Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:24]=[CH:23][C:12]([O:13][C:14]3[NH:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[N:15]=3)=[CH:11][CH:10]=2)O1.Br[C:27]1[N:28]([CH2:36][CH3:37])[N:29]=[C:30]2[CH:35]=[CH:34][CH:33]=[N:32][C:31]=12.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC.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.O>[NH:18]1[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[N:15]=[C:14]1[O:13][C:12]1[CH:11]=[CH:10][C:9]([C:27]2[N:28]([CH2:36][CH3:37])[N:29]=[C:30]3[CH:35]=[CH:34][CH:33]=[N:32][C:31]=23)=[CH:24][CH:23]=1
Reactant: CCn1nc2cccnc2c1Br
Reactant: CC1(C)OB(c2ccc(Oc3nc4ccccc4[nH]3)cc2)OC1(C)C
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: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CCn1nc2cccnc2c1-c1ccc(Oc2nc3ccccc3[nH]2)cc1
Yield: 59.1 %

Procedure:
A mixture of 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-1H-benzimidazole (116 mg), 3-bromo-2-ethyl-2H-pyrazolo[4,3-b]pyridine (71 mg), tetrakis(triphenylphosphine)palladium(0) (36.3 mg), cesium carbonate (153 mg) and DME/water (3/1, 4 ml) was subjected to microwave irradiation at 120° C. for 40 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized from ethyl acetate/hexane to give the title compound (66.0 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([NH:13][C:14]1[C:19](Br)=[C:18]([CH2:21][CH3:22])[N:17]=[CH:16][N:15]=1)[CH3:12].[CH3:23][S-:24].[Na+]>CN1CCCC1=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([NH:13][C:14]1[C:19]([S:24][CH3:23])=[C:18]([CH2:21][CH3:22])[N:17]=[CH:16][N:15]=1)[CH3:12]
Reactant: CCc1ncnc(NC(C)c2ccc3ccccc3c2)c1Br
Reactant: C[S-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCc1ncnc(NC(C)c2ccc3ccccc3c2)c1SC

Procedure:
4.99 g (0.014 mol) of 4-[1'-(β-naphthyl)-ethylamino]-5-bromo-6-ethylpyrimidine are dissolved in 18 ml of N-methylpyrrolidone, and the solution is heated at 60° C. with 3.2 g of sodium methanethiolate (CH3SNa) for 5 hours. The mixture is then extracted with water and ethyl acetate, the extract is washed and the solvent is removed using a rotary evaporator. Purification by chromatography on silica gel (eluant: 3 parts ethyl acetate and 7 parts hexane) yields, in addition to the starting product, 1.42 g of pure substance in the form of a colourless oil. Analysis: C19H21N3S (M=323.46).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[C:5]([O:14][CH3:15])[C:6]([CH3:13])=[CH:7][CH:8]=2)[N:3]=1.CCN(C(C)C)C(C)C.[H][H].O>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([O:14][CH3:15])[C:6]([CH3:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: [H][H]
Reactant: COc1c(C)ccc2c(Cl)nc(Cl)nc12
Agent: [Pd]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C)ccc2cnc(Cl)nc12
Yield: 67.4 %

Procedure:
To a solution of 2,4-dichloro-8-methoxy-7-methylquinazoline (43 g, 0.177 mol) in EtOAc (2580 mL) were added DIPEA (22.9 g, 0.177 mol) and Pd/C (8.6 g) in one portion. The reaction mixture was stirred at room temperature for 6 h under 20 psi of hydrogen. Water (800 mL) was added and the mixture was filtered. The filtrate was separated, the organic layer was washed with water (500 mL). The combined aqueous layers were re-extracted with EtOAc (700 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product. The crude product was re-crystallized from EtOAc (64 mL)/petroleum ether (192 mL) to give the title compound (24.9 g, 67.5%) as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[F:7][C:8]1[CH:9]=[CH:10][C:11]([N+:22]([O-:24])=[O:23])=[C:12]([CH:21]=1)[O:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([NH2:20])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[F:7][C:8]1[CH:9]=[CH:10][C:11]([N+:22]([O-:24])=[O:23])=[C:12]([CH:21]=1)[O:13][C@H:14]1[CH2:15][CH2:16][C@H:17]([NH:20][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:18][CH2:19]1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
120 μl methansulfonyl chloride were added to an ice cooled suspension of 300 mg trans-4-(5-fluoro-2-nitro-phenoxy)-cyclohexylamine hydrochloride and 431 μl triethylamine in 5 ml methylene chloride. The reaction mixture was allowed to warm up slowly to rt over night. Then the mixture was diluted with methylene chloride and washed with 10% potassium hydrogen sulfate. The mixture was filtered through a hydrophobic frit and evaporated. The residue was triturated with ether.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:15])[C:5]1=[O:16].S(Cl)([Cl:19])=O>ClC(Cl)Cl>[Cl:19][CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:15])[C:5]1=[O:16]
Reactant: O=S(Cl)Cl
Reactant: Cn1c(=O)n(CCO)c(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)n(CCCl)c(=O)c2ccccc21
Yield: 95 %

