Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1.[ClH:27].O1CCOCC1>>[ClH:27].[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2ccc3ccccc3c2Br)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Brc1c(COC2CCNCC2)ccc2ccccc12
Yield: 95 %

Procedure:
A solution of 15 (1.117 g, 2.65 mmole) in 4N HCl/dioxane (10 ml) was stirred at room temperature for 1 hr. The solvent was evaporated in vacuo to give a white precipitant which upon washing repeatedly with hexane gave 0.9 g of 1 (2.53 mmole) (95%). Anal (C16H19BrClNO) C,H,N. For chromatographic and spectral analysis, 0.7 g of 1 was dissolved in water (30 ml) and the solution was made basic with conc NH4OH. The resulting oily precipitate was extracted with CH2Cl2 (3×50 ml). The CH2Cl2 fraction was washed with saturated NaHCO3, H2O, brine and dried over anhydrous MgSO4. The dried CH2Cl2 solution was evaporated in vacuo to give 0.6 g of a light yellow oil that solidified upon standing as the free base form of 1. A single component was detected by TLC (hexane/ethyl acetate, 90:10) Rf, 0; (conc NH4OH/methanol/hexane/ethyl acetate, 1:1:3:6) Rf, 0.35; NMR (CDCl3) d 1.7-2.1 (m, 4H, CH2 -ring) d 2.8-3.2 (m, 4H, ring- (CH2)2 --NH), d 3.7 (m, 1H, O--CH-ring), d 4.8 (2H, 5, CH2 --O--) d7.4-8.3 (m, 5H, naphthyl).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][CH3:28])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[O:29]1[C:33]2[CH:34]=[CH:35][C:36](B(O)O)=[CH:37][C:32]=2[CH2:31][CH2:30]1.N1C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][CH3:28])[N:8]([C:36]2[CH:35]=[CH:34][C:33]3[O:29][CH2:30][CH2:31][C:32]=3[CH:37]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)c1ccc2c(c1)CCO2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1nc(CC)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 81.9 %

Procedure:
A mixture of 4′-[(4-butyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (5.0 g), 2,3-dihydro-1-benzofuran-5-ylboronic acid (4.4 g), copper(II) acetate (4.9 g), pyridine (5.4 mL), triethylamine (9.4 mL), molecular sieves 4 A (10 g) and dichloromethane (200 mL) was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (5.4 g, 82%) as a pale-yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=[O:17])[CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([S:15][CH3:16])[N:10]=2)=[CH:4][CH:3]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>>[CH3:20][N:21]([CH3:23])[CH:22]=[C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([S:15][CH3:16])[N:10]=1)[C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:17]
Reactant: COC(OC)N(C)C
Reactant: CSc1nccc(CC(=O)c2ccc(Cl)s2)n1
Product: CSc1nccc(C(=CN(C)C)C(=O)c2ccc(Cl)s2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A solution of 1-(5-chloro-2-thienyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]ethanone (1 eq, 104 mmol) in 290 mL N,N-dimethylformamide dimethyl acetal was stirred at 80° C. for 1 h40 min and then stirred overnight at room temperature. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel (heptane/ethyl acetate 1:1 to 3:7) to afford 32.7 g (86% yield) of 3-(dimethylamino)-1-(5-chloro-2-thienyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]prop-2-en-1-one.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH3:16])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[Cl:19][C:20]1[CH:37]=[C:36]([CH2:38]Br)[CH:35]=[CH:34][C:21]=1[O:22][CH:23]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:24]([O:26][CH3:27])=[O:25]>CN(C=O)C>[CH2:1]([C:5]1[N:14]([CH2:38][C:36]2[CH:35]=[CH:34][C:21]([O:22][CH:23]([C:24]([O:26][CH3:27])=[O:25])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:20]([Cl:19])[CH:37]=2)[C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:16])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)C(Oc1ccc(CBr)cc1Cl)c1ccccc1
Reactant: CCCCc1nc(=O)c2cc(C)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2ccc(C)cc2c(=O)n1Cc1ccc(OC(C(=O)OC)c2ccccc2)c(Cl)c1
Yield: 52.4 %

