Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C@:4]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].[Li+].[BH4-]>C1COCC1>[NH2:5][C:4]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][OH:2]
Reactant: CCCC[C@](N)(Cc1ccccc1)C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCC(N)(CO)Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of methyl ester (0.13 g, 0.55 mmol) from step B in 7.8 mL THF was added LiBH4 (2.3 mL, 4.6 mmol, 2M in THF). After 2 h at reflux, the reaction was cooled to rt and quenched by the dropwise addition of MeOH, followed by acetone. After the volatiles were removed in vacuo, the remaining residue was redissolved in 23 mL 1N HCl and heated to 45° C. for 1.5 h. The volatiles were removed in vacuo, and the remaining residue was redissolved in saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3 (4×), the combined organics layers were dried over Na2SO4, filtered and concentrated to afford 2-amino-2-benzylhexan-1-ol II which was used for the next reaction without further purification. 1H NMR (400 MHz, CDCl3) δ 7.32-7.18 (m, 5H), 3.32 (m, 2H), 7.70 (m, 2H), 1.53-1.31 (m, 6H), 0.93 (t, J=6.8 Hz, 3H) LCMS M+H=208.
Reaction SMILES: [F:1][C:2]1[CH:39]=[CH:38][C:5]([C:6]([NH:8][C@@:9]([C:24]2[CH:29]=[C:28]([O:30][C:31]([F:36])([F:35])[CH:32]([F:34])[F:33])[CH:27]=[C:26]([F:37])[CH:25]=2)([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[CH:4][C:3]=1[C:40]([F:43])([F:42])[F:41].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:53])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:39]=[CH:38][C:5]([C:6](=[S:53])[NH:8][C@@:9]([C:24]2[CH:29]=[C:28]([O:30][C:31]([F:36])([F:35])[CH:32]([F:34])[F:33])[CH:27]=[C:26]([F:37])[CH:25]=2)([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:40]([F:43])([F:42])[F:41]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: Fc1ccc([C@@](Cc2ccccc2)(NC(=S)c2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(OC(F)(F)C(F)F)c2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a stirred solution of (R)-4-fluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide (105 mg, 0.17 mmol), prepared as described in Procedure 3, 4, 5, 6 and 7, in toluene (5.2 mL) was added Lawesson's reagent (83 mg, 0.20 mmol). The reaction mixture was heated at 110° C. After 8 h, the reaction mixture was concentrated and the residue was purified by ISCO column chromatography (EtOAc/hexane 0-100%, SiO2) to provide (R)-4-fluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(trifluoromethyl)benzothioamide (Example 315, 89 mg, 83% yield) as a yellow oil. 1H NMR (500 MHz, CDCl3) δ ppm 7.92 (s, 1H), 7.74-7.72 (m, 1H), 7.68-7.66 (m, 1H), 7.22-6.86 (m, 11H), 6.72 (d, J=5 Hz, 2H), 5.92-5.70 (m, 1H), 4.36 (d, J=15 Hz, 1H), 3.82 (d, J=10 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 195 (C═S); LC/MS: RT=4.393 min [M+H] 632.4 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeCN/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].ClC1C=CC=C(C(OO)=O)C=1.C[Si]([C:31]#[N:32])(C)C>>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[C:11]([C:31]#[N:32])=[N:12][CH:13]=[CH:14][CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:31]#[N:32])=[N:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cc1cccnc1)OCC
Reactant: C[Si](C)(C)C#N
Agent: O=C(OO)c1cccc(Cl)c1
Product: CCOP(=O)(Cc1ccc(C#N)nc1)OCC
Product: CCOP(=O)(Cc1cccnc1C#N)OCC