Procedure:
A mixture of 4.5 parts of 3-(2-hydroxyethyl)-1-methyl-2,4(1H,3H)-quinazolinedione, 8 parts of thionyl chloride and 75 parts of trichloromethane was stirred and refluxed for 5 hours. The reaction mixture was evaporated, yielding 4.5 parts (95%) of 3-(2-chloroethyl)-1-methyl-2,4(1H,3H)-quinazolinedione as a residue (intermediate 171).
Reaction SMILES: O[C:2]1([CH:8]=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1.I[CH2:11][CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-:16].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[CH2:11]([O:16][C:7]1[C:2]([CH:8]=[O:9])=[N:3][CH:4]=[CH:5][CH:6]=1)[CH2:12][CH2:13][CH3:14]
Reactant: O=CC1(O)C=CC=CN1
Reactant: CCCCI
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOc1cccnc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
The title compound was made in a related procedure described by Daines, R. A. et al. (J. Med. Chem. 1993, 36, 3321-3332). To a solution of 2-hydroxy-pyridine-2-carbaldehyde (0.998 g, 8.11 mmol) in DMF (11.4 mL) was added 1-iodobutane (1.10 mL, 9.73 mmol) followed by anhydrous potassium carbonate (3.36 g, 24.3 mmol). After 1 h at 90° C., the solution was cooled to r.t. and poured into ethyl acetate. The organic layer was washed once with water, twice with brine and then was dried over sodium sulfate, filtered and concentrated in vacuo generating 1.31 g (90% yield, 7.30 mmol) of the title compound as a liquid. This material was used in the next step without further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:10]=[C:9]2[O:22][CH2:23][C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25].C(N(CC)CC)C>C(Cl)Cl>[C:1]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:10]=[C:9]2[O:22][CH2:23][C:24]([N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1)=[O:25])(=[O:3])[CH3:2]
Reactant: Nc1ccc2nc(-c3ccccc3)cc(OCC(=O)N3CCOCC3)c2c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2nc(-c3ccccc3)cc(OCC(=O)N3CCOCC3)c2c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of acetyl chloride (0.55 cc) in methylene chloride (5 cc) is added in the course of 10 minutes to a stirred solution of 4-[(6-amino-2-phenyl-4-quinolyl)oxyacetyl]morpholine (2.55 g), prepared according to Example 39, and triethylamine (1.2 cc) in methylene chloride (25 cc). The mixture is stirred for 1 hour at room temperature (approximately 20° C.) and the solvent evaporated off under reduced pressure. The residue is stirred for 10 minutes in an ethyl acetate/water (5:2 by volume) mixture, filtered off, dissolved in a toluene/acetic acid (50:50 by volume) mixture and precipitated with ethyl ether. After filtration and drying, 4-[(6-acetylamino-2-phenyl-4-quinolyl)oxyacetyl]morpholine (2 g), m.p. 261° C., is isolated.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:13]=[C:14]([CH2:17][NH2:18])[O:15][CH:16]=1.C(=O)([O-])O.[Na+]>C(O)C>[CH3:11][C:12]1[CH:13]=[C:14]([CH2:17][NH:18][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[O:15][CH:16]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Cc1coc(CN)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1coc(CNc2ncccc2[N+](=O)[O-])c1
Reaction time: 8 h
Yield: 91.2 %