Procedure:
To a half suspension of 62 mg (0.287 mmol) of the product of Step A of Example 1 in 1.0 mL of anhydrous DMF was added 12 mg (1.05 eq) of a 60% oil dispersion of sodium hydride and the reaction mixture was stirred under an N2 atmosphere. After stirring 10 minutes at room temperature, a solution of 0.127 g (1.2 eq) of the product of Step B dissolved in 1.0 mL DMF was added to the solution of the anion. The reaction mixture was then stirred overnight, then partitioned between water and ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and evaporated in vacuo. The residual oil was purified on a silica gel flash chromatography column eluted with 30% ethyl acetate/hexane to afford 76 mg (52%) of the title compound.
Reaction SMILES: [C:1](=S)(OCC)[S-:2].[K+].[NH2:8][C:9]1[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[C:12]([O:19][CH3:20])=[CH:11][C:10]=1[OH:21]>C(O)C>[SH:2][C:1]1[O:21][C:10]2[CH:11]=[C:12]([O:19][CH3:20])[C:13]([O:17][CH3:18])=[C:14]([O:15][CH3:16])[C:9]=2[N:8]=1
Reactant: COc1cc(O)c(N)c(OC)c1OC
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CCO
Product: COc1cc2oc(S)nc2c(OC)c1OC
Yield: 64.2 %

Procedure:
Potassium O-ethyl dithiocarbonate (321 mg, 2.0 mmol) was added to a solution of the aminophenol (199 mg, 1.0 mmol) in ethanol (5 ml) and the mixture was heated to reflux for 16 hours. The reaction solution was concentrated, water (30 ml) was added thereto and the mixture was adjusted to pH, 3-4 with diluted hydrochloric acid the separated matter was collected by filtration, dried by heating in vacuo and recrystallized from methanol, ether and hexane to provide 155 mg (yield 64%) of 2-mercapto-4,5,6-trimethoxybenzoxazole as reddish-purple needles.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.[NH:24]1[CH2:28][CH2:27][C@H:26](O)[CH2:25]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.Cl>C1COCC1>[O:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@@H:26]3[CH2:27][CH2:28][NH:24][CH2:25]3)[N:9]=2)=[CH:16][CH:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: O[C@H]1CCNC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@@H]1CCNC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (45.50 g, 150 mmol, 1.0 eq), (S)-pyrrolidin-3-ol (bought from CNH, 51.95 g, 277.5 mmol, 1.85 eq) and Ph3P (72.79 g, 277.5 mmol, 1.85 eq) in THF (400 mL) at rt was added DIAD (57.6 mL, 292.5 mmol, 1.95 eq) dropwise over 1.5 h. The mixture was stirred another 30 min and concentrated HCl solution (100 mL) was added dropwise over 30 min. The mixture was stirred overnight at rt. The mixture was then heated to 50° C. for 1 h to push the de-Boc to completion. THF was removed by rotavap. The crude was diluted with toluene and water. The aqueous solution was further washed with EtOAc and toluene. MeOH (70 mL, 10% v/v to the aqueous solution) was added followed by KOH solution (100 g in 100 ml, water). The mixture became warm and precipitate immediately formed. The mixture was cooled in a 4° C. fridge for 2 h and filtered. The solid was washed with water, air-dried and then dried under high-vac for 3 days. Yield 49.45 g (89%), HPLC purity 95%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[S:39]1[CH:43]=[C:42]([CH2:44][CH:45]([NH:62][CH3:63])[C:46]([N:48]([CH3:61])[C@@H:49]([C:57](=[O:60])[NH:58][CH3:59])[CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:47])[C:41]2[CH:64]=[CH:65][CH:66]=[CH:67][C:40]1=2.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:62]([C@@H:45]([C:46](=[O:47])[N:48]([CH3:61])[CH:49]([C:57](=[O:60])[NH:58][CH3:59])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:44][C:42]1[C:41]2[CH:64]=[CH:65][CH:66]=[CH:67][C:40]=2[S:39][CH:43]=1)[CH3:63])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)C(Cc1csc2ccccc12)NC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C(Cc1ccccc1)N(C)C(=O)[C@@H](Cc1csc2ccccc12)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.5 %

