Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].N1C=CC=CC=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.O>ClCCl>[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: CCCCCCCCCCCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
10 mmol palmityl alcohol and 20 mmol pyridine are dissolved in 100 ml dry dichloromethane. 10 mmol toluene4-sulphonyl chloride is slowly added and the mixture is heated to 40° C. with stirring for 1 hour. The reaction is cooled to room temperature and 25 ml cold water is added to stop the reaction. The mixture is washed with 3×50 ml cold, 1% aqueous sulfuric acid to remove the pyridine followed by 3×25 ml cold water and evaporation to yield palmityl toluene-4-sulfonate.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([S:25]([N:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=3Cl)=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:31])[CH:5]=1)(=[O:3])[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([S:25]([N:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=3[N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:31])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(=O)(=O)N(C)C)ccc3Cl)CC2)c(F)c1
Reactant: C1COCCN1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(=O)(=O)N(C)C)ccc3N3CCOCC3)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described for example 1 from 3-[4-(4-Acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-chloro-N,N-dimethyl-benzenesulfonamide and morpholine (60%, light yellow solid, MS (m/e): 519.2 (M+H, 100%)
Reaction SMILES: [OH:1][C:2]([C@H:5]1[N:8]([CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:7](=[O:28])[C@@H:6]1[C@H:29]([OH:31])[CH3:30])([CH3:4])[CH3:3].Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34].Cl>CN(C)C1C=CN=CC=1.ClCCl>[OH:1][C:2]([C@H:5]1[N:8]([CH:9]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH3:30])([CH3:4])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C(C)(C)O)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)[C@H]([C@@H](C)OC(=O)OCc3ccccc3)[C@H]2C(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
(3S,4S)-4-(1-Hydroxy-1-methylethyl)-3-(1-(R)-hydroxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (26 g) and 4-dimethylaminopyridine (16 g) were dissolved in dry dichloromethane (200 ml). Benzyl chloroformate (20 g) was added dropwise thereto over a period of 1 hour with ice-cooling, and the resultant mixture was stirred for 2 hours and warmed to room temperature, followed by stirring at the same temperature as above for 10 hours. 5% Hydrochloric acid (100 ml) was poured into the reaction mixture with ice-cooling, and the resulting mixture was stirred for 0.5 hour and allowed to stand. The organic layer was washed successively with water, a saturated sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave (3S,4S)-4-(1-hydroxy-1-methylethyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][C:3]=1[O:13][CH3:14].C([Li])CCC.[B:20](OC)([O:23]C)[O:21]C>C1COCC1>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([B:20]([OH:23])[OH:21])=[C:3]([O:13][CH3:14])[CH:4]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: COB(OC)OC
Reactant: COc1cc(-n2ccnc2)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(-n2ccnc2)ccc1B(O)O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1-(4-bromo-3-methoxyphenyl)-1H-imidazole in THF (5 mL) was added 2.5 M n-butyl lithium in hexanes (0.348 ml, 0.869 mmol) dropwise at −78° C. over 15 min. After addition was complete, the reaction solution was stirred at −78° C. for 15 min, and trimethyl borate (0.353 mL, 3.16 mmol) was added. The reaction was allowed to warm to RT, and continued to stir overnight. The reaction was quenched with 1 M HCl aqueous solution to pH 2, diluted with water and extracted with DCM (3×). The product remained in the aqueous solution which was concentrated in vacuo to give crude (4-(1H-imidazol-1-yl)-2-methoxyphenyl)boronic acid (120 mg, MS: 219.2 [M+H+]).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH:8]1[C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[OH:24])[CH2:14]2.CCN(CC)CC>CN(C1C=CN=CC=1)C.ClCCl>[C:2](=[O:3])([O:4][CH2:5][CH3:6])[O:24][C:18]1[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=1[CH:8]1[CH:9]2[CH2:10][CH:11]3[CH2:12][CH:13]([CH2:14][CH:7]1[CH2:16]3)[CH2:15]2
Reactant: Cc1ccc(O)c(C2C3CC4CC(C3)CC2C4)c1
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Oc1ccc(C)cc1C1C2CC3CC(C2)CC1C3
Temperature: 0 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
Ethyl chloroformate (0.64 mL, 6.7 mmol) was added dropwise to a solution of 2-admantyl-4-methylphenol (1.09 g, 4.5 mmol), Et3N (1.25 mL, 9 mmol) and DMAP (catalytic amount) in dichloromethane (8 mL) cooled in an ice-water bath to 0° C. The mixture was allowed to warm to room temperature while stirring overnight, then filtered and the filtrate was concentrated. The residue was purified by column chromatography (10-20% ethyl acetate-hexanes) to yield 2-admantyl-4-methyl-phenyl ethyl carbonate as a yellow oil (1.32 g, 94%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]1[C:18]([NH2:23])=[CH:19][CH:20]=[CH:21][CH:22]=1>>[CH3:15][O:16][C:17]1[C:18]([NH:23][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccccc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: COc1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
1-(tert-Butoxycarbonyl)-4-piperidone (4.78 g) and o-anisidine (2.96 g) were condensed in the same manner as described in Preparation Example 37 to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9]#[C:10][Si](C)(C)C)=[CH:7][N:6]=[C:5]([NH2:15])[CH:4]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO>[CH2:1]([C:3]1[C:8]([C:9]#[CH:10])=[CH:7][N:6]=[C:5]([NH2:15])[CH:4]=1)[CH3:2]
Reactant: CCc1cc(N)ncc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnc(N)cc1CC

