Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:20][N:21]1CCCC1=O>>[C:20]([C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6])#[N:21]
Reactant: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)O)c1
Reactant: CN1CCCC1=O
Product: CCCN(CCC)C(=O)c1cc(C#N)cc(C(=O)O)c1
Temperature: 175 °C
Reaction time: 2.5 h

Procedure:
A mixture of 3-bromo-5-[(dipropylamino)carbonyl]benzoic acid (PREPARATION 4, 0.596 g, 1.82 mmol) and copper nitrile (0.325 g, 3.63 mmol) in N-methylpyrrolidinone (1.5 mL) is stirred at 175 degrees C. for 2.5 hour, at which time the mixture is cooled and partitioned between ethyl acetate and hydrochloric acid (3N). The organic layer is washed twice more with hydrochloric acid (3N) and then twice more with saline which had been acidified with a small amount of hydrochloric acid (3N). The organic layer is dried over magnesium sulfate and concentrated under high vacuum to give the title compound, NMR (CDCl3) delta 0.80, 1.02, 1.60, 1.73, 3.17, 3.51, 7.90, 8.31 and 8.41; an aliquot is crystallized from ethyl ether/dichloromethane/hexane—IR (diffuse reflectance) 3017, 2970, 2937, 2898, 2877, 2473, 2432, 2350, 2318, 2236, 1721, 1608, 1588, 1206 and 1196 cm−1.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]C.C([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)#N.[Cl-].[NH4+].C([O:25][CH2:26][CH3:27])C>>[C:26]([C:20]1[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=1)(=[O:25])[CH2:27][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCOCC
Reactant: N#Cc1cccnc1
Reactant: CCCCCCCCCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Product: CCCCCCCCCCC(=O)c1ccncc1
Yield: 58.3 %

Procedure:
To 50 ml of anhydrous ether was added 1.22 g of magnesium for Grignard reaction, and 11.0 g of 1-bromodecane was added to the mixture while stirring. After the magnesium was completely dissolved, a diethyl ether solution of 5.20 g (50 mmol) of 3-cyanopyridine was added dropwise, and the mixture refluxed for 4 hours. After cooling, saturated ammonium chloride solution was added, the diethyl ether layer was separated, and the aqueous layer was further extracted with diethyl ether. The ether layers were combined, washed with water, and then dried over anhydrous sodium sulfate. After concentration under a reduced pressure, the residue was purified by separation by silica gel chromatography (ethyl acetate:hexane=1:4) to give 7.20 g of the desired product (yield 58.3%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:13][OH:14])[CH2:10][CH2:11][CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(C)C=CC=CC=1.C(Cl)CCl.ClC(Cl)C(O)=O>CS(C)=O>[C:1]([NH:8][C@H:9]([CH:13]=[O:14])[CH2:10][CH2:11][CH3:12])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CCC[C@@H](CO)NC(=O)OC(C)(C)C
Agent: O=C(O)C(Cl)Cl
Solvent: ClCCCl
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CCC[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To Boc-norvalinol (7.77 g, 38 mmol), in anhydrous dimethylsulfoxide (153 mL) and toluene (153 mL) was added EDC (73.32 g, 382 mmol). After the solution was cooled to 0° C., dichloroacetic acid (15.8 mL, 191 mmol) was added dropwise. After addition was complete, the reaction was stirred for 15 min. The solution was allowed to warm to room temperature over a period of 2 h. The reaction mixture was concentrated to remove the toluene, then dissolved in ethyl acetate. The solution was washed successively with 1N sodium bisulfate, saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated to afford crude Boc-norvalinal which was used directly in the next step. TLC Rf=0.84 (40% ethyl acetate/hexanes).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[S]>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]=1
Reactant: c1ccc2c(c1)CCNC2
Agent: [S]
Solvent: Cc1ccccc1
Product: C1=NCCc2ccccc21
Yield: 93.1 %

