Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5](=[O:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].[CH3:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH2:3]([O:4][C:5](=[O:7])[CH2:6][N:15]([CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:2]
Reactant: CC(=O)OCCBr
Reactant: CNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of bromoethylacetate, 3.3 mL (30.0 mmol) in 100 mL of tetrahydrofuran was added 4.14 g (30.0 mmol) of potassium carbonate and 3.25 mL of N-methylaniline. The reaction mixture stirred overnight at rt. and was concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and saturated aqueous NaHCO3. The mixture was washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography using EtOAc/hexanes as eluent and concentrated to dryness to give 4.74 g (82%) of the desired product as a tan oil. MS (ion spray) 194.1 (M+1).
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[NH:6][CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1.CO.F[C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=1[Br:24]>CN(C)C=O.O>[Br:23][C:20]1[CH:19]=[C:18]([Br:24])[CH:17]=[CH:22][C:21]=1[N:6]1[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=[C:5]1[CH3:4]
Reactant: Fc1ccc(Br)cc1Br
Reactant: COC(=O)c1c[nH]c(C)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: COC(=O)c1cn(-c2ccc(Br)cc2Br)c(C)n1

Procedure:
14.1 g of 30% strength sodium methylate solution was added to 10.9 g (0.078 mol) of methyl 2-methylimidazole-4-carboxylate in 100 ml of dimethylformamide; the methanol which formed was removed completely. 38.1 g (0.15 mol) of 1-fluoro-2,4-dibromobenzene was added to the dimethylformamide solution remaining, and the mixture was refluxed for 2 hours. Water was then added, extraction carried out with ethyl acetatem and the ethyl acetate phase was washed with water. After removal of the solvent from the organic phase, there was obtained a residue which crystallized on trituration with diisopropyl ether.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:43]1[CH2:47][CH2:46][CH2:45][C@H:44]1[CH2:48][N:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1>ClCCl.CN(C=O)C.C(OCC)(=O)C.O>[N:49]1([CH2:48][C@@H:44]2[CH2:45][CH2:46][CH2:47][N:43]2[C:15]([C:12]2[CH:11]=[CH:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:8][CH:7]=3)=[CH:14][CH:13]=2)=[O:17])[CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Procedure B′: 4′-Trifluoromethyl-biphenyl-4-carboxylic acid (2.7 g, 10.1 mmol) is suspended in dichloromethane (100 mL) and DMF (100 mL). EDC (2.33 g, 12.2 mmol) and HOBt (1.64 g, 12.2 mmol) were added at room temperature in that order. DIEA (4.4 mL, 25.3 mmol) and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (1.56 g, 10.1 mmol) are added to the mixture. The mixture is stirred at room temperature for overnight. Water and ethyl acetate are added to the mixture. The aqueous layer is extracted with dichlormethane (2×), followed by ethyl acetate (2×). The combined organic layers are washed with brine (3×), dried over Na2SO4 and evaporated. The crude product is purified by silica-gel column chromatography (gradient: 100% CH2Cl2 to 10% 2M NH3 in MeOH/CH2Cl2) give the product. MS (ES+) 403.2