Procedure:
The title compound is synthesized according to general procedure GP3 starting from 3.3 g (15 mmol) 4-ethyl-5-trimethylsilanylethynyl-pyridin-2-ylamine and 1.04 g (7.5 mmol) K2CO3 in 30 mL MeOH. The product is purified by chromatography on silica gel using a DCM/MeOH gradient. Yield: 1.78 g (81%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[CH:10]3)=[N:5][N:4]=[C:3]1[SH:17].Br[CH2:19][CH2:20][CH2:21][CH:22]1[O:27][CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][O:23]1.[OH-].[Li+]>CN(C)C=O>[CH3:28][C:25]1([CH3:29])[CH2:24][O:23][CH:22]([CH2:21][CH2:20][CH2:19][S:17][C:3]2[N:2]([CH3:1])[C:6]([C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[N:13]=[CH:12][CH:11]=[CH:10]4)=[N:5][N:4]=2)[O:27][CH2:26]1
Reactant: CC1(C)COC(CCCBr)OC1
Reactant: Cn1c(S)nnc1-c1ccc2ncccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1c(SCCCC2OCC(C)(C)CO2)nnc1-c1ccc2ncccc2c1
Yield: 64.2 %

Procedure:
4-Methyl-5-quinolin-6-yl-4H-[1,2,4]triazole-3-thiol (0.5 g, 2.07 mmol), 2-(3-Bromo-propyl)-5,5-dimethyl-[1,3]dioxane (0.49 g, 2.07 mmol) and lithium hydroxide (50 mg) were heated in dimethylformamide at 100° C. for 3 h. The mixture was cooled and partitioned between water (80 ml) and ethyl acetate (100 ml). The layers were separated and the aqueous re-extracted with ethyl acetate (100 ml). The combined organic portions were washed with brine (100 ml) and then dried (Na2SO4), filtered and evaporated to give a colourless oil. Purification by silica gel chromatography (eluent EtOAc—10% MeOH:EtOAc) which gave the title compound as a colourless solid (0.53 g, 65%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[NH:18]1[CH2:23][CH2:22][S:21][CH2:20][CH2:19]1>O1CCOCC1>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:18]1[CH2:23][CH2:22][S:21][CH2:20][CH2:19]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: C1CSCCN1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccccc1N1CCSCC1
Temperature: 25 °C

Procedure:
A solution of 1-fluoro-2-nitro-benzene (2.0 mmol, 0.21 mL), triethylamine (3.0 mmol, 0.42 mL) and thiomorpholine (3.0 mmol, 0.30 mL) in dioxane (2 mL) was irradiated using microwave for 15 minutes at a temperature of 160° C. The solution was then cooled to room temperature and concentrated in vacuo and the resulting residue was purified using column chromatography on silica gel to provide 4-(2-Nitro-phenyl)-thiomorpholine. To the solution of this nitro compound in MeOH (10 mL) was added Pd on carbon (5% Pd, 100 mg). The resulting reaction mixture was stirred under a hydrogen atmosphere at room temperature for about 15 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to provide compound 39A. HPLC-MS RT=1.06 minutes, mass calculated formula C10H14N2S 194.09, observed LCMS m/z 195.10 (M+H).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH2:15][N:16]1C(=O)C2=CC=CC=C2C1=O)[CH2:4][CH2:5][O:6][C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:2].O.NN>C(O)C>[NH2:16][CH2:15][CH2:14][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCN(CCOc1cccnc1F)CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CCN(CCN)CCOc1cccnc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 99.5 %