Procedure:
30.0 g of 1,2,3,4-tetrahydroisoquinoline and 15.0 g of sulphur powder in 200 ml of toluene are refluxed for 7 hours. After cooling the sulphur is filtered off, the filtrate is evaporated in vacuo. The resulting thick oily residue is distilled in vacuo. 27.5 g of 3,4-dihydroisoquinoline are obtained, b.p. 64°-67° C. at 0.6 mmHg.
Reaction SMILES: O.[OH-].[Na+].[OH:4][C:5]1[CH:18]=[CH:17][C:8]2[S:9][C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=3[C:7]=2[CH:6]=1.[ClH:19].[N:20]1([CH2:26][CH2:27][CH2:28][Cl:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[ClH:29].[ClH:19].[N:20]1([CH2:26][CH2:27][CH2:28][O:16][C:13]2[CH:14]=[CH:15][C:10]3[S:9][C:8]4[CH:17]=[CH:18][C:5]([O:4][CH2:28][CH2:27][CH2:26][N:20]5[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]5)=[CH:6][C:7]=4[C:11]=3[CH:12]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Oc1ccc2sc3ccc(O)cc3c2c1
Reactant: ClCCCN1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: c1cc2sc3ccc(OCCCN4CCCCC4)cc3c2cc1OCCCN1CCCCC1

Procedure:
To 200 ml of water containing 12.0 g (0.3 mole) of sodium hydroxide and 8.5 g (0.039 mole) of 2,8-dihydroxydibenzothiophene are added 200 ml of toluene and 19.8 g (0.1 mole) of 3-piperidinopropyl chloride hydrochloride, and the heterogeneous reaction mixture is stirred and heated to reflux for 16 hours. After cooling, the organic layer is washed with water, dried over magnesium sulfate, and concentrated in vacuo. The free base is chromatographed on alumina, using chloroform as the eluant. After removing the chloroform from the fraction collected, the oily residue is dissolved in ether and treated with ethereal hydrogen chloride. The resulting solid is purified by two recrystallizations from methanol-butanone to give 2,8-bis(3-piperidinopropoxy)dibenzothiophene dihydrochloride, M.P. 240°-242° C.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]([C:10]1[CH:55]=[CH:54][C:13]([CH2:14][C:15]2[C:24]3[C:23]([CH3:26])([CH3:25])[CH2:22][CH2:21][C:20]([CH3:28])([CH3:27])[C:19]=3[CH:18]=[CH:17][C:16]=2[S:29][C:30]2[CH:39]=[CH:38][C:37]3[C:36]([CH3:41])([CH3:40])[CH2:35][CH2:34][C:33]([CH3:43])([CH3:42])[C:32]=3[C:31]=2[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]([OH:53])=[O:52])=[CH:47][CH:46]=2)=[CH:12][CH:11]=1)([OH:9])=[O:8].Cl>O.C(O)C.CN(C)C=O>[C:7]([C:10]1[CH:11]=[CH:12][C:13]([CH2:14][C:15]2[C:24]3[C:23]([CH3:25])([CH3:26])[CH2:22][CH2:21][C:20]([CH3:27])([CH3:28])[C:19]=3[CH:18]=[CH:17][C:16]=2[S:29]([C:30]2[CH:39]=[CH:38][C:37]3[C:36]([CH3:41])([CH3:40])[CH2:35][CH2:34][C:33]([CH3:42])([CH3:43])[C:32]=3[C:31]=2[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]([OH:53])=[O:52])=[CH:47][CH:46]=2)=[O:2])=[CH:54][CH:55]=1)([OH:9])=[O:8]
Reactant: CC1(C)CCC(C)(C)c2c1ccc(Sc1ccc3c(c1Cc1ccc(C(=O)O)cc1)C(C)(C)CCC3(C)C)c2Cc1ccc(C(=O)O)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CC1(C)CCC(C)(C)c2c1ccc(S(=O)c1ccc3c(c1Cc1ccc(C(=O)O)cc1)C(C)(C)CCC3(C)C)c2Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.2 %

Procedure:
A solution of 3.4 g (16 mmol) of sodium periodate in 30 ml of water was added dropwise to 5.3 g (15 mmol) of the thioether from Example 10 in a mixture of 150 ml of ethanol and 40 ml of dimethylformamide at 0° C., and the mixture was then stirred at the same temperature for 2 hours and at room temperature overnight. The reaction solution was then poured into water, the pH was adjusted to 5 with 2N hydrochloric acid, the mixture was extracted with dichloromethane, and the organic extracts were washed with water, dried over magnesium sulfate and evaporated under reduced pressure. Crystallization of the oily residue from ethanol yielded 2.2 g of title compound of melting point 198°-200° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.[C:10]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([O:8][CH3:10])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(Br)ccc1F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CI
Product: COc1cc(Br)ccc1F
Temperature: 40 °C
Yield: 77.3 %

