Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:35]=[CH:34][C:12]([N:13]([CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:11][CH:10]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[Si:17]([O:16][CH2:15][CH2:14][N:13]([C:12]1[CH:34]=[CH:35][C:9]([OH:8])=[CH:10][CH:11]=1)[CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:31])([CH3:32])[CH3:33])([CH3:29])[CH3:28])([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OCCN(CCO[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCN(CCO[Si](C)(C)C(C)(C)C)c1ccc(O)cc1
Reaction time: 8 h
Yield: 99.9 %

Procedure:
The benzyl ether 3A (11.4 g, 22.1 mmol) was dissolved in THF, Pd/C catalyst (1.6 g) was added and the suspension stirred overnight under H2 atmosphere. The catalyst was filtered off, the solvent evaporated to afford 4A (9.4 g, 100%) as an oil.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Cl:15])=[C:11](OC)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][S:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Cl:15])=[C:11]([C:23]2[CH:24]=[CH:25][C:20]([S:19][CH3:18])=[CH:21][CH:22]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cnn(Cc2ccccc2)c(=O)c1Cl
Reactant: CSc1ccc(B(O)O)cc1
Product: CSc1ccc(-c2cnn(Cc3ccccc3)c(=O)c2Cl)cc1

Procedure:
2-Benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone (J. Het. Chem., 1996, 33, 1579-1582) was converted to the 5-hydroxy-analog according to the method of Example 7 and then to the 5-(trifluoromethyl)sulfonyloxy-analog according to the method of Example 8. Subsequent coupling to 4-(methylthio)phenylboronic acid, according to the method of Example 9, provided 2-benzyl-4-chloro-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone. This intermediate was coupled with 4-chloro-3-fluorophenylboronic acid according to the method of Example 6. This product was N-debenzylated according to the method of Example 11 and N-alkylated with 2-iodo-1,1,1-trifluoroethane according to the method of Example 20. The resulting sulfide was oxidized to the corresponding sulfoxide with one equivalent of meta-chloroperoxybenzoic acid to provide the methylsulfoxide which was converted to the sulfonamide final product according to the method of Example 68 (yield: 500 mg, 75%). mp 214-215° C. 1H NMR (300 MHz, CDCl3) δ 4.82 (s, 2H), 4.88 (q, J=9 Hz, 2H), 6.88 (m, 1H), 7.09 (dd, J=9 Hz, 3 Hz, 1H), 7.31 (d, J=9 Hz, 1H), 7.32 (d, J=9 Hz, 2H), 7.90 (s, 1H), 7.92 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 462 (M+H)+. Anal. calc. for C18H12F4ClN3O3S: C, 46.81; H, 2.61; N, 9.09. Found: C, 46.79; H, 2.59; N, 8.86.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].[OH2:13]>>[CH2:2]([OH:1])[C@H:3]1[O:4][C@H:11]([O:12][C@:9]2([CH2:11][OH:12])[O:13][C@H:3]([CH2:2][OH:1])[C@@H:5]([OH:6])[C@@H:7]2[OH:8])[C@H:9]([OH:10])[C@@H:7]([OH:8])[C@@H:5]1[OH:6]
Reactant: O
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O

Procedure:
To a Hobart mixer is added 23% fructose, 57% non dairy creamer, 15% instant soluble coffee, 3.5% carboxymethyl cellulose and 1.5% mocha flavor system. The ingredients are blended into a uniform mixture. An agglomerating solution formed from a 60/40 mixture of sucrose and water (6.5%) is added and the mixture is agitated until the desired agglomerated particles are formed. The resulting agglomerated particles are placed in a vacuum oven at 90° F. (33° C.) and 4.5 TORR (mm HG) to reduce the moisture below 3.5%. The dried agglomerated particles are then sized so as to pass through a 12 mesh screen.
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>>[C:13]([N:6]1[CH:7]=[N:8][C:4]([CH2:3][C@@H:2]([C:9]([OH:11])=[O:10])[NH2:1])=[CH:5]1)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Product: N[C@@H](Cc1cn(C(=O)OCc2ccccc2)cn1)C(=O)O

