Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](O)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.FC(F)(F)S(OC1C=CC(F)=CC=1[N+]([O-])=O)(=O)=O.[CH3:30][O:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35]2.C(O)CCO.S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)C.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:37]2[CH2:36][CH2:35][C:34]3[C:39](=[CH:40][CH:41]=[C:32]([O:31][CH3:30])[CH:33]=3)[CH2:38]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: COc1ccc2cc(B(O)O)ccc2c1
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Agent: O=S(=O)([O-])[O-]
Agent: O=[N+]([O-])c1cc(F)ccc1OS(=O)(=O)C(F)(F)F
Agent: [Mg+2]
Solvent: OCCCO
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(c1ccc(F)cc1[N+](=O)[O-])C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
Synthesized from 4-fluoro-2-nitrophenol (3.0 g) according to an analogous synthetic method to Preparation Example 80 described below, 4-fluoro-2-nitrophenyl trifluoromethanesulfonate (5.5 g) was obtained. To a suspension of (6-methoxynaphthalen-2-yl)boronic acid (2.5 g) in diethyl ether (60 ml) was added 1,3-propanediol (0.9 ml), and the solution was stirred for 2 hours at room temperature. Tetrahydrofuran and anhydrous magnesium sulfate were sequentially added thereto, the solution was stirred, then filtered, and the filtrate was concentrated in vacuo. To a solution of the resulting 2-(6-methoxynaphthalen-2-yl)-[1,3,2]dioxaborinane (3.1 and 4-fluoro-2-nitrophenyl trifluoromethanesulfonate (2.8 g) in N,N-dimethylformamide (50 ml) were added tetrakis(triphenylphosphine)palladium(0) (350 mg) and cesium carbonate (6.0 g), and the solution was stirred for 2 hours at 100° C. under a nitrogen atmosphere. Ethyl acetate and tetrahydrofuran were sequentially added thereto, the solution was stirred, then insoluble material was removed by filtration, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo, the resulting solid was washed with a hexane-diethyl ether system to provide 2-(4-fluoro-2-nitrophenyl)-6-methoxy-1,2,3,4-tetrahydronaphthalene (2.4 g). The total amount of this compound was used according to an analogous synthetic method to Example 22 to provide the title compound (1.6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[N:12][N:11]=1.C(O)(CC)C>C(OCC)C>[ClH:9].[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=3)=[N:11][N:12]=2)=[CH:25][CH:24]=1
Reactant: Nc1ccc(O)cc1
Reactant: COc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Solvent: CCOCC
Solvent: CCC(C)O
Product: COc1ccc(-c2nnc(Nc3ccc(O)cc3)c3ccccc23)cc1
Product: Cl
Temperature: 100 °C
Yield: 99.4 %

Procedure:
4-Aminophenol (340 mg, 3.1 mmol), 1-chloro-4-(4-methoxyphenyl)phthalazine (837 mg, 3.1 mmol), and sec-butanol (12 mL, 3.1 mmol) were combined in a resealable tube and heated to 100° C. overnight. The reaction progress was monitored by LCMS, and upon completion, the orange reaction was cooled diluted with diethyl ether. The resulting precipitate was filtered and washed with diethyl ether, and the solid was dried in vacuo to provide 4-(4-(4-methoxyphenyl)phthalazin-1-ylamino)phenol hydrochloride (1.17 g, 100% yield) as an orange solid. MS [M+H]=344.0. Calc'd for C19H21N5O: 343.13.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([OH:22])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn].O>[O:22]=[C:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[C:10]2[CH:11]=[C:12]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[NH:1]1
Reactant: CCO
Reactant: O=C(O)Cc1cccc(-c2cccc3[nH]ccc23)c1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1cccc(-c2cccc3c2CC(=O)N3)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To the suspension of [3-(1H-indol-4-yl)-phenyl]-acetic acid (3.52 g, 14 mmol) in t-BuOH:ethanol:acetic acid (93 mL:56 mL:67 mL) was added pyridinium tribromide (14.14 g, 42 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added acetic acid (60 mL). Water (2 mL) and zinc dust (14 g, excess) were added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (3×), sat. NaHCO3, brine, dried over Na2SO4 and concentrated to give 2.59 g (70%) of [3-(2-oxo-2,3-dihydro-1H-indol-4-yl)-phenyl]-acetic acid.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][C:21]1[N:30]=[CH:29][C:28]2[CH:27]([NH2:31])[CH2:26][CH2:25][CH2:24][C:23]=2[N:22]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O.CCOC(C)=O.CO>C1COCC1.CO>[NH2:31][CH:27]1[CH2:26][CH2:25][CH2:24][C:23]2[N:22]=[C:21]([CH2:20][CH2:19][OH:18])[N:30]=[CH:29][C:28]1=2
Reactant: CC(C)(C)[Si](OCCc1ncc2c(n1)CCCC2N)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: NC1CCCc2nc(CCO)ncc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5,6,7,8-tetrahydroquinazolin-5-amine (570 mg, 1.32 mmol) in 10 mL of THF at 0° C. was treated with a 1M TBAF solution in THF (1.56 mL, 1.56 mmol). After stirring at room temperature overnight, the reaction mixture was directly submitted to flash chomatograph (SiO2, EtOAc to EtOAc/MeOH=100:15 to EtOAc/2M NH3 in MeOH=1:1) to give crude product as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[N:6][C:5]([C:13]#[N:14])=[C:4]([C:15]#[N:16])[N:3]=1.[NH3:17].O.Cl>CN(C)C=O>[NH2:17][C:2]1[C:7]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[N:6][C:5]([C:13]#[N:14])=[C:4]([C:15]#[N:16])[N:3]=1
Reactant: CC(C)(C)Nc1nc(C#N)c(C#N)nc1Cl
Reactant: N
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)Nc1nc(C#N)c(C#N)nc1N
Temperature: 25 °C
Yield: 69.4 %