Procedure:
To a solution of 23A (3.3 g, 17.3 mmol) and K2CO3 (4.78 g, 34.6 mmol) in DMF (20 mL) was added methyl iodide (1.46 mL, 23.4 mmol) at rt. The mixture was heated at 40° C. for 2.0 h. After cooling to rt, it was diluted with diethyl ether, washed with water and brine, dried over MgSO4. The crude residue was purified by flash column chromatography (EtOAc:hexanes=1:6) to give 2.74 g (77%) of 23B as a viscous oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.89 (s, 3H), 6.95-7.00 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:31][N:32]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:20]=[C:2]([C:35]2[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21]
Reactant: Cn1cc(B(O)O)cn1
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2cnn(C)c2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 49.9 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (0.2 g, 0.42 mmol) and (1-methyl-1H-pyrazol-4-yl)boronic acid (0.105 g, 0.505 mmol) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (0.16 g, 1.51 mmol) was added and solution purged with argon for 15 min. Pd(PPh3)4 (0.048 g, 0.042 mmol) was then added and the reaction mixture again purged with argon for 10 min. The reaction mixture was heated at 100° C. for 2 h. The reaction mixture was then diluted with water and extracted with 10% MeOH/DCM. The combined extracts were dried over Na2SO4 and the solvent removed under reduced pressure to afford the crude product which was purified by column chromatography to afford the title compound (0.100 g, 50%). LCMS: 478.20 (M+1)+; HPLC: 95.82% (@ 254 nm) (Rt; 4.322; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.12 (s, 1H), 8.10 (t, 1H), 7.81 (s, 1H), 7.33 (s, 1H), 7.13 (s, 1H), 5.86 (s, 1H), 4.27 (d, 2H, J=4.8 Hz), 3.81-3.83 (m, 5H), 3.21-3.26 (m, 2H), 2.98-3.08 (m, 3H), 2.20 (s, 3H), 2.17 (s, 3H), 2.10 (s, 3H), 1.63-1.66 (m, 2H), 1.48-1.52 (m, 2H), 0.86 (t, 3H, J=7.2 Hz).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:24]([OH:26])=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN=C=N[CH2:51][CH2:52][CH2:53]N(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:14]1([CH2:13][O:20][C:21]2[CH:22]=[C:23]([CH:27]=[C:28]([O:38][CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:29]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:24]([O:1][C@@H:2]2[O:10][C@H:9]([CH2:11][O:12][C:24](=[O:26])[C:23]3[CH:22]=[C:21]([O:20][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:29]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[C:28]([O:38][CH2:39][C:51]4[CH:52]=[CH:53][CH:41]=[CH:40][CH:45]=4)[CH:27]=3)[C@@H:7]([O:8][C:24](=[O:26])[C:23]3[CH:27]=[C:28]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:29]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[C:21]([O:20][CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:22]=3)[C@H:5]([O:6][C:24](=[O:26])[C:23]3[CH:27]=[C:28]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:29]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[C:21]([O:20][CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:22]=3)[C@H:3]2[O:4][C:24](=[O:26])[C:23]2[CH:27]=[C:28]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:29]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[C:21]([O:20][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:22]=2)=[O:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(OC[C@H]1O[C@@H](OC(=O)c2cc(OCc3ccccc3)c(OCc3ccccc3)c(OCc3ccccc3)c2)[C@H](OC(=O)c2cc(OCc3ccccc3)c(OCc3ccccc3)c(OCc3ccccc3)c2)[C@@H](OC(=O)c2cc(OCc3ccccc3)c(OCc3ccccc3)c(OCc3ccccc3)c2)[C@@H]1OC(=O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Yield: 9.4 %

Procedure:
A mixture of 1.17 mmol of D-glucose, 8.57 mmol of 3,4,5-tribenzyloxybenzoic acid, 10.68 mmol of EDC.HCl and 9.84 mmol of DMAP was suspended in 130 mL of CH2Cl2 and was heated at reflux overnight. The cooled reaction mixture was then extracted with 1N HCl (3×), saturated NaHCO3 (2×), and brine (2×), the organic layer was dried over MgSO4, filtered, and concentrated. The resulting residue was purified by column chromatography over silica gel (75:24:1 CH2Cl2:toluene:ethyl acetate) to provide 0.253 g (9%) of product. 1H NMR (CDCl3, 400 MHz) δ 7.45-7.15 (m, 85H), 6.21 (d, J=8.0 Hz, 1H), 6.05 (t, J=10.0 Hz, 1H), 5.84 (dd, J=10.0, 8.0 Hz, 1H), 5.73 (t, J=10.0 Hz, 1H), 5.14-4.92 (m, 30H), 4.76 (m, 1H), 4.44 (m, 1H), 4.35 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=3[N:19]=2)[CH:7]=[CH:8][CH:9]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[C:53](O)=[O:54].CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:22][C:2]([F:1])([F:21])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH:20][C:53](=[O:54])[C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][N:47]=4)[C:18]=3[N:19]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1ncnc2ccc(-c3cccc(OC(F)(F)F)c3)nc12
Reactant: O=C(O)c1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ncnc2ccc(-c3cccc(OC(F)(F)F)c3)nc12)c1ccccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 0.1 %