Procedure:
(2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid (0;19 g; 0.78 mmol) was dissolved in methylene chloride (10 mL). 1-Hydroxy-7-azabenzotriazole (0.11 g; 0.78 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.16 g; 0.86 mmol) were added. The reaction mixture was stirred for 15 min at room temperature. 3-(Benzo[b]thiophen-3-yl)-N-methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)propionamide (0.32 g ; 0.78 mmol) was dissolved in methylene chloride (10 mL) and added. Diisopropylethylamine (0.13 mL; 0.78 mmol) was added. The reaction mixture was stirred for 12 hours at room temperature. Methylene chloride (10 mL) was added. The reaction was washed with water (20 mL), an aqueous solution of sodium hydrogen sulfate (10%; 20 mL), an aqueous solution of sodium hydrogen carbonate (saturated; 20 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (2×20 cm) using ethylacatate/methylene chloride (1:1) as eluent to afford 0.26 g of ((3E)-4-(((1R)-2-(benzo[b]thiophen-3-yl)-1-(methyl-(1-methylcarbamoyl-2-phenylethyl)carbamoyl)ethyl)methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamic acid tert-butylester.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:41](Cl)([C:44]1[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=1)(=[O:43])=[O:42]>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[N:11]([S:41]([C:44]3[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc3c12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCc1c(C(=O)OC(C)C)ncc2c1c1cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc1n2S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 g of 4-methoxymethyl-6-(triisopropylsilyloxy)-beta-carboline-3-carboxylic acid isopropyl ester, 132 mg of 4-dimethylaminopyridine and 0.45 ml of triethylamine were mixed in 10 ml of dichloromethane at about 4° C. with 615 m of tosyl chloride and then stirred at room temperature for 1 hour. After 16 hours of standing at room temperature, it was diluted with dichloromethane and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. After chromatography on silica gel in the system of cyclohexane/ethyl acetate 1:1, 1.32 g of the title compound was obtained from the isolated organic phase.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:18][C:17]([C:15]1[CH:14]=[CH:13][N:12]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[N:7]=3)=[CH:9][N:10]=[C:11]2[N:16]=1)([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:27]
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(-c4ccncc4)n3)cnc2n1

Procedure:
3-(2-Chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)-imidazo[1,2-α]pyrimidine (from Example 34) (403 mg, 1.0 mmol), 4-tributylstannylpyridine (736 mg, 2.0 mmol), tetrakis(triphenylphosphine)palladium(0) (115 mg, 10 mol %) and copper(I) iodide (115 mg) in 1,4-dioxane (20 ml) were heated at reflux overnight. Purification by column chromatography on silica using 3-6% MeOH/CH2Cl2 as the eluent afforded 7-(1-methyl-1-triethylsilanyloxyethyl)-3-[2-(pyridin-4-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidine: 1H NMR (400 MHz, d6-DMSO) δ 10.23 (1H, d, J 7.3), 8.98 (1H, d, J 5.4), 8.89 (1H, s), 8.85-8.80 (2H, m), 8.36 (2H, d, J 5.9), 8.14 (1H, d, J 5.5), 7.70 (1H, d, J 7.3), 1.65 (6H, s), 0.95 (9H, t, J 7.8), 0.66 (6H, q, J 7.8).
Reaction SMILES: C(S([N:7]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1)[CH:8]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)[CH2:9]/[CH:10]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])=O)(C)(C)C.Cl.C([O-])(O)=O.[Na+]>CO>[F:34][C:33]([F:35])([F:36])[C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:7][CH:8]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[CH2:9]/[CH:10]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])=[CH:28][CH:29]=1
Reactant: COC(=O)/C=C/CC(c1ccc(C(F)(F)F)cc1)N(Cc1ccc(C(F)(F)F)cc1)S(=O)C(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)/C=C/CC(NCc1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 138 %