Procedure:
2.0 g (0.008 mol) of 2-chloro-3-tert-butylamino-5,6-dicyanopyrazine was dissolved in 100 ml of dry N,N-dimethylformamide, and ammonia gas was blown into it under stirring at room temperature. Two hours later, the reaction solution was poured into 1 liter of water and neutralized with hydrochloric acid. The precipitated solid was collected by filtration and recrystallized from isobutyl alcohol to obtain 1.2 g of slightly yellow crystals (yield: 69.4%, melting point: at least 250° C.).
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8](O)=[O:9])=[O:4].Cl.[NH:38]1[CH2:41][CH:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:23]=3[C:33]([F:34])([F:35])[F:36])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([N:38]1[CH2:41][CH:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]1)=[O:9])=[O:4]
Reactant: COC(=O)C1CNC1
Reactant: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)C1CN(C(=O)CCNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Reaction time: 1 h
Yield: 40 %

Procedure:
(R/S)-3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Int-V, 25 mg, 0.050 mmol), methyl azetidine-3-carboxylate-HCl (7.54 mg, 0.050 mmol), 4-methylmorpholine (20.13 mg, 0.199 mmol), and HATU (24.60 mg, 0.065 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-methyl 1-(3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoyl)azetidine-3-carboxylate (11.9 mg, 0.020 mmol, 39.9% yield): LCMS=600.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.14-8.26 (2 H, m), 7.54-7.77 (7 H, m), 5.12 (1 H, s), 4.00-4.34 (4 H, m), 3.73 (3 H, d, J=5.27 Hz), 3.39-3.56 (3 H, m), 2.36 (2 H, q, J=6.44 Hz); HPLC peak RT=2.5 min (Method E).
Reaction SMILES: CO.[H-].[Na+].[F:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.C[O:15][C:16](=[O:24])[CH:17]([CH3:23])[CH2:18][C:19]([O:21][CH3:22])=[O:20]>C1(C)C=CC=CC=1>[CH3:22][O:21][C:19](=[O:20])[C:18](=[CH:10][C:9]1[CH:12]=[CH:13][C:6]([F:5])=[CH:7][CH:8]=1)[CH:17]([CH3:23])[C:16]([OH:24])=[O:15]
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)CC(C)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C(=Cc1ccc(F)cc1)C(C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.7 %

