Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([NH:27][C:28]4[CH:32]=[C:31]([CH2:33][C:34]([OH:36])=O)[NH:30][N:29]=4)=[N:22][CH:23]=[N:24]3)=[CH:19][C:18]=2[O:37][CH3:38])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43].Cl.CN(C)CCCN=C=NCC.OC1C=CC=C[N+]=1[O-]>CN(C)C=O.ClCCl>[C:1]([O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([NH:27][C:28]4[CH:32]=[C:31]([CH2:33][C:34]([NH:43][C:42]5[CH:44]=[CH:45][CH:46]=[C:40]([F:39])[CH:41]=5)=[O:36])[NH:30][N:29]=4)=[N:22][CH:23]=[N:24]3)=[CH:19][C:18]=2[O:37][CH3:38])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1cccc(F)c1
Reactant: COc1cc2c(Nc3cc(CC(=O)O)[nH]n3)ncnc2cc1OCCC1CCN(CCOC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [O-][n+]1ccccc1O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(Nc3cc(CC(=O)Nc4cccc(F)c4)[nH]n3)ncnc2cc1OCCC1CCN(CCOC(C)(C)C)CC1
Yield: 65.4 %

Procedure:
{3-[(7-{2-[1-(2-tert-butoxyethyl)piperidin-4-yl]ethoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetic acid (210 mg, 0.4 mmol) in dimethylformamide (2.1 ml) was reacted with 3-fluoroaniline (58 mg, 0.52 mmol) in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (107 mg, 0.56 mmol) and 2-hydroxypyridine-1-oxide (53 mg, 0.48 mmol) at 55° C. for 1.5 hours. The reaction mixture was cooled, diluted with dichloromethane (7 ml) and purified by chromatography on silica gel. Elution with dichloromethane:methanol (9:1) and increased polarity to dichloromethane:methanol:ammonia (9:1:0.1) yielded 2-{3-[(7-{2-[1-(2-tert-butoxyethyl)piperidin-4-yl]ethoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide (162 mg, 65% yield) as a light pink solid:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](Cl)=CC=1.[Cl:9][CH2:10][SiH2:11][CH:12](Cl)Cl.[CH2:15]([Li])[CH2:16][CH2:17][CH3:18]>O1CCCC1.CCCCCC.[Cl-].[Li+]>[Cl:9][CH2:10][Si:11]([CH2:2][CH2:7][CH2:6][CH3:5])([CH2:15][CH2:16][CH2:17][CH3:18])[CH3:12]
Reactant: ClC[SiH2]C(Cl)Cl
Reactant: Clc1ccc(Br)cc1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Si](C)(CCl)CCCC
Temperature: 25 °C
Yield: 11.6 %

Procedure:
A solution of 14.4 g (0.075 mol) of 4-bromochlorobenzene and 9.5 ml (12.3 g, 0.075 mol) of chloromethyl(dichloro)methylsilane in 150 ml of tetrahydrofuran was cooled to -60° under nitrogen and stirred while 94 ml (0.15 mol) of 1.6 molar n-butyllithium in hexane was added dropwise at a rate that held the mixture between -65° and -55°. The resulting slurry was allowed to warm to room temperature, giving a solution that was diluted with hexanes until no more lithium chloride precipitated. Filtration, evaporation of the filtrate, dissolution of the residue in hexanes, refiltration, and evaporation left 19.8 g of a pale orange liquid. Distillation gave first 1.8 g (12%) of chloromethyl(dibutyl)methylsilane, bp 45° C. (0.05 mm), followed by 6.8 g (35%) of the title compound as a colorless liquid: bp 90° C. (0.05 mm); nD21 1.5246; ir (neat) 2925, 1580, 1380, 1260, 1090, 1015, 820, 740 cm-1 ; nmr (CDCl3) 0.4 (3H, s), 0.6-1.5 (9H, m), 2.9 (2H, s), 7.0-7.4 (4H, q).
Reaction SMILES: Br[CH2:2][C:3]1[S:7][C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=3[N:12]=2)=[CH:5][CH:4]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C1C=CC=CC=1>[N:20]1([CH2:2][C:3]2[S:7][C:6]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=4[N:12]=3)=[CH:5][CH:4]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1ccc2oc(-c3ccc(CBr)s3)nc2c1
Reactant: C1COCCN1
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc2oc(-c3ccc(CN4CCOCC4)s3)nc2c1
Yield: 91.7 %