Procedure:
The sulfinamide from Step 3 (450 mg, 0.84 mmol) was dissolved in methanol (3 mL) and the solution was cooled in ice. HCl (4M in dioxane, 0.5 mL) was added and the solution was stirred for 30 min. NaHCO3 was added to neutralize the solution and methanol was removed by evaporation. The residue was extracted into CH2Cl2; this was washed with water, brine, dried (MgSO4) and evaporated and the residue was purified by chromatography on silica using 10-25% ethyl acetate in iso-hexane to give the product (500 mg).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.CCCCCC.[CH:19]1([CH2:25][C:26](OC)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1.C(O)(=O)C.O>[CH:19]1([CH2:25][C:26](=[O:27])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COP(C)(=O)OC
Reactant: COC(=O)CC1CCCCC1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)CC1CCCCC1)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a stirred solution of dimethyl methylphosphonate (10.3 g, 0.083 mol) in 150 ml of anhydrous THF at -78° C. was added dropwise a solution of n-butyl lithium in hexane (1.67N, 50 ml, 0.083 mol) under argon atmosphere. After 30 minutes, a solution of methyl cyclohexylacetate (5.0 g, 0.035 mol) in 10 ml of anhydrous THF was further added and the mixture was stirred for 30 minutes. The reaction solution was allowed to warm to 0° C., diluted with 5 ml of acetic acid and 10 ml of water, and concentrated. 30 ml of water was added to the residue, and then the mixture was extracted with ethyl acetate (50 ml×2). The combined ethyl acetate layers were washed with water (20 ml×1) and brine (20 ml×1), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled under reduced pressure to give a colorless transparent oil of dimethyl 3-cyclohexyl-2-oxopropylphosphonate (7.4 g, 0.0298 mol, yield 85.3%, b.p. 118°-122° C./0.23 mmHg), which was assigned the structure by the following data:
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C:15]1=[O:20])(=[O:13])=[O:12])([O-:4])=[O:3].[CH:21]([O:34][C:35]([NH:37][C:38]1[CH:43]=[CH:42][N:41]([CH2:44][C:45](O)=[O:46])[C:40](=[O:48])[N:39]=1)=[O:36])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH:21]([O:34][C:35]([NH:37][C:38]1[CH:43]=[CH:42][N:41]([CH2:44][C:45]([N:17]2[CH2:18][CH2:19][N:14]([S:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[N+:2]([O-:4])=[O:3])(=[O:12])=[O:13])[C:15](=[O:20])[CH2:16]2)=[O:46])[C:40](=[O:48])[N:39]=1)=[O:36])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)Cn1ccc(NC(=O)OC(c2ccccc2)c2ccccc2)nc1=O
Reactant: O=C1CNCCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Product: O=C(Nc1ccn(CC(=O)N2CCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])C(=O)C2)c(=O)n1)OC(c1ccccc1)c1ccccc1
Yield: 195.6 %

Procedure:
The title compound (2.53 g, 78%) was synthesized by reaction of 1-(2-nitro-benzenesulfonyl)-piperazin-2-one HCl salt (679 mg, 2.0 mmol) with [4-N-(benzhydryloxycarbonyl)-cytosin-1-yl]-acetic acid (1.90 g, 5.0 mmol) as per the procedure of example 77.
Reaction SMILES: [Na].[N+:2]([C:5]1[C:6]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]([S:14](O)=O)[CH:8]=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])([O-])=O.Cl>C(O)C.[Zn]>[NH2:2][C:5]1[C:6]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:7]([SH:14])[CH:8]=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Oc2ccccc2)c(S(=O)O)c1
Agent: Cl
Agent: [Na]
Agent: [Zn]
Solvent: CCO
Product: Nc1cc(C(=O)O)cc(S)c1Oc1ccccc1
Reaction time: 2 h

Procedure:
Zinc powder (38 g) is added to warm solution (70°C) of the mono sodium salt of 5-nitro-4-phenoxy-3-sulfinobenzoic acid (10 g) in ethanol (190 ml), and while stirring 5 N hydrochloric acid (190 ml) is added dropwise. The reaction mixture is kept under nitrogen for an additional 2 hours at 70°C. After cooling and filtration, the ethanol is distilled off in vacuo. After standing in a refrigerator for 16 hours, the precipitated material is collected by filtration and washed with concentrated hydrochloric acid (15 ml). This material is then suspended in water (300 ml) and the pH adjusted to 2 by addition of 2 N sodium hydroxide. The obtained crude 5-amino-3-mercapto-4-phenoxybenzoic acid is collected and recrystallized from aqueous ethanol. The acid is obtained with a melting point of 199° - 200°C.
Reaction SMILES: BrC1C=CC(O)=C(OC)C=1C=O.[Br:13][C:14]1[C:28]([CH2:29][O:30]CC)=[CH:27][C:17]([O:18][CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[C:16]([O:33][CH3:34])[CH:15]=1.[BH4-].[Na+].[Br:37][C:38]1[CH:45]=[C:44]([O:46][CH3:47])[C:43]([O:48][CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])=[CH:42][C:39]=1[CH:40]=[O:41]>CO.O>[Br:13][C:14]1[CH:15]=[C:16]([O:33][CH3:34])[C:17]([O:18][CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:26])[CH3:25])=[CH:27][C:28]=1[CH:29]=[O:30].[Br:37][C:38]1[CH:45]=[C:44]([O:46][CH3:47])[C:43]([O:48][CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:55])([CH3:54])[CH3:56])=[CH:42][C:39]=1[CH2:40][OH:41]
Reactant: CCOCc1cc(OCOCC[Si](C)(C)C)c(OC)cc1Br
Agent: COc1c(O)ccc(Br)c1C=O
Agent: COc1cc(Br)c(C=O)cc1OCOCC[Si](C)(C)C
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: COc1cc(Br)c(CO)cc1OCOCC[Si](C)(C)C
Reaction time: 0.5 h