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH:14]=[O:15])=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.CO.O1CCCC1.[BH4-].[Na+]>CCCCCC.C(OCC)(=O)C.O>[CH:1]1([C:4]2[C:13]([CH2:14][OH:15])=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCCCCC
Product: OCc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
2-Cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde (30 gm) was added methanol (30 ml) and tetrahydrofuran (270 ml) at room temperature. The reaction mixture was then cooled to 0° C. and then added sodium borohydride (5.8 gm) for 30 minutes at 0 to 5° C. The reaction mass was stirred for 1 hour 30 minutes and then added water (150 ml) and ethyl acetate (150 ml). The reaction mass was stirred for 10 minutes, and then the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with sodium sulfate and then concentrated to obtain a residual solid. To the residual solid was added n-hexane (150 ml) and stirred for 30 minutes. The separated solid was filtered and dried to obtain 29 gm of (2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)methanol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:9][NH:8]/[C:7](=[N:10]\[C:11]([C:13]2[C:18]([NH2:19])=[N:17][C:16]([NH2:20])=[C:15]([Cl:21])[N:14]=2)=[O:12])/[NH:6]1.[C:22]1([CH2:28][C:29](Cl)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[C:22]1([CH2:28][C:29]([NH:1][CH2:2][CH2:3][CH2:4][C@H:5]2[CH2:9][NH:8]/[C:7](=[N:10]\[C:11]([C:13]3[C:18]([NH2:19])=[N:17][C:16]([NH2:20])=[C:15]([Cl:21])[N:14]=3)=[O:12])/[NH:6]2)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NCCC[C@H]1CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N1
Solvent: CN(C)C=O
Product: Nc1nc(N)c(C(=O)/N=C2\NC[C@H](CCCNC(=O)Cc3ccccc3)N2)nc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [(S)-4-(3-amino-propyl)-imidazolidin-(2E)-ylidene]-amide (Ex. 31) (0.030 g, 0.96 mmol) in DMF (2 ml), phenylacetyl chloride (0.013 ml, 0.096 mmol) is added. The yellow solution is stirred at room temperature for 10 minutes. Purification by catch and release resin (SCX-2) eluting with MeOH and 7M NH3 in MeOH affords the title compound; [M+H]+ 430.98
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[CH:7]=[C:6]([Cl:17])[N:5]=1.[CH3:18]I>C1COCC1.CCOC(C)=O>[Cl:17][C:6]1[CH:7]=[C:8]([N:10]([CH3:18])[C:11]2[CH:16]=[N:15][CH:14]=[N:13][CH:12]=2)[CH:9]=[C:4]([Cl:3])[N:5]=1
Reactant: CI
Reactant: Clc1cc(Nc2cncnc2)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(c1cncnc1)c1cc(Cl)nc(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
NaH (103 mg, 4.29 mmol, 1.10 eq) was added to a flame-dried round-bottom flask and anhydrous THF (9.5 mL) was added. The slurry was cooled to 0° C. and compound 13 (938 mg, 3.89 mmol, 1.00 eq) was added as a solution in THF (9.5 mL). After stirring at 0° C. for 30 minutes methyl iodide (267 μL, 4.29 mmol, 1.10 eq) was added and the reaction was allowed to warm to room temperature while stirring overnight. The reaction was diluted with EtOAc and washed with water (1×). The aqueous layer was back extracted (1×) with EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 920 mg (93%) of the title compound as a tan solid: 1H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.87 (s, 2H), 6.77 (s, 2H), 3.36 (s, 3H); [M+1]+: 255.0.
