
Product: CCOC(=O)C(CN1C(=O)c2cccc(O)c2C1=O)C1(C)OCCO1

Procedure:
Ethyl 3-(4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.46 g, 67%) in the same manner as described in the above example 5 (20) from ethyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.40 g, 1.96 mmol) and 3-hydroxyphthalic anhydride (0.42 g, 2.16 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])[N:6]=[N:5][C:4]=1[CH:16]([CH3:18])[CH3:17].[CH3:19][O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:30]=2[CH3:36])=[CH:25][CH:24]=1)=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:19][O:20][C:21]([C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:2][C:3]3[N:7]([C:8]4[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=4[Cl:15])[N:6]=[N:5][C:4]=3[CH:16]([CH3:18])[CH3:17])=[CH:31][C:30]=2[CH3:36])=[CH:27][CH:28]=1)=[O:22]
Reactant: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1CCl
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2C)cc1
Temperature: 55 °C

Procedure:
To a solution of 5-chloromethyl-1-(2,6-dichloro-phenyl)-4-isopropyl-1H-[1,2,3]triazole (0.1 g, 0.328 mmol) in dimethylformamide (3 mL) is added 4′-hydroxy-2′methyl-biphenyl-4-carboxylic acid methyl ester (0.079 g, 0.326 mmol) and cesium carbonate (0.21 g, 0.646 mmol). The reaction is heated to 55° C. for 2.5 h and is cooled to room temperature. The reaction mixture is concentrated under reduced pressure. The residue is dissolved in 1N hydrochloric acid and ethyl acetate. The layers are separated and the aqueous is extracted again with ethyl acetate. The organic layers are combined and are washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 4′-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2′-methyl-biphenyl-4-carboxylic acid methyl ester. ES/MS m/e (35Cl/37Cl) 510.2/512.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.[C:14](Cl)(Cl)=[S:15]>ClCCCl.C(Cl)Cl.O>[N:1]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:11])([F:13])[F:12])[N:3]=1)=[C:14]=[S:15]
Reactant: S=C(Cl)Cl
Reactant: N#Cc1ccc(N)nc1C(F)(F)F
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(N=C=S)nc1C(F)(F)F
Temperature: 80 °C
Yield: 65 %

Procedure:
A mixture of 6-amino-2-(trifluoromethyl)nicotinonitrile (648 mg, 3.5 mmol) and thiophosgene (0.4 mL, 5.2 mmol) in DCE (8 mL) was heated to 80° C. overnight. The mixture was cooled to room temperature and diluted with DCM/water. The two layers were separated and the aqueous layer was extracted with DCM (3×). The organics were combined, washed with a saturated solution of sodium bicarbonate (2×), dried over sodium sulfate, and evaporated to dryness to afford 521 mg of 6-isothiocyanato-2-(trifluoromethyl)nicotinonitrile (70% pure) as a brown oil. 1H NMR (300 MHz, DMSO-d6) δ 8.73 (d, 1H), 7.93 (d, 1H).