Procedure:
To a solution of 6-(3-(trifluoromethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine (50 mg, 163 mmol) in DMF (1 mL) was added HATU (124 mg, 330 mmol), pyridine-2-carboxylic acid (20 mg, 163 mmol) and DIPEA (0.07 mL, 330 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was treated with water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), concentrated to dryness and the crude product was purified by prep-TLC (10% Methanol in CH2Cl2) to afford N-(6-(3-(trifluoromethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-yl)picolinamide as a yellow solid (57 mg, 85% yield). MS (ESI) calcd for C20H12F3N5O2 (m/z): 411.09. found: 412 [M+1].
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(CON)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added tert-butyl 3-[(aminooxy)methyl]piperidine-1-carboxylate 152 (0.312 g, 1.358 mmol), 1-hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 153 (0.37 g, 84%) as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1Br)[CH2:8][CH2:7][CH2:6]2.[Li]CCCC.C([O:20][B:21](OCC)[O:22]CC)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9]([CH2:8][CH2:7][CH2:6]2)=[CH:10][C:11]=1[B:21]([OH:22])[OH:20]
Reactant: COc1cc2c(cc1Br)CCC2
Reactant: CCOB(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc2c(cc1B(O)O)CCC2
Temperature: -78 °C
Reaction time: 18 h

Procedure:
A dry 250 mL round bottom flask was charged with 6-bromo-2,3-dihydro-1H-inden-5-yl methyl ether (9.38 grams, 41.27 mmol) and placed under high vacuum for 18 hours. THF (51.6 mL) was added via syringe. The solution was homogeneous and clear. The reaction was cooled with a dry ice/acetone bath for 15 minutes, then n-BuLi was added semi-dropwise. A color change to pale yellow was observed. The reaction was stirred at −78° C. for 1 hour, followed by drop-wise addition of triethylborate (7.73 mL, 45.43 mmol). After continued stirring and cooling at −78° C. for 2 hours, the reaction was quenched with 10% aq. HCl (50 mL, 3M), the cooling bath was removed, and the reaction was allowed to warm to ambient temperature. The reaction was poured in water and extracted two times with ethyl acetate. The organics were combined, dried with MgSO4, filtered and concentrated to 8.0 grams of 6-methoxy-2,3-dihydro-1H-inden-5-ylboronic acid as a white, somewhat tacky, solid. The solid turned blue over 48 hours. The boronic acid was used without further purification.
Reaction SMILES: [C:1]1(=[O:17])[N:5]([CH:6]([CH3:11])[CH2:7][C:8]([OH:10])=O)[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.C(N1[CH:29]=[CH:28]N=C1)(N1C=CN=C1)=O.[Cl:30][C:31]1[CH:32]=[CH:33][C:34]2[N:40]=[C:39]([NH:41][NH2:42])[CH:38](C3C=CC=CC=3Cl)[N:37]=[CH:36][C:35]=2[CH:50]=1>O1CCCC1>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]2[N:40]=[C:39]([NH:41][NH:42][C:8](=[O:10])[CH2:7][CH:6]([N:5]3[C:1](=[O:17])[C:2]4=[CH:16][CH:15]=[CH:14][CH:13]=[C:3]4[C:4]3=[O:12])[CH3:11])[CH2:38][N:37]=[C:36]([C:29]3[CH:28]=[CH:34][CH:35]=[CH:50][C:31]=3[Cl:30])[C:35]=2[CH:50]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNC1=Nc2ccc(Cl)cc2C=NC1c1ccccc1Cl
Reactant: CC(CC(=O)O)N1C(=O)c2ccccc2C1=O
Solvent: C1CCOC1
Product: CC(CC(=O)NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)N1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 26, 3-phthalimidobutyric acid and carbonyldiimidazol are reacted in tetrahydrofuran. To this mixture is added 7-chloro-2-hydrazino-(o-chlorophenyl)-3H-1,4-benzodiazepine to give 3-phthalimidobutyric acid, 2-[7-chloro-5-(o-chlorophenyl)3H-1,4-benzodiazepin-2-yl]hydrazide which is warmed with acetic acid to give N-[2-[8-chloro-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepin-1-yl]propyl]phthalimide.
Reaction SMILES: C[O-].[Na+].[CH2:4]([N:6]1[C:11](=[O:12])[C:10]2=[N:13][O:14][C:15]([CH3:16])=[C:9]2[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:7]1)[CH3:5].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO>[CH2:4]([N:6]1[C:11](=[O:12])[C:10]2=[N:13][O:14][C:15]([CH:16]=[CH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:9]2[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:7]1)[CH3:5]
Reactant: CCn1nc(-c2ccccc2)c2c(C)onc2c1=O
Reactant: O=Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCn1nc(-c2ccccc2)c2c(C=Cc3ccccc3)onc2c1=O