Reaction SMILES: C(N(CC)/[CH:4]=[CH:5]/[C:6]([C:8]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:9]=1[O:10][CH2:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15])=O)C.CO.C([O-])(=O)C.[Na+].C(O)(=O)C(O)=O.[CH2:43]([NH:47][NH2:48])[CH2:44][CH2:45][CH3:46]>CC(OC)(C)C.O>[CH2:43]([N:47]1[C:6]([C:8]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:9]=2[O:10][CH2:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[CH:5][CH:4]=[N:48]1)[CH2:44][CH2:45][CH3:46]
Reactant: CCN(/C=C/C(=O)c1ccc(OC)cc1OCc1ccccc1C(=O)OC)CC
Reactant: CCCCNN
Agent: CC(=O)[O-]
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CO
Product: CCCCn1nccc1-c1ccc(OC)cc1OCc1ccccc1C(=O)OC
Yield: 104.8 %

Procedure:
To a 5 L round bottomed flask was added (E)-methyl 2-[[2-[3-(diethylamino)-1-oxo-2-propenyl]-5-methoxyphenoxy]methyl]benzoate (150 g, 0.37 mol), 2.9 L of methanol and 0.45 L of water. After complete dissolution, a premixed quantity of sodium acetate (294 g, 3.58 mol) and n-butylhydrazine oxalate salt (133 g, 0.746 mol) was added via a powder funnel in rapid portions over a period of 20 minutes. The reaction mixture was blanketed with nitrogen during the reaction period. After 20 hours the reaction mixture was partitioned between 3 L of ethyl acetate and 3 L of water. The aqueous was removed and poured into 2 L of ethyl acetate and the aqueous was separated once again. This operation was repeated once more with 1.2 L of ethyl acetate (a total of 6 L of ethyl acetate used in total). The combined organic extracts were dried (magnesium sulfate) and concentrated under reduced pressure to 187 g of a thick oil. Flash chromatography (50% TBME/Hex) afforded the title compound (153 g, 73% yield) as a colourless oil which slowly solidified on standing: 1H NMR (300 MHz, CDCl3) δ 8.02 (1H, d), 7.6 (1H, d), 7.52-7.22 (3H, m), 7.12 (1H, d), 6.64 (1H, d), 6.54 (1H, dd), 6.20 (1H, s), 5.48 (2H, s), 4.01 (2H, t), 3.89 (s 3H), 3.76 (3H, s), 1.7-1.5 (2H, m), 1.2-1.05 (2H, m), 0.7 (3H, t).
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:20].[CH2:22]([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[OH:36])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+]>CN1C(=O)CCC1.CO.[Cu]Cl>[CH2:22]([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[O:36][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:21])=[C:7]([CH3:20])[CH:8]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Br)c2)cc1C
Reactant: Oc1ccc(Cl)cc1Cc1ccccc1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1cc(Oc2cccc(Oc3ccc(Cl)cc3Cc3ccccc3)c2)ccc1CCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
A solution of 3-[4-(3-bromo-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (0.1 g, 0.3 mmol), 2-benzyl-4-chloro-phenol (69 mg, 0.32 mmol), copper(I) chloride (14 mg, 0.14 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (0.01 mL, 0.07 mmol), and cesium carbonate (113 mg, 0.35 mmol) in NMP (3 mL) is heated to 120° C. The reaction is stirred overnight and cooled to rt. The reaction is then quenched with 1N aqueous HCl and extracted with ethyl ether. The organic is washed with brine, dried over sodium sulfate, and filtered. The solvent is removed to afford the crude ester intermediate. The intermediate is treated with 5N NaOH (0.4 mL, 2.2 mmol) in MeOH (5 mL) and heated to reflux. The reaction is stirred at reflux for 2 hours and then cooled. The reaction is quenched with 1N aqueous HCl to obtain pH=4. The aqueous layer is extracted with ethyl ether. The organic layer is washed with brine, dried over sodium sulfate, and filtered. The solvent is removed to afford the crude product. The crude is purified by prep HPLC to afford 63 mg (47%) of desired product. 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C29H25ClO4 472, found 473 and 475 (M+1 and M+3, 100%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:21])[NH:11][C:12]1([C:15]3[CH:19]=[C:18](Br)[S:17][CH:16]=3)[CH2:14][CH2:13]1)[CH2:2]2.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:18]2[S:17][CH:16]=[C:15]([C:12]([NH:11][C:10](=[O:21])[O:9][CH:3]3[CH:4]4[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]4)[CH2:2]3)([CH3:14])[CH3:13])[CH:19]=2)=[CH:25][CH:24]=1