Procedure:
2-(5-Bromomethyl-2-thienyl)-5-nitrobenzoxazole (2.0 g, 0.006 mole) and morpholine (2.6 g, 0.03 mole) are dissolved in 100 ml of benzene and heated at reflux for 36 hours. The precipitated morpholine hydrobromide is removed by filtration and the benzene is evaporated yielding an oil. Crystallization from ethanol yields 1.9 g of product, melting point 149°-151°C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:12].[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]>>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH3:12])[CH:4]=1)(=[O:10])=[O:9]
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1Br
Reactant: NCCCCO
Product: Cc1cc(S(=O)(=O)NCCCCO)ccc1Br

Procedure:
Using a method analogous to that described in Example 1, 4-bromo-3-methylphenyl sulphonyl chloride was reacted with 4-aminobutanol, and the title compound obtained as a white solid after recrystallisation from ether/petrol.
Reaction SMILES: O1CCCCC1[O:7][NH:8][CH2:9][CH:10]=[CH:11][C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1.[O:21]1CCC[CH2:23][CH:22]1NO.S1C=C(C(Br)C=C)C2C=CC=CC1=2.O>CN(C=O)C>[OH:7][N:8]([CH2:9][CH:10]=[CH:11][C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)[C:22](=[O:21])[CH3:23]
Reactant: ONC1CCCCO1
Reactant: C(=Cc1cc2ccccc2s1)CNOC1CCCCO1
Agent: C=CC(Br)c1csc2ccccc12
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(O)CC=Cc1cc2ccccc2s1
Reaction time: 2 h
Yield: 66 %

Procedure:
O-Tetrahydropyranyl-3-benzo[b]thien-2-ylprop-2-enyl hydroxylamine. Tetrahydropyranylhydroxyl amine (0.51 g, 4.34 mmole) in DMF (10 mL) was added to a solution of 3-benzo[b]thienylbromoprop-2-ene (0.50 g, 1.98 mmole) in DMF (10 mL). After being allowed to stir for two hours the reaction was poured into water and extracted with ether. The organic layer was washed with NaHCO3 and brine. The organic layer was dried over MgSO4 and evaporated. The residue was chromatographed on silica gel eluting with 40% ether in hexanes to give the desired product as a yellow oil (66%).
Reaction SMILES: [O:1]=[Re:2](Cl)(Cl)Cl.C1(P([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([CH:51]1[NH:55][CH2:54][CH2:53][O:52]1)C1C=CC=CC=1>C1C=CC=CC=1>[O:1]([CH:51]1[NH:55][CH2:54][CH2:53][O:52]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1.[Re+5:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=[Re](Cl)(Cl)Cl
Reactant: c1ccc(CC2NCCO2)cc1
Solvent: c1ccccc1
Product: [Re+5]
Product: c1ccc(OC2NCCO2)cc1
Temperature: 25 °C

Procedure:
To a clear solution of the 2-(2-hydroxyphenyl)-(4S)-isopropyloxazolidine (3.7 g, 18.0 mmol) in benzene (150 mL), at reflux, was added bis(triphenylphosphine) oxorhenium(V) trichloride (1.5 g, 1.80 mmol). The resulting green solution was refluxed for 2 h, cooled to room temperature and concentrated to approximately 50 mL. The green precipitate was collected and washed with diethyl ether (3×50 mL), to afford the chiral rhenium complex (1.10 g, 83%) as a green solid. 1H-NMR (CD2Cl2): δ 7.60−7.37 (m, 19H), 7.12 (ddq, J=8.2, 7.1 and 1.8 Hz, 1H), 6.91 (td, J=7.1 and 1.8 Hz, 1H), 6.63 (dd, J=8.2 and 0.8 Hz), 4.48 (dd, J=9.8 and 4.3 Hz, 1H), 3.96 (t, J=9.8 Hz, 1H), 3.57 (ddd, J=9.8, 4.0 and 2.8 Hz, 1H), 2.92 (m, 1H), 1.00 (d, J=6.6 Hz, 3H), 0.82 (d, J=7.1 Hz, 3H). 31P-NMR (CD2Cl2): −18.5. An analogous procedure was carried out to synthesize the benzyloxazolidine analogue using 2-(2-hydroxyphenyl)-(4S)-benzyloxazolidine as a starting material.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([S:19][CH3:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH3:21])(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.[Cl-].[Na+].O>[CH3:21][C:11]1[NH:10][C:18]2[C:13]([CH:12]=1)=[CH:14][C:15]([S:19][CH3:20])=[CH:16][CH:17]=2
Reactant: CSc1ccc2c(c1)cc(C)n2S(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1ccc2[nH]c(C)cc2c1
Yield: 71.4 %