Procedure:
The starting material was prepared as follows: 2-Bromo-4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-benzaldehyde was prepared in 79% yield by the substitution of 4-bromo-3-formyl-2-methoxy-phenol (Hazlet et. al., J. Org. Chem., 27, 3253-55 (1962)) in the procedure described in Example 24(a), step(vi). 1H NMR (300 MHz, CDCl3)δ 10.16(s, 1H), 7.68 (s, 1H), 7.07 (s, 1H), 5.28 (s, 2H), 3.94 (s, 3H), 3.77 (t, 2H, J=8.4 Hz), 0.94 (t, 2H, J=8.4 Hz), −0.03 (s, 9H). Preparation of [2-(4-Bromo-5-ethoxymethyl-2-methoxy-phenoxymethoxy)-ethyl]-trimethyl-silane: Sodium borohydride (275 mg, 7.2 mmol) was added in portions over 10 min to a solution of 2-bromo-4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-benzaldehyde (1.3 g, 3.6 mmol) in MeOH (20 mL) at 0° C. After 30 min, the reaction was diluted with H2O (40 mL) and extracted with EtOAc (2×30 mL). Organics were washed with brine (30 mL), dried (Na2SO4) and concentrated in vacuo to give 1.31 g of [2-bromo-4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-methanol as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.29 (s, 1H), 7.05 (s, 1H), 5.27 (s, 2H), 4.66 (d, 2H, J=6.6 Hz), 3.87 (s, 3H), 3.79 (t, 2H, J=8.4 Hz), 1.92 (t, 1H, J=6.6 Hz), 0.96 (t, 2H, J=8.4 Hz), 0.01 (s, 9H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:15]1[C:23]([OH:24])=[N:22][C:21]2[C:16]1=[N:17][CH:18]=[N:19][C:20]=2[NH2:25])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[C:27]([O:29][CH3:30])=[O:28]>C1COCC1>[CH2:8]([N:15]1[C:23]([O:24][C:27]([O:29][CH3:30])=[O:28])=[N:22][C:21]2[C:16]1=[N:17][CH:18]=[N:19][C:20]=2[NH2:25])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ncnc2c1nc(O)n2Cc1ccccc1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Oc1nc2c(N)ncnc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
Triethylamine (202 mg, 2 mmol) and N,N-dimethylaminopyridine (111 mg 0.5 mmol) were added to 9-benzyl-8-hydroxyadenine (241 mg, 1 mmol) dissolved in anhydrous THF (20 ml). After stirring at room temperature for 1 h, methyl chloroformate (113 mg, 1.2 mmol) was added thereto, and the mixture was stirred overnight at room temperature. The resulting reaction mixture was extracted by ethyl acetate (50 ml) and water (50 ml), and the resulting organic layer was concentrated under vacuum followed by addition of ether (20 ml) to obtain the desired compound as crystals (300 mg, Yield: 100%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[N+:7]([C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12])([O-:9])=[O:8].F[C:18]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:19]=1[C:20]#[N:21].Cl>CN(C=O)C>[N+:7]([C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][C:18]1[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][C:19]=1[C:20]#[N:21])([O-:9])=[O:8]
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(F)(F)F)ccc1Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
Add cesium carbonate (1.3 g, 4 mmol) to a solution of 2-nitro-aniline (276 mg, 2 mmol) and 2-fluoro-5-trifluoromethyl-benzonitrile (378 mg, 2 mmol) in DMF (10 mL) at room temperature then stir the resulting dark red solution at room temperature for 16 hours and 2 hours at 50° C. Cool down and pour into a mixture of ice and concentrated hydrochloric acid (50 mL, v/v). Extract the aqueous phase with dichloromethane (3×300 mL), wash with water and brine and dry over MgSO4 to yield the titled compound as a yellow solid (480 mg, 80%): mp 160–161° C.; 1H NMR (CDCl3) δ 7.14 (ddd, 1H), 7.48 (dd, 1H), 7.58 (dd, 1H), 7.60 (d, 1H), 7.76 (dd, 1H), 7.92 (d, 1H), 8.27 (dd, 1H), 9.63 (bs, 1H). MS (ES/neg) m/z (rel intensity) 306.1 (100).