Procedure:
reacting L-histidine with benzyl chloroformate, resulting in an N′-carbobenzoxy-L-histidine;
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:30]=[CH:29][C:8]([C:9]([N:11]2[CH2:16][CH2:15][C:14]3([O:21][CH:20]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH2:19][C:18](=O)[CH2:17]3)[CH2:13][CH2:12]2)=[O:10])=[CH:7][C:6]=1[CH3:31])([CH3:3])[CH3:2].[CH2:32]([Mg]Br)[CH3:33].N1C=CC=CC=1.S(Cl)(Cl)=O>C1COCC1>[CH2:32]([C:18]1[CH2:19][CH:20]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[O:21][C:14]2([CH2:13][CH2:12][N:11]([C:9]([C:8]3[CH:29]=[CH:30][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[C:6]([CH3:31])[CH:7]=3)=[O:10])[CH2:16][CH2:15]2)[CH:17]=1)[CH3:33]
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CC(=O)CC(c2cccnc2)O3)ccc1OC(C)C
Reactant: CC[Mg]Br
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCC1=CC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)OC(c2cccnc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.2 %

Procedure:
A solution of 3-(4-isopropoxy-3-methyl-benzoyl)-10-(3-pyridyl)-11-oxa-3-azaspiro[5.5]undecan-8-one (148 mg, 0.35 mmol) in THF (1.8 mL) was cooled to 0° C. and treated with ethyl-magnesium bromide (42 μL of 1 M, 0.42 mmol). The reaction mixture was stirred for 2 h and was quenched by the addition of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate (3×100 mL) and the combined organics were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was diluted with dichloromethane (2 mL) and treated with pyridine (34 μL, 0.42 mmol). The reaction mixture was cooled to 0° C. and treated with thionyl chloride (28 μL, 0.39 mmol) dropwise. The reaction mixture was stirred for 90 min, quenched with ice-cold water (5 mL), and diluted with CH2Cl2 (80 mL). The mixture was washed with dilute HCl (5%, 2×15 mL), water (2×20 mL), and sodium bicarbonate (5%, 15 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified on silica gel utilizing a gradient 50-100% ethyl acetate in hexanes to yield [8-ethyl-10-(3-pyridyl)-11-oxa-3-azaspiro[5.5]undec-7-en-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (90 mg) ESI-MS m/z calc. 434.26, found 435.3 (M+1)+; Retention time: 1.74 minutes (3 min run).
Reaction SMILES: C([O:4][C:5]1[C:6]([C:12]#[N:13])=[N:7][C:8]([F:11])=[CH:9][N:10]=1)C=C.[Cl-].[Al+3].[Cl-].[Cl-].O>C1(C)C=CC=CC=1>[F:11][C:8]1[N:7]=[C:6]([C:12]#[N:13])[C:5](=[O:4])[NH:10][CH:9]=1
Reactant: C=CCOc1ncc(F)nc1C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1nc(F)c[nH]c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58 %

Procedure:
In 5 mL of toluene was dissolved 1.0 g of 3-(allyloxy)-6-fluoro-2-pyrazinecarbonitrile. After adding 0.82 g of aluminum chloride, the mixture was stirred at room temperature for 1.5 hours. Water (5 mL) was added to the reaction mixture, the aqueous layer was separated, and the organic layer was extracted first with 3 mL of water and then with 2 ml of water. The aqueous layers were united and washed with 5 mL of toluene, and extracted with 15 mL of ethyl acetate. The organic layer thus obtained was washed with 3 mL of water and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Thus, 0.45 g of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile was obtained as a yellow-colored solid product.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19].CCCCCC.C(OCC)(=O)C>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1.O>[C:1]([C:4]1([CH2:19][CH2:18][C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)C1CCCCC1=O
Reactant: C=CC(=O)OC(C)(C)C
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)C1(CCC(=O)OC(C)(C)C)CCCCC1=O
Temperature: 40 °C
Reaction time: 18 h

Procedure:
To a suspension of 2-acetylcyclohexanone (100 g, 0.71 mol), potassium carbonate (118.3 g, 0.85 mol) and benzyltriethylammonium chloride (3.18 g, 0.014 mol) in toluene (280 ml), was added, in one portion, tert-butyl acrylate (137.1 g, 155.2 ml, 1.07 mol) at room temperature. The suspension was stirred at 40° C. for 18 hours, diluted with distilled water (1 L) and toluene (500 ml), and the layers separated. The aqueous layer was extracted with toluene (3×500 ml), the combined toluene extracts dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a brown oil, (197.8 g). Rf. 0.41 (silica, hexane/ethyl acetate, 3:1). The crude product was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.S(O)(O)=O.[CH2:16](N)[CH2:17][NH2:18]>C(O)CO.O>[CH3:11][C:10]1[C:2]([NH:1][CH2:16][CH2:17][NH2:18])=[C:3]2[C:7](=[CH:8][CH:9]=1)[NH:6][N:5]=[CH:4]2
Reactant: Cc1ccc2[nH]ncc2c1N
Reactant: NCCN
Agent: O=S(O)O
Solvent: O
Solvent: OCCO
Product: Cc1ccc2[nH]ncc2c1NCCN