Procedure:
To a solution of 1-benzenesulfonyl-2-methyl-5-methylsulfanyl-1H-indole (156 mg, 0.49 mmol) in 10 mL of ethanol was added 10 mL of 10% aqueous sodium hydroxide solution. The mixture was warmed at reflux for 18 hours. The mixture was then diluted with 10 mL of brine and extracted with three 20 mL portions of ethyl acetate. The combined organic layers were washed with two 10 mL portions of 10% aqueous sodium hydroxide solution, two 20 mL portions of saturated aqueous ammonium chloride, two 20 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto silica gel and chromatographed on silica gel using ethyl acetate-hexanes (1:99, then 2:98, then 3:97, then 5:96) to afford 62 mg (71.2% yield) of 2-methyl-5-methylsulfanyl-1H-indole.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([CH:11]([C:14](=[O:25])[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)[O:12][CH3:13])[C:5]=1[F:26].O[Li].O>C1COCC1.CO.O>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][NH:15][C:14]([CH:11]([O:12][CH3:13])[C:6]2[C:5]([F:26])=[C:4]([CH:9]=[CH:8][C:7]=2[F:10])[C:3]([OH:27])=[O:2])=[O:25])=[CH:18][CH:19]=1)#[N:24]
Reactant: COC(=O)c1ccc(F)c(C(OC)C(=O)NCc2ccc(C#N)cc2)c1F
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(C(=O)O)c1F
Yield: 91.2 %

Procedure:
A solution of (RS)-3-[(4-cyano-benzylcarbamoyl)-methoxy-methyl]-2,4-difluoro-benzoic acid methyl ester (2.05 g) and LiOH.H2O (241 mg) in THF/MeOH/H2O 1:1:0.5 (75 ml) was stirred 1 h at rt. The organic solvents were evaporated, ice cold H2O (50 ml) was added and the pH was lowered (pH=2) by addition of 2 N aq. HCl sol. The product was extracted with AcOEt (2×120 ml). The organic layers were washed with brine (100 ml), combined and dried over Na2SO4. Evaporation of the solvent yielded 1.80 g of (RS)-3-[(4-cyano-benzylcarbamoyl)-methoxy-methyl]-2,4-difluoro-benzoic acid. White solid. MS 359.4 ([M−H]).
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-:2].N12CCCN=C1CCCCC2.[C:19](OC(=O)C)(=[O:21])[CH3:20].C(OCC)(=O)C>C1COCC1>[CH3:20][C:19]1[O:21][CH:2]=[N:1][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: [C-]#[N+]CC(=O)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ncoc1C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A stirred mixture of 10.0 g of methyl isocyanoacetate, 15.1 g of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 133 ml of anhydrous THF was cooled to 0° C., and a solution of 10.2 g of acetic anhydride in 33 ml of THF was added dropwise over 15 minutes. The mixture was stirred overnight at room temperature and stripped of solvent. The residue was mixed with 250 ml of ethyl acetate, the mixture was washed with water, dried (MgSO4), filtered and stripped of solvent. The residue was chromatographed on silica gel with a 1:1 v:v ethyl acetate/hexane mixture as eluent. The middle fractions gave methyl 5-methyl-4-oxazolecarboxylate (4A) as a white solid, m.p.: 46.5°-47.0° C.
Reaction SMILES: CC(C)CC[NH2:5].[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][C:11]=12.[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=O)=[CH:24][CH:23]=1)([O-:21])=[O:20]>>[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([CH2:26][NH:5][C:16]([C:14]2[CH:13]=[CH:12][C:11]3[N:10]([CH:9]=[CH:8][N:7]=3)[CH:15]=2)=[O:18])=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: CC(C)CCN
Reactant: O=C(O)c1ccc2nccn2c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: O=C(NCc1ccc([N+](=O)[O-])cc1)c1ccc2nccn2c1