Procedure:
To a solution of compound 4 (1.50 g, 4.20 mmol) in ethanol (135 mL) was added hydrazine monohydrate (2.04 mL, 42.0 mmol). The mixture was stirred at room temperature for 14 h. The precipitate was filtered and then washed with ethanol (2×10 mL). The filtrate was evaporated under vacuum and the residue was chromatographed (Al2O3, CH2Cl2/EtOH, 9/1, v/v) to give compound 5 (949 mg, 4.18 mmol) as a yellow oil. Yield 99%; Rf (Al2O3, CH2Cl2/EtOH, 9/1, v/v) 0.36; IR (CCl4) ν 1120, 1190, 1250, 1283, 1453, 1466, 2700-3000 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.08 (t, 3H, J=7.1 Hz), 1.54 (se, 2H), 2.67 (m, 6H), 2.94 (t, 2H, J=6.0 Hz), 4.12 (t, 2H, J=6.0 Hz), 7.13 (ddd, 1H, 5JH-F=0.9 Hz, J=4.8, 7.9 Hz), 7.32 (ddd, 1H, 4JH-F=10.1 Hz, J=1.6, 7.9 Hz), 7.76 (td, 1H, 4JH-F=1.6 Hz, J=1.6, 4.8 Hz); ESI-MS m/z 227.9 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:18][C:16]2=[C:17]3[C:12](=[C:13]([O:19][CH3:20])[CH:14]=[CH:15]2)[O:11][C@@H:10]2[C@:5]3([CH:6]=[CH:7][C@H:8]([OH:21])[CH2:9]2)[CH2:4][CH2:3]1.CN1CC2C=CC(OC)=C3C=2[C@]2([C@@H](O3)CC(=O)C=C2)CC1>>[OH:11][C:12]1[CH:17]=[C:16]([CH:15]=[CH:14][C:13]=1[O:19][CH3:20])[CH2:18][N:2]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:21])=[CH:7][CH:6]=1)[CH3:1]
Reactant: COc1ccc2c3c1O[C@H]1C[C@@H](O)C=C[C@@]31CCN(C)C2
Agent: COc1ccc2c3c1O[C@H]1CC(=O)C=C[C@@]31CCN(C)C2
Product: COc1ccc(CN(C)CCc2ccc(O)cc2)cc1O

Procedure:
Barton and Kirby, J. Chem. Soc. (1962) 806, disclose the first synthetic route to (−)−galanthamine from racemic narwedine which had been prepared in very low yield from N-(3-hydroxy-4-methoxy-benzyl)-N-methyl-2-(4-hydroxyphenyl)-ethylamine. They found that (−)−narwedine crystallised preferentially when (+)−galanthamine or a mixture of (+)−galanthamine and (+)−epigalanthamine was present, and used this to resolve racemic narwedine.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]([N:17](C)[C:18](=O)C)[CH:13]=[C:14]([Br:16])[CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCOCC1.[OH-].[Na+]>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]([NH:17][CH3:18])[CH:13]=[C:14]([Br:16])[CH:15]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)N(C)c1cc(Br)cc(S(=O)(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CNc1cc(Br)cc(S(=O)(=O)c2ccccc2)c1
Yield: 958.7 %