Procedure:
m.p. 153°-155° C., recrystallized from water (yield 31% of theory) by reacting 4-amino-5-methylindazole with an excess of ethylenediamine sulphite in ethylene glycol-water (1:1 v/v) for 24 hours at 110° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9]O.P(Br)(Br)[Br:12].C(=O)(O)[O-].[Na+]>ClCCl>[Br:12][CH2:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: BrP(Br)Br
Reactant: OCc1cc(F)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(F)c(CBr)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
To a solution of (2,5-difluoro-phenyl)-methanol (4.8 g, 33.6 mmol) in dichloromethane (40 mL) was added drop wise phosphorus tribromide (94 g, 33.6 mmol). The mixture was stirred at room temperature for 16 h. The reaction was poured onto ice/water. The aqueous phase was made basic with sodium bicarbonate. The aqueous phase was extracted with dichloromethane. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with (hexanes/ethyl acetate 90:10) to give the title compound (3.5 g, 50%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30](Br)=[C:29]4[C:25]=3[C:26](=[O:35])[N:27]([CH3:34])[CH2:28]4)[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[C:12]([O:40][CH3:41])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:42]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:44])[CH3:43]>>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30]([N:48]4[CH2:49][CH2:50][N:45]([C:42](=[O:44])[CH3:43])[CH2:46][CH2:47]4)=[C:29]4[C:25]=3[C:26](=[O:35])[N:27]([CH3:34])[CH2:28]4)[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[C:12]([O:40][CH3:41])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CC(=O)N1CCNCC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCN(C(C)=O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 199 using Diethyl[4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-3-methoxybenzyl]phosphonate and 1-acetylpiperazine. MS (ES+): m/z 706.38 (100) [MH+]; HPLC: tR=0.99 min (UPLC, purity).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH2:11].N1C=CC=CC=1.[C:18](Cl)(Cl)=[O:19]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[N:11]=[C:18]=[O:19]
Reactant: O=C(Cl)Cl
Reactant: COc1cc(N)c(F)cc1C
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(N=C=O)c(F)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Fluoro-5-methoxy-4-methyl-phenylamine (78 mg, 0.50 mmol) was dissolved in 10 ml of toluene at room temperature. DMAP (1 eq, 61 mg), pyridine (1.3 eq, 0.06 ml) were added followed by phosgene (1.33 eq, 0.34 ml, 20% solution in toluene). The mixture was allowed to stir at room temperature for 3 hours, forming a fine white precipitate. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was diluted with dichloromethane and concentrated in vacuo again to give 1-fluoro-2-isocyanato-4-methoxy-5-methyl-benzene (90 mg, quantitative) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([OH:11])[C:3]=1C=O.CO[CH:14]([O:17][CH3:18])[O:15][CH3:16].[N+]([O-])([O-])=O.[NH4+].C(=O)([O-])[O-].[Na+].[Na+]>CO>[Cl:1][C:2]1[C:3]([CH:14]([O:15][CH3:16])[O:17][CH3:18])=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1c(O)ccc(F)c1Cl
Reactant: COC(OC)OC
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(OC)c1c(O)ccc(F)c1Cl
Temperature: 25 °C
Yield: 65.2 %

Procedure:
2-Chloro-3-fluoro-6-hydroxybenzaldehyde (79.0 g, 452 mmol) was taken in a single neck flask equipped with a condenser and a nitrogen inlet. To this, trimethylorthoformate (96.0 g, 99.0 mL, 905 mmol) and a solution of ammonium nitrate (3.6 g, 45 mmol) in methanol (40 mL) were added and heated to reflux for 16 hours. The reaction mixture was cooled to room temperature, poured into saturated aqueous sodium carbonate solution, stirred for few minutes, and extracted with ethyl acetate (300 mL, 200 mL). The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated to give crude product. It was purified by column chromatography on silica gel using 10% ethyl acetate in hexane as eluent to give 65 g (64% yield) of the title compound. 1HNMR (CDCl3, 300 MHz): δ=8.52 (s, 1H), 7.04 (dd, J=9.0 Hz, 1H), 6.74-6.78 (m, 1H), 5.84 (s, 1H), 3.47 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([NH:18]C(=O)OC(C)(C)C)=[CH:15][CH:16]=3)[O:11][C:10]([CH3:27])([CH3:26])[C:9]=2[CH:28]=[CH2:29])=[CH:4][CH:3]=1.Cl.O1CCOCC1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=3)[O:11][C:10]([CH3:26])([CH3:27])[C:9]=2[CH:28]=[CH2:29])=[CH:4][CH:3]=1
Reactant: C=CC1=C(c2ccc(F)cc2)c2ccc(NC(=O)OC(C)(C)C)cc2OC1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C=CC1=C(c2ccc(F)cc2)c2ccc(N)cc2OC1(C)C