Procedure:
The title compound was prepared as described in Example 1A, substituting (4-nitrophenyl)methanamine for 3-methylbutan-1-amine and imidazo[1,2-a]pyridine-6-carboxylic acid for 4-nitrobenzoic acid.
Reaction SMILES: C[C:2]([CH3:5])([O-])[CH3:3].[K+].[OH:7][C:8]1[C:12]([OH:13])=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:10][C:9]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].Br[CH:25]([CH3:27])[CH3:26]>CS(C)=O>[CH:2]([O:13][C:12]1[C:8]([O:7][CH:25]([CH3:27])[CH3:26])=[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:10][C:11]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH3:5])[CH3:3]
Reactant: CCOC(=O)c1oc(C(=O)OCC)c(O)c1O
Reactant: CC(C)(C)[O-]
Reactant: CC(C)Br
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1oc(C(=O)OCC)c(OC(C)C)c1OC(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.6 %

Procedure:
A solution of 1.25 g (11.11 mmol, 1.08 equiv) of potassium tert-butoxide in 7 mL of dimethyl sulfoxide is added rapidly to a room temperature solution of 1.26 g (5.16 mmol) of diethyl 3,4-dihydroxy-2,5-furandicarboxylate (Johnson, T. B. and Johns, C. O., J. Am. Chem. Soc., 28, 489 (1906)) in 10 mL of dimethyl sulfoxide under a nitrogen atmosphere. The resulting solution is stirred at room temperature for 5 minutes and treated with 3.28 g (26.63 mmol, 5.16 equiv) of 2-bromopropane. The resulting reaction mixture is stirred for 24 hours at room temperature under a nitrogen atmosphere and poured onto water. The aqueous mixture is extracted with ethyl acetate (3x). The combined extracts are washed with water (2x) and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated in vacuo to give 1.23 g of diethyl 3,4-diisopropoxy-2,5-furandicarboxylate as a solid.
Reaction SMILES: C[Si](C)(C)[N:3]1[CH2:7][C@H:6]([O:8][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][C@H:4]1[C:13]([O:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[Br:22][CH2:23][C:24](F)=[O:25].[Si](F)(C)(C)C>ClCCl>[Br:22][CH2:23][C:24]([N:3]1[CH2:7][C@H:6]([O:8][Si:9]([CH3:10])([CH3:11])[CH3:12])[CH2:5][C@H:4]1[C:13]([O:15][Si:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[O:25]
Reactant: C[Si](C)(C)OC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C)CN1[Si](C)(C)C
Reactant: O=C(F)CBr
Agent: C[Si](C)(C)F
Solvent: ClCCl
Product: C[Si](C)(C)OC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C)CN1C(=O)CBr
Temperature: 25 °C
Yield: 95 %