Procedure:
A mixture of 10.4 parts of 2-chloro-3-nitropyridine, 8 parts of 4-methyl-2-furanmethanamine, 7.6 parts of sodium hydrogen carbonate and 120 parts of ethanol was stirred overnight at reflux temperature. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted with 1,1'-oxybisethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 14.9 parts (91.2%) of N-[(4-methyl-2-furanyl)methyl]-3-nitro-2-pyridinamine as a residue (int. 3).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH3:16])[CH2:8][CH2:7][C:6]1=[O:17])=[O:4].[Li+].[CH3:19][CH:20]([N-]C(C)C)[CH3:21].C(Br)C=C>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH3:16])[CH2:8][CH:7]([CH2:21][CH:20]=[CH2:19])[C:6]1=[O:17])=[O:4]
Reactant: COC(=O)C1C(=O)CCc2cccc(OC)c21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC1Cc2cccc(OC)c2C(C(=O)OC)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
A solution of 10.2 g (43.5 mmol) 1,2,3,4-tetrahydro-8-methoxy-2-oxo-1-naphthalene carboxylic acid methyl ester in 108 mL of THF in a three-neck, round-bottomed flask, equipped with a dropping funnel, was added dropwise 63.8 mL (95.7 mmol) of LDA (1.5 M in cyclohexane) at −30° C. to −40° C. under a nitrogen atmosphere. The solution was allowed to warm to 0° C. and 6.0 mL (69.6 mmol) of allylbromide was added. After stirring the mixture for one hour at room temperature, TLC analysis showed no starting material remaining. The reaction was quenched with 3N hydrochloric acid to pH 2-3 and extracted with ethyl acetate (2×1 L). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting oil was purified by liquid chromatography on 800 g silica gel 60 (230-400 m), eluting with hexane-acetone (3:1), and collecting 40 mL fractions. Fractions 36-63 gave 10.3 g (87%) of pure title compound as a yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:17][OH:18].C(O)C>O>[I:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[N:17][OH:18])[NH2:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(I)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1ccc(I)cc1
Temperature: 25 °C
Yield: 67.8 %

Procedure:
A mixture of 4-iodobenzonitrile (7.69 g), anhydrous sodium carbonate (6.25 g), hydroxylamine hydrochloride (8.74 g), in water (60 ml) and sufficient ethanol to maintain a clear solution, was heated at 90°-100° C. for 4 hours. The reaction mixture was cooled to ambient temperature and evaporated until a precipitate formed. The solid was collected by filtration, washed with water and recrystallised from acetonitrile to give 4-iodobenzamidoxime (5.97 g), m.p. 155°-161° C.; microanalysis, found: C, 31.4; H, 2.7; N, 10.2%; C7H7IN2 O 0.2H2O requires: C, 31.6; H, 2.81; R, 10.5%; NMR: 5.82(2H,s), 7.46(2H,d), 7.73(2H,d), 9.69(1H,s); m/z 263(M+H).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:22]([NH:24][C:25]1[CH:33]=[CH:32][C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=1)=[O:23])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:21])[NH2:20])=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[S:34](Cl)([C:37]1[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=1)(=[O:36])=[O:35].N(CC)(CC)CC.[BrH:52].N(CC)(CC)CC.Cl>CN(C=O)C.CCN(CC)CC>[NH:1]([S:34]([C:37]1[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=1)(=[O:36])=[O:35])[C@@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:22]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([N+:29]([O-:31])=[O:30])=[CH:32][CH:33]=1)=[O:23])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:20])[NH2:21])=[O:12])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6].[BrH:52]
Reactant: CC(C)C[C@@H](N)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N[C@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)Nc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
6.26 g (10 mM) of 2HBr.H-D-Leu-Gly-Arg-pNA (prepared according to Example 7f, see Table 3) were dissolved in 30 ml of distilled DMF. The solution was cooled to -15°, and first 2.80 ml (20 mM) of Et3N and immediately afterwards 1.91 g (10 mM) of tosyl chloride were added, while stirring, in the absence of humidity. After a reaction time of about 2 to 3 hours at -15°, the reaction mixture was allowed to further react overnight at room temperature. The reaction mixture was again cooled to -15°. The precipitated mixture of Et3N.HBr and Et3N.HCl was removed by filtration and washed with a small amount of cold DMF. The filtrate and the washing solution were combined and concentrated to dryness in vacuo at 50°. The residue was dissolved in 75 ml of 50% AcOH. The solution was purified on a column of "Sephadex" G-15 equilibrated with 50% AcOH. The main fraction of the AcOH eluate which was split by treatment with trypsin with release of p-nitroaniline was concentrated to dryness in vacuo at 40°. The residue was dissolved in 100 ml of MeOH, and the solution was again concentrated to dryness. The residue was dried in a vacuum desiccator at 60° over P2O5 to obtain 6.65 g (95.0% of the theory) of amorphous compound Tos-D-Leu-Gly-Arg-pNA.HBr which was homogeneous in the SS as shown by TLC. Elementary analysis and calculation from the empirical formula C27H39N8SO7Br gave the following values: C=46.85% (46.35%), H=5.66% (5.62%), N=16.28% (16.02%), S=4.43% (4.58%) and Br=11.22% (11.42%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:10]([OH:12])=[O:11])[C:7]([OH:9])=O)=[CH:2]1.[NH2:13][CH:14]1[C:27](=[O:28])[N:16]2[CH:17]([C:22]3[NH:26][N:25]=[N:24][N:23]=3)[C:18]([CH3:21])([CH3:20])[S:19][C@H:15]12.[Na][Na]>>[C:10]([CH:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[C:7]([NH:13][CH:14]1[C:27](=[O:28])[N:16]2[CH:17]([C:22]3[NH:23][N:24]=[N:25][N:26]=3)[C:18]([CH3:20])([CH3:21])[S:19][C@H:15]12)=[O:9])([OH:12])=[O:11]
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Reactant: O=C(O)C(C(=O)O)c1ccsc1
Agent: [Na][Na]
Product: CC1(C)S[C@@H]2C(NC(=O)C(C(=O)O)c3ccsc3)C(=O)N2C1c1nnn[nH]1
Yield: 67 %