Procedure:
To a freshly prepared solution of sodium methoxide (108 mg, 1.96 mmol) in methanol (2 ml), a solution of 6-ethyl-3-methyl-4-phenyl-6H-isoxazolo[3,4-d]pyridazin-7-one (500 mg, 1.96 mmol) (Dal Piaz, V.; Giovannoni, M. P.; Castellana, C.; et al, J. Med. Chem. 1997, 40, 1417-1421) in of dry methanol (2 ml) was added and the mixture was stirred for a while. Then, benzaldehyde (0.40 ml, 3.92 mmol) was added dropwise and the final mixture was refluxed for 2 hours. The resulting suspension was let to cool down and the final product (514 mg, 76%-yield) was collected by filtration.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][C:5](=[O:8])[NH:4][C:3]1=[O:9].[C:10](OC(=O)C)(=[O:12])[CH3:11].S(=O)(=O)(O)O>>[C:10]([N:6]1[CH2:7][CH:2]([CH3:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CNC(=O)NC1=O
Agent: O=S(=O)(O)O
Product: CC(=O)N1CC(C)C(=O)NC1=O

Procedure:
In the manner described in I, 65 gm (0.5 mol) of 5-methyl-5,6-dihydrouracil and 817 gm (8 mols) of acetic acid anhydride and 2 ml of concentrated sulfuric acid were heated to boiling for ten hours with continuous distilling off of the acetic acid produced. The product, isolated after separating of the surplus acetic acid anhydride and purified by recrystallization from isopropanol, had a melting point of 111° C to 113° C. The analysis values were as follows:
Reaction SMILES: C([Li])(C)(C)C.CCCCCC.I[C:13](=[CH2:22])[CH2:14][C@H:15]1[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[O:16]1.[S:23](Cl)([Cl:26])(=[O:25])=[O:24]>C(OCC)C>[CH3:20][C:17]1([CH3:21])[O:16][C@@H:15]([CH2:14][C:13]([S:23]([Cl:26])(=[O:25])=[O:24])=[CH2:22])[CH2:19][O:18]1
Reactant: O=S(=O)(Cl)Cl
Reactant: C=C(I)C[C@H]1COC(C)(C)O1
Agent: [Li]C(C)(C)C
Solvent: CCCCCC
Solvent: CCOCC
Product: C=C(C[C@H]1COC(C)(C)O1)S(=O)(=O)Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl lithium in hexane (1.7M, 2 eq) is added dropwise to a solution of (S)-4-(2-iodoallyl)-2,2-dimethyl-1,3-dioxolane (1 eq) in diethyl ether at −78° C., and the reaction stirred at −78° C. for 30 min. Sulfuryl dichloride (1 eq) is added, the mixture warmed to room temperature and the solvents removed under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24].S(=O)(=O)(O)O.[CH2:31](O)[CH3:32]>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:31][CH3:32])=[O:24]
Reactant: CC1(C2CCCC2)Cc2cc(OCCCC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCCOc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Reaction time: 18 h

Procedure:
To a suspension of 4-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-oxy]butanoic acid (0.5 g, 0.0012 mole) in absolute ethanol (50 ml) is added conc. sulfuric acid and the mixture is refluxed for 1 hr., treated with 3 Å molecular sieves and stirred at 25° for 18 hours. The reaction mixture is treated with more conc. sulfuric acid (0.2 ml) refluxed for 1 hr, filtered and treated with solid potassium carbonate. The ethanol is distilled at reduced pressure to give ethyl 4-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]butanoate which is purified by chromatography on silica gel eluted with methylene chloride-tetrahydrofuran (100:1).