Procedure:
Into a solution of trimethylsilyl (2S,4R)—N-(trimethylsilyl)-4-(trimethylsilyloxy)-pyrrolidine-2-carboxylate (6.95 g, 20.0 mmol) in 15 ml of anhydrous dichloromethane was drop wise added a solution of bromoacetyl fluoride (2.82 g, 20.0 mmol) in 5 ml of dichloromethane with vigorous stirring at room temperature. Exothermic reaction occurred with liberation of Me3SiF. The reaction mixture was stirred at room temperature for 2 h and then the reaction mixture was evaporated to dryness at reduced pressure, which gave 7.53 g (yield 95%) of trimethylsilyl (2S,4R)—N-(bromoacetyl)-4-(trimethylsilyloxy)pyrrolidine-2-carboxylate as off-white solid: 1H-NMR (CDCl3) δ 0.04 (m, 9H), 0.21 (m, 9H), 1.80-2.4 (m, 2H), 3.3-3.6 (m, 1H), 3.61-3.80 (m, 2H), 4.3-4.6 (m, 2H); 13C-NMR (CDCl3) δ −0.27 (CSi), −0.01 (CSi), 26.94, 38.04, 55.71, 59.26, 70.33, 165.28, 171.82.
Reaction SMILES: C[C:2]([CH3:5])([O-])[CH3:3].[K+].[CH3:7][O:8][C:9]([C:11]1[CH:20]=[CH:19][C:14]2[NH:15][C:16](=[O:18])[NH:17][C:13]=2[CH:12]=1)=[O:10].[CH2:21](Br)[CH:22]=[CH2:23].Cl>CC(N(C)C)=O>[CH3:7][O:8][C:9]([C:11]1[CH:20]=[CH:19][C:14]2[N:15]([CH2:23][CH:22]=[CH2:21])[C:16](=[O:18])[N:17]([CH2:3][CH:2]=[CH2:5])[C:13]=2[CH:12]=1)=[O:10]
Reactant: C=CCBr
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1ccc2[nH]c(=O)[nH]c2c1
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: C=CCn1c(=O)n(CC=C)c2cc(C(=O)OC)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium tert-butoxide (2.57 g) was added to a solution of 2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester (2 g) in DMA (30 ml). Allyl bromide (2 ml) was added, and the mixture was stirred for 2 h at room temperature. The mixture was acidified with 2N aqueous HCl and then extracted with EtOAc. The combined organic layers were dried over Na2SO4 and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, EtOAc/heptane 1:2) to give the title compound (2.2 g) as a yellow oil. MS (m/e)=273.2 [M+H+].
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1>CC#N>[Br-:23].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: COc1ccc(OCCCBr)cc1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: COc1ccc(OCCC[N+]23CCC(C(O)(c4ccccc4)c4ccccc4)(CC2)CC3)cc1
Product: [Br-]
Yield: 77.8 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0483 g, 0.164 mmol) and 1-[(3-bromopropyl)oxy]-4-(methyloxy)benzene (0.052 g, 0.21 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0687 g, 77.5%). EI-MS m/z 458 (M+) Rt (2.03 min).
Reaction SMILES: [SH:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH-].[Na+].Cl.[CH3:15][N:16]([CH3:25])[C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Cl>C(O)C.O>[CH3:15][N:16]([CH3:25])[C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][S:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN(C)c1ccccc1CCl
Reactant: Sc1cnc2ccccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)c1ccccc1CSc1cnc2ccccc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.4 %

Procedure:
To a solution of 1 g of 2-mercaptoquinoxaline in 40 ml of ethanol was added a solution of 530 mg of sodium hydroxide in 2 ml of water, and subsequently added 1.27 g of 2-dimethylaminobenzyl chloride hydrochloride. The resulting mixture was stirred at room temperature for 18 hrs., and the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was washed successively with 5% aqueous sodium hydroxide solution, water, and saturated aqueous sodium chloride solution, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was placed under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (hexane/acetone) to give 1.5 g of 2-(2-dimethylaminobenzylthio)quinoxaline as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:66]=[CH:65][C:7]([O:8][P:9]2([O:55][C:56]3[CH:61]=[CH:60][C:59]([N+:62]([O-])=O)=[CH:58][CH:57]=3)[N:14]=[P:13]([O:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=3)([O:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[N:12]=[P:11]([O:45][C:46]3[CH:51]=[CH:50][C:49]([N+:52]([O-])=O)=[CH:48][CH:47]=3)([O:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-])=O)=[CH:38][CH:37]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-])=O.NC1C=CC=CC=1.[H][H]>O=[Pt]=O.C1COCC1>[NH2:1][C:4]1[CH:66]=[CH:65][C:7]([O:8][P:9]2([O:55][C:56]3[CH:61]=[CH:60][C:59]([NH2:62])=[CH:58][CH:57]=3)[N:14]=[P:13]([O:25][C:26]3[CH:27]=[CH:28][C:29]([NH2:32])=[CH:30][CH:31]=3)([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[N:12]=[P:11]([O:45][C:46]3[CH:51]=[CH:50][C:49]([NH2:52])=[CH:48][CH:47]=3)([O:35][C:36]3[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=3)[N:10]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(OP2(Oc3ccc([N+](=O)[O-])cc3)=NP(Oc3ccc([N+](=O)[O-])cc3)(Oc3ccc([N+](=O)[O-])cc3)=NP(Oc3ccc([N+](=O)[O-])cc3)(Oc3ccc([N+](=O)[O-])cc3)=N2)cc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: Nc1ccccc1
Product: Nc1ccc(OP2(Oc3ccc(N)cc3)=NP(Oc3ccc(N)cc3)(Oc3ccc(N)cc3)=NP(Oc3ccc(N)cc3)(Oc3ccc(N)cc3)=N2)cc1