Procedure:
(2.69 mmole) of 2-(3-thienyl)malonic acid (British Pat. No. 1,125,557) with 645 mg. (2.69 mmole) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, according to the procedure of Example CXLVII, affords 810 mg, (67% yield) of 6-(2-carboxy-2-[3-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam as its disodium salt. The infrared spectrum of the product KBr disc) shows absorptions at 1775 cm-1 (β-lactam), 1670 cm-1 (amide I), 1620 cm-1 (carboxylate) and 1525 cm-1 (amide II). The NMR spectrum (D2O) shows absorptions at 7.80-7.00 ppm (multiplet, thienyl hydrogens), 5.88 ppm (doublet, C-6 hydrogen), 5.65 ppm (doublet of doublets, C-5 hydrogen), 5.40 ppm (doublet, C-3 hydrogen), 1.60 ppm (doublet, C-2 methyl hydrogens) and 1.00 ppm doublet, C-2 methyl hydrogens).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[N:8]([CH2:13][CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:7]2=[O:19].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N12CCCN=C1CCCCC2.[C:58]([NH2:62])([CH3:61])([CH3:60])[CH3:59]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:62][C:58]([CH3:61])([CH3:60])[CH3:59])[N:8]([CH2:13][CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:7]2=[O:19]
Reactant: CC(C)(C)N
Reactant: CS(=O)(=O)CCn1c(=O)[nH]c2c(Br)cccc2c1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)Nc1nc2c(Br)cccc2c(=O)n1CCS(C)(=O)=O
Temperature: 40 °C
Reaction time: 4 h
Yield: 38.9 %

Procedure:
A glass microwave reaction vessel was charged with 8-bromo-3-(2-(methylsulfonyl)ethyl)quinazoline-2,4(1H,3H)-dione (200 mg, 0.576 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (382 mg, 0.864 mmol, Sigma Aldrich) in DMF (2 mL) followed by 1,8-diazabicyclo-[5.4.0]undec-7-ene (0.172 mL, 1.152 mmol, Sigma Aldrich). The reaction mixture was stirred for 5 min. tert-butylamine (0.30 mL, 2.88 mmol) was added. The reaction was stirred at 40° C. for 4 h. The mixture was diluted with EtOAc (30 mL) and washed with water, brine, dried (MgSO4), filtered and concentrated. The residue was purified with silica gel chromatography (eluted with 0-10% EtOAc in DCM) to give 8-bromo-2-(tert-butylamino)-3-(2-(methylsulfonyl)ethyl)quinazolin-4(3H)-one (516c; 90 mg, 0.224 mmol, 39% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 402 (M+1).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH:5]([C:7]([O:9][CH2:10][CH:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[NH2:6]>ClCCl.C([O-])(O)=O.[Na+]>[CH:13]1[C:12]2[CH:11]([CH2:10][O:9][C:7]3[O:8][C:1](=[O:2])[NH:6][N:5]=3)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: NNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1[nH]nc(OCC2c3ccccc3-c3ccccc32)o1
Reaction time: 0.25 h