Procedure:
After careful addition of absolute methanol (0.1 mL) to a suspension of sodium hydride (60% in mineral oil, 20 g, 0.5 mol) in anhydrous toluene (200 mL), a solution of 4-fluoro-benzaldehyde (31 g, 0.25 mol) and 2-methyl-succinic acid dimethyl ester (60 g, 0.38 mol) in anhydrous toluene (100 mL) was added at room temperature under a stream of nitrogen. The resulting mixture was stirred at room temperature for 30 minutes and then quenched by the slow addition of water (20 mL). The mixture was acidified by the addition of concentrated hydrochloric acid, and extracted with ethyl acetate (200 mL×3). The combined organic layers were dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (elution with 30% ethyl acetate in petroleum ether) to afford 2-(4-fluoro-benzylidene)-3-methyl-succinic acid 1-methyl ester (20 g, 33%) as a white solid. 1H NMR (400 MHz, acetone-d6) δ ppm 7.77 (s, 1H), 7.54 (d, J=8.8 Hz, 2H), 7.25 (d, J=8.8 Hz, 2H), 3.82 (q, 7.2 Hz, 1H), 1.40 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([C:8]1[C:13]2[CH2:14][O:15][CH2:16][C:12]=2[C:11]([OH:17])=[C:10]([CH3:18])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[H-].[Na+].[H][H].[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][Cl:28]>CS(C)=O>[ClH:28].[ClH:28].[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][O:17][C:11]1[C:12]2[CH2:16][O:15][CH2:14][C:13]=2[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9][C:10]=1[CH3:18]
Reactant: CN(C)CCCl
Reactant: [H][H]
Reactant: Cc1nc(Cc2ccccc2)c2c(c1O)COC2
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CS(C)=O
Product: Cc1nc(Cc2ccccc2)c2c(c1OCCN(C)C)COC2
Product: Cl
Reaction time: 15 h

Procedure:
12.1 g (50 millimoles) of 4-benzyl-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-ol are suspended in 40 ml of dry dimethylsulfoxide and converted to the sodium salt by adding 1.75 g (60 millimoles) of sodium hydride (85% strength) in oil at 20° C. When the evolution of hydrogen has ceased, 8.1 g (75 millimoles) of freshly distilled β-dimethylaminoethyl chloride are added dropwise and the mixture is left to stand for 15 hours at 10° C. The dimethylsulfoxide is distilled off in a high vacuum. The residue is taken up in methylene chloride, the salts and unconverted pyridinol are washed out with dilute sodium hydroxide solution and the methylene chloride phase is dried and concentrated under reduced pressure. The residue is converted to the hydrochloride by means of dilute hydrochloric acid and the hydrochloride is recrystallized from a mixture of ethanol and ether. 10.0 g of 4-benzyl-6-methyl-1,3-dihydro-furo[3,4-c]pyridin-7-yl β-dimethylaminoethyl ether bis-hydrochloride, melting point 213° -214° C., are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[NH:18][CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4.C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].[Na+].[Cl-]>ClCCl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:27]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4
Reactant: Oc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(O)cc13
Reaction time: 2 h
Yield: 52.1 %