Procedure:
0.10 g (0.000275 mol) of N-(3-benzenesulphonyl-5-bromophenyl)-N-methylacetamide was dissolved in a mixture of 5.5 ml of dioxane and 5.5 ml of 1N NaOH and heated at reflux for 1 hr. Subsequently, the organic solvent was distilled off and the residue was made neutral with 1N HCl and extracted with ethyl acetate. The organic phase was washed with water and sat. sodium chloride solution, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel with ethyl acetate/hexane 1:2. There was obtained 0.86 g (96%) of (3-benzenesulphonyl-5-bromophenyl)-methylamine as a pale yellow solid; m.p.: 143-145° C.
Reaction SMILES: C([O:3][C:4](=[S:20])[CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)C.F[C:22](F)(F)[C:23]([O:25][C:26](=O)[C:27](F)(F)F)=O.O1C=CC=C1>ClCCl>[O:25]1[CH:26]=[CH:27][CH:22]=[C:23]1[C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:4]([OH:3])=[S:20]
Reactant: CCOC(=S)C(CCCCCC(=O)O)c1ccccc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccoc1
Solvent: ClCCl
Product: O=C(CCCCCC(C(O)=S)c1ccccc1)c1ccco1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred, ice-cold solution of 7.75 g. of ethyl-7-carboxy-2-phenylthioheptanoate in 25 ml. of dichloromethane is added 3.5 ml. of trifluoroacetic anhydride during 2 minutes. The solution is stirred at ambient temperature for 10 minutes, recooled to 0° C. and treated with 9 ml. of furan during 2 minutes. The resulting solution is stirred at ambient temperature for 18 hours and then partitioned with 1:1 ether-petroleum either and aqueous sodium bicarbonate. The organic phase is washed with water and brine, dried and evaporated. The resulting crude ester (6.75 g.) is dissolved in 75 ml. of ethanol containing 4.95 g. of 85% potassium hydroxide and 10 ml. of water. This solution is refluxed for 20 minutes, cooled and concentrated in vacuo. The residue is partitioned with water and ether. The aqueous layer is acidified with dilute hydrochloric acid and extracted with ether. This extract is washed with water and brine, dried and evaporated, giving the product as an oil, identified as having a PMRδ 2.80 (2, t, J=7).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[I:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:18])=[C:15]([OH:17])[CH:16]=1.Cl[CH2:20][O:21][CH3:22]>ClCCl.CCOCC>[I:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:18])=[C:15]([O:17][CH2:20][O:21][CH3:22])[CH:16]=1
Reactant: Cc1ccc(I)cc1O
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: COCOc1cc(I)ccc1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
N,N-Diisopropylethylamine (8.3 mL, 47.4 mmol) (Aldrich) was added to a suspension of 5-iodo-2-methyl-phenol (10.1 g, 43.1 mmol) (from Example 17 supra) in dichloromethane (40 mL) with cooling in an ice-water bath. Chloromethyl-methyl ether (6.5 mL, 86.1 mmol) (Aldrich) was added dropwise and the mixture stirred at room temperature for 5 hours. The mixture was then diluted with ether (200 mL) and washed with water (200 mL), followed by 0.1 N HCl (2×200 mL) and brine (200 mL). Aqueous layers were back washed with ether (200 mL). Organic solutions were combined, dried (MgSO4), filtered and concentrated. Residue was filtered through silica gel (Biotage 40 L) eluting with dichloromethane-hexenaes (1:4 V/v). Fractions were combined and concentrated to give 4-iodo-2-methoxymethoxy-1-methyl-benzene as colorless oil. (Yield 9.05 g, 75.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:18]([I:19])=[C:11]2[NH:12][C:13]([CH3:17])=[N:14][C:15](=O)[N:10]2[N:9]=1.C(N(C(C)C)CC)(C)C.O=P(Cl)(Cl)[Cl:31]>C1(C)C=CC=CC=1>[Cl:31][C:15]1[N:10]2[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:18]([I:19])=[C:11]2[N:12]=[C:13]([CH3:17])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(=O)n2nc(-c3ccccc3Cl)c(I)c2[nH]1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Cl)n2nc(-c3ccccc3Cl)c(I)c2n1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
To a solution of 7-(2-chlorophenyl)-8-iodo-2-methyl-1H-pyrazolo[1,5-a][1,3,5]triazin-4-one (I-1A-1d; 1.00 g, 2.6 mmol) and diisopropylethylamine (0.68 ml, 3.8 mmol) in toluene (30 ml) at room temperature was added POCl3 (1.28 ml, 14 mmol), dropwise. The mixture was heated at reflux for 5 hours, cooled to room temperature, and then concentrated, in vacuo, to a viscous oil. The residue was then purified by passing through a plug of silica gel on a sintered glass funnel using 20% ethyl acetate in hexanes as eluant to provide I-1A-1e as a yellow solid (0.93 g, 89%): +APcI MS (M+1) 316.3; 1H NMR (400 MHz, CD2Cl2) δ 7.57 (d, J=7.9 Hz, 1H), 7.53-7.43 (m, 3H), 2.74 (s, 3H).
Reaction SMILES: C(OC)(=[O:4])C=C.C(P)(C)(C)C.[C:12]([P:16]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([P:16](=[O:4])([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])([CH3:14])([CH3:15])[CH3:13]
Reactant: COC(=O)CCP(CCC(=O)OC)C(C)(C)C
Reactant: C=CC(=O)OC
Agent: CC(C)(C)P
Product: COC(=O)CCP(=O)(CCC(=O)OC)C(C)(C)C