Reactant: O=C(NC1(c2csc(Br)c2)CC1)OC1CN2CCC1CC2
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Product: CC(C)(NC(=O)OC1CN2CCC1CC2)c1csc(-c2ccc(F)cc2)c1
Yield: 49.3 %

Procedure:
Using general procedure E, quinuclidin-3-yl(1-(5-bromothiophen-3-yl)cyclopropyl)carbamate (0.227 g, 0.742 mmol), 4-fluorophenyl boronic acid (0.208 g, 1.49 mmol), tricyclohexylphosphine (0.021 g, 0.075 mmol), potassium phosphate (0.866, 4.08 mmol) and palladium acetate (8.0 mg, 36 mol) gave the title compound as a gray solid (0.142 g, 49%). 1H NMR (400 MHz, CDCl3) δ 7.60-7.45 (m, 2H), 7.24-7.19 (m, 1H), 7.10-6.97 (m, 3H), 5.23 (br s, 1H), 4.72-4.61 (m, 1H), 3.30-3.04 (m, 1H), 3.03-2.25 (m, 5H), 2.09-1.02 (m, 11H) ppm. 13C NMR (400 MHz, CDCl3) δ 162.3 (d, J=247.1 Hz), 154.5, 149.8, 143.6, 130.7, 127.4 (d, J=8.1 Hz), 121.8, 118.9, 115.8 (d, J=21.6 Hz), 70.8, 55.5, 53.4, 47.3, 46.4, 29.0, 25.4, 24.4, 19.4 ppm. Purity: 95.8% UPLCMS (210 nm & 254 nm); retention time 0.90 min; (M+1) 389.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl-].C([N:14]([CH2:17][CH3:18])[CH2:15]C)C.N1CCC1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:7]([N:14]2[CH2:15][CH2:18][CH2:17]2)=[O:9])[CH:10]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cncc(Br)c1
Agent: C1CNC1
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1cncc(Br)c1)N1CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a stirred suspension of 5-bromonicotinic acid (1.0 g, 4.95 mmol) in 15 mL of anhydrous methylene chloride at 0° C. under nitrogen was added oxaylic chloride (817 mg, 6.44 mmol). The reaction mixture was stirred at 0° C. for 30 minutes. Then triethylamine (1.25 g, 12.38 mmol) was added slowly, and followed by the addition of azetidine (565 mg, 9.90 mmol) at 0° C. The reaction was warmed to ambient temperature, and stirred for another hour. The reaction mixture was diluted with methylene chloride, quenched with water, washed with 10% potassium carbonate aqueous solution twice, dried through magnesium sulfate, and the solvent was evaporated to dry. The residue was purified by flash chromatography using a gradient of methanol in methylene chloride to give a yellow liquid as 3-bromo-5-(azetidin-1-ylcarbonyl)-pyridine (846 mg, 70.9% yield). Following, to a stirred solution of 3-bromo-5-(azetidin-1-ylcarbonyl)-pyridine (600 mg, 2.50 mmol) and tetrakis(triphenylphosphine)palladium(0) (240 mg, 0.21 mmol) in 40 mL of xylene at ambient temperature under nitrogen was added hexamethylditin (1.58 g, 4.50 mmol). The reaction was heated to 150° C. overnight. The reaction mixture was filtrated through Celite, and the filtrate was vacuumed to dry. The residual was dissolved in methylene chloride, washed with water twice, dried through MgSO4, and then the solvent was evaporated. The precipitate was purified by flash chromatography using a gradient of ethyl acetate in hexane to give a yellow solid as 3-trimethylstannyl-5-(azetidin-1-ylcarbonyl)-pyridine (846 mg, 83.0% yield). 1H NMR (300 MHz, CDCl3) δ 8.65-8.70 (m, 2H), 8.04 (t, J=1.9 Hz, 1H), 4.31 (t, J=7.63 Hz, 2H), 4.00-4.10(m, overlapped with H2O), 2.27 (m, J=6.2 Hz, 2H MS APCI, m/z=323/325/327 (M+H) HPLC 1.61 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15]Br)=[CH:7][CH:6]=1)=[O:4].C(=O)(O)[O-:18].[Na+].CCOC(C)=O>CS(C)=O.CCCCCC>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=[O:18])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C([O-])O