Procedure:
A 1000-mL stirrer-equipped autoclave was charged with 40.0 g (0.041 mol) of hexakis(4-nitrophenoxy)cyclotriphosphazene (2), aniline (75 mL), and 0.1 g of PtO2 catalyst. The mixture was agitated vigorously under 50 psi of hydrogen pressure at 50° C. until no further pressure drop was recorded (~30 h). The reaction mixture was filtered and the filtrate was poured slowly into toluene (1000 mL). Impure 3 precipitated from solution. After filtration, the crude 3 was recrystallized from o-dichlorobenzene and from THF to yield 30 g (92%) of pure 3, mp 189°-190° C. A 31P NMR spectrum in THF showed a singlet at 11.2 ppm, which indicated complete conversion of NO2 to NH2 groups.
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][C@H:25]2[CH3:31])[N:20]=[C:19]([Cl:32])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C.Cl.CCOCC>C(Cl)Cl>[Cl:32][C:19]1[N:20]=[C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][C@H:25]2[CH3:31])[C:22]([F:23])=[C:17]([NH:9][NH2:8])[N:18]=1
Reactant: C[C@@H]1CN(C)CCN1c1nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@H]1CN(C)CCN1c1nc(Cl)nc(NN)c1F
Reaction time: 64 h

Procedure:
To a solution of tris(1,1-dimethylethyl)2-{2-chloro-6-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (215.28 g, 374.3 mmol) in DCM (1870 mL) was added 2 N HCl in Et2O (1870 mL, 3740 mmol). The solution was mechanically stirred for 64 h, and the resulting suspension was allowed to settle. Most of the solvent was then decanted, and the remaining solid was triturated with DCM (1000 mL) and collected by vacuum filtration. The solid was washed with DCM and dried under high vacuum to provide 2-chloro-4-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-6-hydrazinopyrimidine, assumed trihydrochloride (138.22 g, 96% yield) as a light yellow powder. LCMS: (M+H)+: 275.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[C:10]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[N:9]=2)=[CH:4][CH:3]=1.Cl[P:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[OH-:39].[K+]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:27]1([P:26]([CH2:14][C:13]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][C:10]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[N:11][C:12]=2[CH:16]([CH3:18])[CH3:17])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:39])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: [OH-]
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CP(=O)(c1ccccc1)c1ccccc1
Temperature: 108 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
With ice-bath cooling, 1.05 g (2.95 mmol) of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]methanol was initially charged in 7 g of toluene and admixed with stirring with 820 mg (3.69 mmol) of chlorodiphenylphosphine. The mixture was heated at 108° C. for 3 h. After cooling to room temperature, 553 mg (4.43 mmol) of aqueous potassium hydroxide solution (45 percent strength) and 97.5 mg (0.29 mmol) of tetrabutylammonium bromide was added, and the mixture was stirred vigorously at 60° C. for 1 h. The heat source was removed and the reaction mixture, which was still warm, was admixed with 20 ml of water. The mixture was slowly cooled to 4° C., and the precipitated solid was filtered off. The product was washed with cold water and toluene and dried under reduced pressure at 40° C. 1.04 g (64.1 percent; content: 97.6 percent) of N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide was isolated in the form of a colorless solid.