Procedure:
The procedure of Example 1 is again followed except that 860 parts of methyl acrylate are reacted with 452 parts of t-butylphosphine. 4.9 Parts of azobis-1-isovaleronitrile are used as catalyst. The liquid reaction product, t-butyl bis(carbomethoxyethyl)phosphine is oxidized to give t-butyl bis(carbomethoxyethyl)phosphine oxide which is then hydrolyzed. The product, t-butyl bis(β-carboxyethyl)phosphine oxide is isolated as an off-white crystalline solid having a m.p. of 174° C.
Reaction SMILES: [CH3:1][C:2]12[C:14]3[C:10]([CH:11]=[CH:12][CH2:13]1)=[CH:9][CH:8]=[CH:7][C:6]=3[CH2:5][CH2:4][CH2:3]2>C(O)C.[Pd]>[CH3:1][C:2]12[C:14]3[C:6]([CH2:5][CH2:4][CH2:3]1)=[CH:7][CH:8]=[CH:9][C:10]=3[CH2:11][CH2:12][CH2:13]2
Reactant: CC12CC=Cc3cccc(c31)CCC2
Agent: [Pd]
Solvent: CCO
Product: CC12CCCc3cccc(c31)CCC2
Reaction time: 6 h
Yield: 94.1 %

Procedure:
3a-Methyl-2,3,3a,4-tetrahydro-1H-phenalene (1.83 g) was dissolved in ethanol (12 ml), the solution was added with 10% palladium/carbon (0.183 g), and the mixture was stirred for 6 hours under a hydrogen flow. The reaction mixture was filtered through Celite, then the solvent of the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using a small amount of silica gel (developing solvent: n-hexane) to obtain the title compound (1.74 g, yield: 94%).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[CH:19][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC([O-])(C)C.[Na+].Br[C:27]1[S:28][CH:29]=[C:30]([C:32]([N:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]2)=[O:33])[N:31]=1.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C(OCC)(=O)C>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:27]4[S:28][CH:29]=[C:30]([C:32]([N:34]5[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH2:39]5)=[O:33])[N:31]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[CH:19][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2csc(Br)n2)CC1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2csc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)n2)CC1
Temperature: 60 °C
Yield: 57.7 %

Procedure:
Compound 4 (0.075 g, 0.30 mmol) was combined with sodium 2-methylpropan-2-olate (0.085 g, 0.89 mmol) and compound 72 (0.14 g, 0.38 mmol) in toluene (2 mL). This mixture was degassed by bubbling nitrogen through this solution for ˜2 min followed by the addition of Pd2(dba)3 (0.014 g, 0.015 mmol) and t-Butyl-XPhos (0.025 g, 0.059 mmol). The reaction was heated overnight at 60° C. Additional compound 72, 0.28 g, 0.76 mmol), Pd2(dba)3 (25 mg), t-Butyl-XPhos (54 mg), and the sodium 2-methylpropan-2-olate (0.085 g, 0.89 mmol) were added to the reaction which was heated overnight at 100° C. The reaction was cooled to 20° C. and poured into a separation funnel, with ethyl acetate and water. The layers were partitioned and the aqueous layer was washed with ethyl acetate. The combined organic fractions were dried over MgSO4 and concentrated. The product was purified by flash column chromatography, eluting with a gradient of DCM-6% methanol/0.3% NH4OH/DCM to yield compound 74 (95 mg) as a brown film. LCMS-ESI (POS), M/Z, M+1: Found 549.3.