Procedure:
2 equivalents of phosgene (1.89M in toluene; 4.2 ml) are added to a solution of 3.91 mmol of 9H-fluoren-9-ylmethyl hydrazinecarboxylate in 40 ml of dichloromethane and 40 ml of saturated aqueous NaHCO3 solution. The mixture is stirred for 15 minutes and then worked up as usual, giving 5-(9H-fluoren-9-ylmethoxy)-3H-[1,3,4]oxadiazol-2-one (“AB”)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([OH:23])=O)[N:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([Cl:26])=[O:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1

Procedure:
1.2 g of ((3,5-bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetic acid in 15 mL thionylchloride was stirred 30 min. at 60° C. The solvent was removed to give 1.3 g desired product. (M+H)+: 334
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH3:23][C@H:24]1[N:29]([CH3:30])[C@@H:28]([CH3:31])[CH2:27][N:26]([C:32]2[N:37]=[CH:36][C:35]([C:38](OC)=[O:39])=[CH:34][N:33]=2)[CH2:25]1.Cl>C1(C)C=CC=CC=1.CO>[CH3:14][O:13][C:11]1[CH:10]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH:22][C:38]([C:35]3[CH:36]=[N:37][C:32]([N:26]4[CH2:27][C@H:28]([CH3:31])[N:29]([CH3:30])[C@H:24]([CH3:23])[CH2:25]4)=[N:33][CH:34]=3)=[O:39])[NH:20][N:21]=2)[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=1
Reactant: COC(=O)c1cnc(N2C[C@@H](C)N(C)[C@@H](C)C2)nc1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4C[C@@H](C)N(C)[C@@H](C)C4)nc3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 39.4 %

Procedure:
Trimethylaluminium (2M in toluene, 1.04 ml, 2.08 mmol) was added dropwise to a suspension of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (205 mg, 0.83 mmol) and methyl 2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)pyrimidine-5-carboxylate (220 mg, 0.83 mmol) in toluene (5.257 ml) at 25° C. The resulting solution was stirred at 60° C. for 18 h. The reaction mixture was poured into methanol (50 mL) and acidified with HCl (2M aqueous solution, to obtain a clear freely stirring solution). The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. The impure material was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (157 mg, 39%) as a white solid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([O:19][C:20](=[O:27])[C@@H:21]([OH:26])[CH2:22][S:23][CH2:24][CH3:25])[CH:17]=[CH2:18].[C:28]([S:31][CH2:32][C@@H:33]([CH3:37])[C:34](O)=[O:35])(=[O:30])[CH3:29]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:16]([O:19][C:20](=[O:27])[C@@H:21]([O:26][C:34](=[O:35])[C@H:33]([CH3:37])[CH2:32][S:31][C:28](=[O:30])[CH3:29])[CH2:22][S:23][CH2:24][CH3:25])[CH:17]=[CH2:18]
Reactant: C=CCOC(=O)[C@@H](O)CSCC
Reactant: CC(=O)SC[C@@H](C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)[C@H](CSCC)OC(=O)[C@H](C)CSC(C)=O
Reaction time: 8 h

Procedure:
Dicyclohexylcarbodiimide (1.13 g, 5.5 mmol) in dichloromethane (20 ml) was added to a stirred solution of the product of step b) (0.95 g, 5 mmol), (S)-3-(Acetylthio)-2-methylpropanoic acid (0.81 g, 5 mmol) and 4-(dimethylamino)pyridine (0.06 g, 0.5 mmol) in dichloromethane (30 ml). The mixture was stirred overnight, filtered and the solvent evaporated. The residue was dissolved in ethyl acetate, filtered and washed with potassium hydrogen sulphate solution, sodium bicarbonate solution and brine and the solvent evaporated. Chromatography on silica with ethyl acetate/petroleum ether as eluant gave the sub-title compound (1.1 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[CH:6][CH:5]=1)([O-])=O>[C].[Pd].C(O)=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([P:10](=[O:17])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])=[CH:6][CH:5]=1
Reactant: CCOP(=O)(OCC)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: O=CO
Product: CCOP(=O)(OCC)c1ccc(N)cc1
Temperature: 25 °C

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of diethyl 4-nitrophenylphosphonate (1.07 g, 4.13 mmol, 1.00 equiv), TEA (3 mL), Palladium carbon (0.025 g). This was followed by the addition of formic acid (2 mL) dropwise with stirring at room temperature. The resulting solution was heated to reflux for 3 hr. The reaction was then quenched by the addition of 5 mL of water and the solids were filtered out. The resulting filtrate was extracted with 5×10 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate. This resulted in 800 mg (85%) of diethyl 4-aminophenylphosphonate as a white solid.