Procedure:
To a stirred solution of 3-hydroxymorphinan (20 mg, 0.061 mmol) and triethylamine (26 μL, 0.183 mmol) in dry Dichloromethane (0.3 mL) was added benzyl chloroformate (10.5 μL, 0.073 mmol) at 0° C. The mixture was stirred for 2 h, and to the mixture was added sat aq NaCl solution (2 mL) and the mixture was extracted with EtOAc (3 mL×3). The combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated, after column chromatography of the crude product gave 12 mg (51%) of title compound: 1H NMR (300 MHz, CDCl3) δ7.3˜7.5 (5H, m) 6.9 (1H, t); 6.8 (1H, d); 6.6 (1H, t); 5.1 (2H, s); 4.3 (1H, dd); 3.9 (1H, m); 3.1 (1H, m); 2.7 (2H, m); 2.3 (1H, d); 1.0˜1.8 (10H, m).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([F:31])[C:29]=1[F:30])[C:24]([OH:26])=O.CCN=C=NCCCN(C)C.Cl.Cl.[C:45]1([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:50]=[CH:49][C:48]([NH:51][C:52](=[O:62])[CH2:53][C:54](=[O:61])[N:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)=[CH:47][CH:46]=1>CN(C=O)C.O>[C:45]1([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:46]=[CH:47][C:48]([NH:51][C:52](=[O:62])[CH2:53][C:54](=[O:61])[N:55]2[CH2:56][CH2:57][N:58]([C:24](=[O:26])[C:23]3[CH:27]=[C:28]([F:31])[C:29]([F:30])=[C:21]([F:20])[CH:22]=3)[CH2:59][CH2:60]2)=[CH:49][CH:50]=1
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Reactant: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC(=O)N1CCN(C(=O)c2cc(F)c(F)c(F)c2)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
HOBt (34 mg, 0.25 mmol) and DIPEA (67.9 mg, 0.51 mmol) were added to a stirred solution of 3,4,5-trifluorobenzoic acid (37 mg, 0.21 mmol) in DMF (2 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (48 mg, 0.25 mmol) followed by N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide hydrochloride (75 mg, 0.2 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water. The resulting precipitate was filtered and purified by column chromatography using silica gel 60-120 mesh (40% ethyl acetate in hexane) to afford 42 mg (42%) of N-Biphenyl-4-yl-3-oxo-3-[4-(3,4,5-trifluoro-benzoyl)-piperazin-1-yl]-propionamide. LCMS: 482.16 (M+1)+ 94.2%, 1H NMR: (CDCl3): δ 9.5 (s, 1H), 7.58 (m, 6H), 7.43 (t, 2H), 7.34 (m, 1H), 7.08 (t, 2H), 3.7 (bs, 8H), 3.54 (s, 2H).
Reaction SMILES: [P:1]([O-:5])([O-:4])([O-:3])=[O:2].[F:6][C:7]1[C:12]([F:13])=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:8]=1[C:18]1[N:19]=[C:20]([NH:23][C:24](=[O:39])[CH2:25][C:26]2[C:34]3[C:33](=[O:35])[N:32]([CH3:36])[C:31](=[O:37])[N:30]([CH3:38])[C:29]=3[S:28][N:27]=2)[S:21][CH:22]=1.[CH3:40]C(C)([O-])C.[Na+]>C1COCC1.CCCCCC>[P:1]([OH:5])([OH:4])([O:3][CH2:40][N:19]1[C:18]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:16])([F:15])[F:17])=[C:12]([F:13])[C:7]=2[F:6])=[CH:22][S:21][C:20]1=[N:23][C:24](=[O:39])[CH2:25][C:26]1[C:34]2[C:33](=[O:35])[N:32]([CH3:36])[C:31](=[O:37])[N:30]([CH3:38])[C:29]=2[S:28][N:27]=1)=[O:2]
Reactant: CC(C)(C)[O-]
Reactant: Cn1c(=O)c2c(CC(=O)Nc3nc(-c4ccc(C(F)(F)F)c(F)c4F)cs3)nsc2n(C)c1=O
Reactant: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1c(=O)c2c(CC(=O)N=c3scc(-c4ccc(C(F)(F)F)c(F)c4F)n3COP(=O)(O)O)nsc2n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure as described in step 1 of method B for the preparation of phosphate derivatives by the reaction of N-{4-[2,3-difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[1,2]thiazolo[5,4-d]pyrimidin-3-yl)acetamide (1.95 g, 3.771 mmol) with sodium-tert-butoxide (0.362 g, 3.771 mmol) in dry THF (12 ml) and hexane (40 ml) to yield 2.00 g of product as an off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 3.22 (s, 3H), 3.48 (s, 3H), 3.98 (s, 2H), 7.25 (s, 1H), 7.59 (t, J=8.1 Hz, 1H), 8.03 (t, t, J=7.2 Hz, 1H).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1.[C:18]1(=O)[CH2:21][CH2:20][CH2:19]1>O1CCOCC1>[C:5]([C:18]1([NH:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:12][CH:13]=2)[CH2:21][CH2:20][CH2:19]1)#[N:6]
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=C1CCC1
Reactant: C[Si](C)(C)C#N
Solvent: C1COCCO1
Product: N#CC1(Nc2ccc(CC(=O)O)cc2)CCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
Trimethylsilyl cyanide (0.69 g, 7 mmol) was added dropwise to a mixture of 4-aminophenylacetic acid (0.755 g, 5 mmol) and cyclobutanone (0.49 g, 7 mmol) in dioxane (20 ml). The mixture was stirred for 8 hours at 80° C. The mixture was concentrated and chromatographed (dichloromethane:acetone, 60:40) to yield [4-(1-cyanocyclobutylamino)phenyl]acetic acid (46a) (1.138 g, 4.95 mmol, 99%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[C:16]([CH3:17])=[C:15]([CH3:18])[N:14]([CH3:19])[C:13]=1[C:20]([O-:22])=[O:21].[K+:23].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH3:19][N:14]1[C:15]([CH3:18])=[C:16]([CH3:17])[C:12]([NH:11][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[C:13]1[C:20]([O-:22])=[O:21].[K+:23]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: Cc1c(N)c(C(=O)[O-])n(C)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1c(Nc2ccccc2[N+](=O)[O-])c(C(=O)[O-])n(C)c1C
Reaction time: 12 h