Procedure:
The compound obtained in (2) described above (182 mg) and 4N hydrochloric acid-dioxane solution (4 mL) were treated in the same manner as Reference Example 5(5) to give the titled compound as a crude product.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][OH:22]>>[OH:22][CH2:21][CH2:20][C:19]([NH:18][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:24])[CH3:23]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)(N)CCO
Product: CC(C)(CCO)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 8e, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) and 3-amino-3-methyl-1-butanol (CAN 42514-50-1; 58.46 mg, 0.51 mmol) as starting materials, and isolated (15 mg, 10.9%) as off white solid; LC-MS (UV peak area, ESI) 100%, 320.4 (M+H).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH3:9])[CH2:5][CH2:4]1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.CC(C)([O-])C.[K+]>C(O)CCC>[CH3:9][CH:6]1[CH2:7][CH2:8][CH:3]([CH2:2][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH2:4][CH2:5]1
Reactant: c1c[nH]cn1
Reactant: CC1CCC(CBr)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCO
Product: CC1CCC(Cn2ccnc2)CC1

Procedure:
1-Bromomethyl-4-methylcyclohexane (3.1 g, 0.0162 mol) was added dropwise to a stirred, boiling solution of imidazole (1.12 g, 0.0165 mol) and potassium t-butoxide (1.85 g, 0.0165 mol) in dry n-butanol, under dry nitrogen. After the addition, the reaction mixture was stirred and heated under reflux for 10 h.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](O)[CH:13]=2)[O:8][C:7](=[O:16])[CH:6]=1.C(N(CC)CC)C.[CH3:29][N:30]=[C:31]=[O:32]>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:31](=[O:32])[NH:30][CH3:29])[CH:13]=2)[O:8][C:7](=[O:16])[CH:6]=1
Reactant: CN=C=O
Reactant: O=c1cc(Oc2c(Cl)cccc2Cl)c2cc(O)ccc2o1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1ccc2oc(=O)cc(Oc3c(Cl)cccc3Cl)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(2,6-dichlorophenoxy)-6-hydroxycoumarin (0.5 g, 1.55 mmole) in dimethyl formamide, under nitrogen, at room temperature is treated with triethylamine (0.7 mL, 5 mole), then treated with CH3NCO (0.5 mL, 5.5 mole) and allowed to stir at room temperature for about 1 hour. When the reaction is complete by HPLC analysis, the reaction mixture is poured onto water and extracted with methylene chloride. The extracts are concentrated in vacuo to give a residue. The residue is crystallized from methylene chloride/hexane to afford the title product as white crystals, 0.382 (71% yield), mp 292°-299° C., identified by 1HNMR, 13CNMR and IR analyses.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].C(N(CC)CC)C.[CH2:23]([S:27](Cl)(=[O:29])=[O:28])[CH2:24][CH2:25][CH3:26].C(Cl)(Cl)Cl>C(Cl)Cl.C(Cl)(Cl)Cl.CCCCCC.O>[CH2:23]([S:27]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:29])=[O:28])[CH2:24][CH2:25][CH3:26]
Reactant: O=C(O)CCCCCCCCCCCO
Reactant: CCCCS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCCCS(=O)(=O)OCCCCCCCCCCCC(=O)O

Procedure:
12-Hydroxydodecanoic acid (1 g) was dissolved in methylene chloride (25 ml), and triethylamine (2 ml) was added to the solution. To the mixture, while it was ice-cooled and stirred, was added dropwise 1-butanesulfonyl chloride (0.72 ml). After 1.5 hours of stirring, the reaction mixture was distributed into chloroform and water, and the chloroform layer was dried with anhydrous sodium sulfate and concentrated. The residue thus obtained was subjected to chromatography on a silica gel column with an eluent system of chloroform-hexane (2:1) to give 12-butanesulfonyloxydodecanoic acid (0.99 g). The product (220 mg) was dissolved in N,N-dimethylformamide (DMF). N-Hydroxysuccinimide (76 mg) and N,N'-dicyclohexylcarbodiimide (149 mg) were added, and the mixture was stirred for 12 hours. The precipitates obtained were removed by filtration and the filtrate was concentrated to give the active ester of 12-butanesulfonyloxydodecanoic acid. The active ester was dissolved in DMF, and 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (251 mg) and triethylamine (0.73 ml) were added. The mixture was stirred for 12 hours. The reaction mixture was concentrated, and the residue was subjected to chromatography on a silica gel column with an eluent system of chloroform-methanol (6:1) to give SPK232 in the yield of 134 mg.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]1[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].Cl.O>C(O)(=O)C>[O:1]=[C:2]1[O:6][CH:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]1[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCOC1=C(c2ccccc2)C(CCC(=O)OCC)OC1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CCCCCOC1=C(c2ccccc2)C(CCC(=O)O)OC1=O
Temperature: 100 °C
Yield: 79.8 %