Reactant: COC(=O)c1ccc(CBr)c2ccccc12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CS(C)=O
Product: COC(=O)c1ccc(C=O)c2ccccc12
Temperature: 95 °C
Yield: 52.1 %

Procedure:
To a stirred solution of 4-bromomethyl-naphthalene-1-carboxylic acid methyl ester (Preparation 51, 10.5 g, 37.63 mmol) in DMSO (99.36 mL) was added sodium bicarbonate (6.32 g, 75.27 mmol) at room temperature. Resulting reaction mixture was heated at 95° C. for 3 hours. Progress of the reaction was monitored by TLC using 10% EtOAc in hexane. Rf of new spot and starting material was 0.7 and 0.8 respectively. After consumption of starting material, reaction mixture was quenched with water (400 mL) and extracted with EtOAc (2×300 mL). Combined organic layer was dried over sodium sulphate and evaporated off in vacuo to get brown colored thick mass. Crude compound was purified by column chromatography using 100-200 mesh silica gel. Desired product was eluted in 4.5% EtOAc in hexane to afford faint green solid (4.2 g, 52.17%). Compound the same as that from Preparation 3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:12]=1[NH2:13]>CO.O>[CH3:10][C:11]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:12]=1[NH:13][C:2]1[N:7]=[C:6]([NH:13][C:12]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:11]=2[CH3:10])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Solvent: CO
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1ncc(F)c(Nc2cc([N+](=O)[O-])ccc2C)n1
Temperature: 70 °C

Procedure:
2,4-Dichloro-5-fluoropyrimidine (33 mg, 0.2 mmol) was dissolved in a mixture of MeOH (1 ml) and H2O (0.1 ml). 2-Methyl-5-nitroaniline (122 mg, 0.8 mmol) was added and the mixture was refluxed for 2 days (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-Acetone, 9:1) to give N2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6+CD3OD): δ 8.31 (d, 1H, J=2.3 Hz), 8.20 (d, 1H, J=2.3 Hz), 8.06 (d, 1H, J=3.5 Hz), 7.91 (dd, 1H, J=2.3, 8.2 Hz), 7.65 (dd, 1H, J=2.9, 8.8 Hz), 7.41 (m, 1H), 7.28 (d, 1H, J=8.2 Hz), 2.28 (s, 3H), 2.24 (s, 3H); LCMS purity: 87.4%; MS (m/e): 399.20 (M+, 100).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=1)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH2:57]([C:59]1[CH:60]=[C:61]([CH:66]=[C:67]([CH3:70])[C:68]=1[OH:69])[C:62]([NH:64]O)=[NH:63])[CH3:58]>CN(C=O)C.O1CCOCC1>[CH2:57]([C:59]1[CH:60]=[C:61]([C:62]2[N:64]=[C:12]([C:7]3[CH:6]=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[CH:10]=[C:9]([CH3:11])[N:8]=3)[O:14][N:63]=2)[CH:66]=[C:67]([CH3:70])[C:68]=1[OH:69])[CH3:58]
Reactant: Cc1cc(CC(C)C)cc(C(=O)O)n1
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCc1cc(-c2noc(-c3cc(CC(C)C)cc(C)n3)n2)cc(C)c1O
Reaction time: 1 h
Yield: 15.2 %

Procedure:
To a solution of 4-isobutyl-6-methyl-pyridine-2-carboxylic acid (480 mg, 2.09 mmol) and DIPEA (810 mg, 6.27 mmol) in DMF (20 mL), PyBOP (1150 mg, 2.21 mmol) is added at 0° C. The mixture is stirred for 15 min at 0° C. before 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine (429 mg, 2.21 mmol) is added and stirring is continued for 1 h at 0° C. The reaction is quenched by adding water, the mixture is diluted with sat. aq. NaHCO3-solution and extracted twice with EA. The combined org. extracts are dried over MgSO4, filtered and concentrated to give the crude hydroxy-amidine ester intermediate; LC-MS: tR=0.90 min, [M+H]+=370.16. This material is dissolved in dioxane (10 mL) and the mixture is stirred at 80° C. for 15 h. The solvent is evaporated and the crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give the title compound (112 mg) as a pale purple oil; LC-MS: tR=1.12 min, [M+H]+=352.17.