Procedure:
38 g of 1-chloro-2-nitrobenzene, 38.8 g of potassium 3-amino-1,4,5-trimethyl-1H-pyrrole-2-carboxylate (crude product from Example 2) and 36 g of ground potassium carbonate (particle size: 0.07 mm) are stirred in 120 ml of 1-methyl-2-pyrrolidone under nitrogen at an internal temperature of 140° C. After 12 hours, a further 3.3 g of 1-chloro-2-nitrobenzene are added. For working up, the mixture is filtered hot, and the residue on the filter is rinsed 3 times with 10 ml of hot (100° C.) 1-methyl-2-pyrrolidone each time. The combined filtrates are further processed without purification.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[C:7]([C:9](O)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([CH:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH2:20]2)=[O:18])=[CH:12][CH:11]=1)#[N:8].CCOCC>C1COCC1>[ClH:2].[Cl:2][C:9]([C:7]#[N:8])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([CH:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH2:20]2)=[O:18])=[CH:12][CH:11]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: N#CC(O)(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cl
Product: N#CC(Cl)(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Yield: 117.7 %

Procedure:
) PCl5 (0.027 mol) was added to a solution of (±)-N-[4-(cyanohydroxyphenylmethyl) phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide (0.023 mol) in THF (50 ml). The reaction mixture was stirred and refluxed for 2 hours. Et2O was added and the precipitate was filtered off and dried, yielding 7.2 g (80%) of (±)-N-[4-(chlorocyanophenylmethyl)phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide monohydrochloride (compound 496).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH:12](OCC)=[O:13]>>[CH:12]([NH:1][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)=[O:13]
Reactant: NCc1nc2ccccc2o1
Reactant: CCOC=O
Product: O=CNCc1nc2ccccc2o1

Procedure:
A mixture of 4.29 g (28.9 mmol) of 2-(aminomethyl)benzoxazole (PREPARATION 6) and 20 ml of ethyl formate is heated at 80° for 2 hr, after which the excess ethyl formate is removed under reduced pressure. The residue is chromatographed on silica gel (350 ml) eluting with methanol/dichloromethane (2/98), the appropriate fractions are pooled and concentrated to give the product, which is crystallized from dichloromethane/hexane to give the title compound, mp 98°-99°; MS (m/z) at 176; IR 1655, 1621, 1519, 1241, 750 cm-1 ; NMR (CDCl3) 4.81, 6.45, 7.36, 7.53, 7.70, 8.39 δ.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[NH:7][CH:8]=[CH:9][C:2]=12.[C:10]([O:14][C:15](=[O:34])[N:16]([C:26]1[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][N:27]=1)[CH2:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)([CH3:13])([CH3:12])[CH3:11].[OH-].[K+]>CO>[C:10]([O:14][C:15](=[O:34])[N:16]([C:26]1[CH:31]=[CH:30][C:29]([CH:32]([OH:33])[C:9]2[C:2]3[C:3](=[N:4][CH:5]=[CH:6][N:1]=3)[NH:7][CH:8]=2)=[CH:28][N:27]=1)[CH2:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: c1cnc2[nH]ccc2n1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C=O)cn2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(O)c3c[nH]c4nccnc34)cn2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
To 5H-Pyrrolo[2,3-b]pyrazine (3, 0.150 g, 1.26 mmol) in 2.2 mL of methanol, (5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (6, 0.52 g, 1.5 mmol) and potassium hydroxide (0.230 g, 4.10 mmol) were added. The reaction was allowed to stir at room temperature overnight, then concentrated and poured into saturated sodium bicarbonate, and extracted with ethyl acetate. The organic portion was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum and purified by silica gel chromatography to provide the desired compound (7, 0.22 g, 38%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1c[nH]c2cc(O)ccc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1c[nH]c2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-hydroxy-1H-indole-3-carboxylic acid (1.05 g) in N,N-dimethylformamide (11.0 mL) were added sodium carbonate (722 mg) and benzyl bromide (0.775 mL), followed by stirring at room temperature overnight. To the reaction suspension was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain benzyl 6-hydroxy-1H-indole-3-carboxylate (1.04 g).