Procedure:
A mixture of ethyl 3-(5-oxo-4-pentyloxy-3-phenyl-2,5-dihydro-2-furyl)propionate (3 g) and 3N hydrochloric acid (28 ml) in acetic acid (28 ml) was heated at 100° C. for 2 hours with stirring. After cooling the mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine successively and dried. Evaporation of the solvent gave a residue which was recrystallized from a mixture of n-hexane and ethyl acetate to give 3-(5-oxo-4-pentyloxy-3-phenyl2,5-dihydro-2-furyl)propionic acid (2.20 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[CH:3]=1.[OH:17][CH2:18][CH2:19][N:20]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)[CH3:21]>>[Cl:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[F:15])[NH:8][C:4]1[CH:3]=[C:2]([NH:26][C:25]2[CH:24]=[CH:23][C:22]([N:20]([CH2:19][CH2:18][OH:17])[CH3:21])=[CH:28][CH:27]=2)[N:7]=[CH:6][N:5]=1
Reactant: Fc1ccc(Nc2cc(Cl)ncn2)cc1Cl
Reactant: CN(CCO)c1ccc(N)cc1
Product: CN(CCO)c1ccc(Nc2cc(Nc3ccc(F)c(Cl)c3)ncn2)cc1
Yield: 10 %

Procedure:
Using an analogous reaction procedure to that described in Example 6, 6-chloro-4-(3'-chloro-4'-fluoroanilino)pyrimidine (0.258 g) was reacted with 4-[N-(2-hydroxyethyl)-N-methylamino]aniline (0.166 g). The product so obtained was recrystallised from a mixture of methylene chloride, methanol and hexane to give 4-[3'-chloro-4'-fluoroanilino]6-[4'-{N-(2-hydroxyethyl) -N-methylamino}anilino]pyrimidine in 10% yield;
Reaction SMILES: [CH2:1]([N:8]([C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[CH:12][C:11]=1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>CN(C=O)C>[CH2:1]([N:8]([C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[CH:12][C:11]=1[O:26][CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)C(=O)N(Cc1ccccc1)Cc1ccc(-c2cccc3ccccc23)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)N(Cc1ccccc1)Cc1ccc(-c2cccc3ccccc23)cc1OCC(=O)OC(C)(C)C
Temperature: 75 °C

Procedure:
A solution of Example 20C (300 mg, 0.68 mmol) in DMF (5.0 mL) was treated with K2CO3 (189 mg, 1.36 mmol) and t-butyl bromoacetate (121 μL, 0.82 mmol), heated at 75° C. for 1.5 hours, quenched with water, and extracted with ethyl acetate. The extract was washed with brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel 4:1 hexanes/ethyl acetate to provide the desired product.
Reaction SMILES: [CH2:1]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].Cl[CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>CS(C)=O>[CH3:19][Si:20]([CH2:23][NH:15][CH2:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:17][CH:16]=1)([CH3:22])[CH3:21]
Reactant: C[Si](C)(C)CCl
Reactant: CCCCCCCCCc1ccc(CN)cc1
Solvent: CS(C)=O
Product: CCCCCCCCCc1ccc(CNC[Si](C)(C)C)cc1
Reaction time: 16 h
Yield: 36.5 %

Procedure:
A solution of 1.3 g (6 mmol) of 4-(nonyl)benzylamine (from Step A) and 700 mg (6 mmol) of chloromethyltrimethylsilane in 5 mL of DMSO was stirred at 90° C. for 3 h, then at rt for 16 h. The mixture was partitioned between MTBE and 1N NaOH. The organic layer was separated, washed with sat'd NaCl, dried and concentrated. Flash chromatography using 9:1 v/v hexane/EtOAc as the eluant afforded 700 mg of N-(trimethylsilylmethyl)-4-(nonyl)benzylamine.