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C(N(C(C)C)CC)(C)C.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].O1CCCC1>CN(C)C=O.C(Cl)(Cl)Cl.O>[Si:21]([O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C=O)cc1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C=O)cc1O[Si](C)(C)C(C)(C)C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a cooled solution of 3-hydroxy-4-methoxybenzaldehyde 12 (10.0 g, 65.7 mmol) in dry N,N-dimethyl formamide (75 mL) was added diisopropylethylamine (16.99 g, 131.4 mmol). Before the addition of 1.0 M solution of tert-butyldimethylsilyl chloride in tetrahydrofuran (11.89 g or 78.9 mL, 78.85 mmol) the mixture was stirred under nitrogen for 10 min. After complete addition over 30 min, the reaction mixture was left overnight (12-16 h). Reaction completion was checked by TLC (chloroform on silica gel plate). Water was added to the reaction mixture, extracted with dichloromethane and the organic layer was washed with a saturated sodium bicarbonate solution, water and dried. Removal of solvent in vacuo yielded as an oil which was subjected to column chromatography (eluant: chloroform) to afford as an yellow viscous oil 13 (100%). 1H NMR: δ 0.21 (s, 6H, 2×CH3), 1.01 (s, 9H, 3×CH3), 3.91 (s, 3H, OCH3), 6.94 (d, 1H, J=8.5 Hz, 5H), 7.36 (d, 1H, J=2 Hz, 2H), 7.47 (dd, 1H, J=8.5, 2 Hz, 6H), 9.89 (s, 1H, CHO). Anal. Calcd for C14H22O3Si: C, 63.12, H, 8.32. Found: C, 63.09, H, 8.30.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C1([OH:24])C=CC=CC=1.[O:25]=[C:26]([O-:37])[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[Na+].[OH-].[Na+].C(Cl)(Cl)=O>C(N(CC)CC)C.C(Cl)Cl.O>[CH3:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)([C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[CH3:9].[C:26]([OH:37])([OH:24])=[O:25]
Reactant: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: Oc1ccccc1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(O)O
Reaction time: 0.08 h

Procedure:
A polymerization reactor was charged with 4.3 liters of water, 6.0 liters of methylene chloride, 2280 g. of bis(4-hydroxyphenol)propane-2,2 i.e., bisphenol-A also referred to herein as "BPA", 35 ml. of phenol also known as "hydroxy benzene", 10 g. of triethylamine, 3.4 g. of sodium gluconate, and 415 ml. of a 35% (w/w) of an aqueous sodium hydroxide solution. The admixture was equilibrated to form a substantially uniform agitated two-phase admixture by stirring for approximately 5 minutes while a pH of approximately 11.3 to 11.7 was attained. Phosgene was introduced from a calibrated flow meter at 63 g. per minute. By means of an automatic pH control a caustic 35% w/w aqueous sodium hydroxide solution was intermittently added to the reactor at a rate of 170 to 190 ml. per minute to maintain the reaction pH within the abovenoted pH range during the course of the reaction. After approximately 20-22 minutes phosgene flow was stopped, and the polymer reaction mixture was continuously agitated for an additional 2 minutes. The aqueous layer was sampled to determine residual "BPA" monomer which for control purposes was required to be less than 15 parts per million. The organic phase was separated and diluted with 4000 ml. of methylene chloride, washed twice with a dilute hydrochloric acid, (4000 ml. of a 2% w/v solution), and twice with 4000 ml. of deionized water. The resulting polymer solution was flash evaporated with steam and the resulting precipitate was collected and dried in nitrogen.