Procedure:
Treatment of 3-(diethylphosphonomethyl)pyridine (Biochemistry 19, 3400) with m-chloroperbenzoic acid followed by trimethylsilyl cyanide gives both 3-(diethylphosphonomethyl)-2-cyanopyridine and 5-(diethylphosphonomethyl)-2-cyanopyridine, the starting materials for compounds under a) and b).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:23]=[CH:22][N:13]3[C:14](=[O:21])[C:15]([C:18](O)=[O:19])=[CH:16][N:17]=[C:12]3[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C([Cl:27])=O>CN(C=O)C.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:23]=[CH:22][N:13]3[C:14](=[O:21])[C:15]([C:18]([Cl:27])=[O:19])=[CH:16][N:17]=[C:12]3[CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cnc2cc(C#Cc3cccc(F)c3)ccn2c1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cnc2cc(C#Cc3cccc(F)c3)ccn2c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 8-((3-fluorophenyl)ethynyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (50 mg, 0.162 mmol, 1 equiv) and 1 drop DMF in dichloromethane was added oxalyl dichloride (1 mL) dropwise. The reaction mixture was stirred at room temperature for 3 h and concentrated to give the desired product, which was directly used for the next step.
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[CH2:9][NH:8][C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[NH:5]2.[C:15]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:16]([C:21]([NH:23][C:24]2[N:29]=[CH:28][C:27](C(Cl)=O)=[CH:26][CH:25]=2)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=1>>[CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[CH2:9][N:8]([C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21]([C:16]3[C:15]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:22])=[N:29][CH:28]=1)[C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[NH:5]2
Reactant: c1ccc2c(c1)NCc1cscc1N2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Product: O=C(Nc1ccc(N2Cc3cscc3Nc3ccccc32)cn1)c1ccccc1-c1ccccc1

Procedure:
As described for Example 400, 9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepine is reacted with 6-[([1,1'-biphenyl]-2-carbonyl)amino]-pyridine-3-carbonyl chloride to give the product as a solid.
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][OH:17])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(COc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1ccc(COc2ccccc2)cc1
Reaction time: 3 h
Yield: 173.9 %

Procedure:
To a flask containing [4-(phenoxymethyl)phenyl]acetic acid (1.0 g, 4.13 mmol), in THF (20 mL) under external ice cooling was added a 1.0M sol of LiAlH4 in THF (8.3 mL, 8.3 mmol) (effervescence noted). The reaction mixture was stirred for three hours under ice cooling, then allowed to stir at room temperature for 48 hours. The reaction mixture was quenched with water (4.1 mL) and 1N NaOH (24 mL) then extracted into EtOAc (200 mL). The organic layer was washed with brine (150 mL). The organics were dried over Na2SO4, filtered and concentrated in vacuo to furnish 1.64 g of the title compound as a white solid (174%), containing aluminum salt impurities. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.90 (t, J=6.64 Hz, 2H) 3.88 (t, J=6.44 Hz, 2H) 5.05 (s, 2H) 6.93-7.02 (m, 3H) 7.22-7.36 (m, 4H) 7.40 (d, J=8.20 Hz, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([N+:25]([O-])=O)[C:13]4[C:17]([CH:18]=3)=[N:16][N:15]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH:14]=4)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1>[Pd].C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([NH2:25])[C:13]4[C:17]([CH:18]=3)=[N:16][N:15]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH:14]=4)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=[N+]([O-])c1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Reaction time: 8 h

Procedure:
6-(1H-Indol-4-yl)-4-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (2.54 g), ethyl acetate (100 ml) and 10% palladium on carbon (250 mg) were placed under an atmosphere of hydrogen and the mixture stirred overnight. The mixture was filtered through Celite and the solvent removed in vacuo to give the title compound as an off white solid (2.27 g).
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH3:39])[N:36]=5)[CH:31]=[CH:30][C:29]4=[O:40])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O.C(O)(C(F)(F)F)=O.[Cl:66]CCl>>[ClH:66].[ClH:66].[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH3:39])[N:36]=5)[CH:31]=[CH:30][C:29]4=[O:40])[CH2:24][CH2:25]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: ClCCl
Reactant: COc1ccc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2n1
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2n1
Product: Cl
Reaction time: 1 h

Procedure:
A solution of 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)(1-{2-[7-(methyloxy)-2-oxo-1,8-naphthyridin-1(2H)-yl]ethyl}-4-piperidinyl)carbamate (160 mg, 0.3 mmol) in TFA/dichloromethane (2 ml/2 ml) was allowed to stand at room temperature for 1 hour then evaporated to dryness, azeotroping with chloroform. The residue was dissolved in dichloromethane/methanol (10 ml/10 ml) and treated with MP-carbonate resin (2.5 mmol of carbonate per gramme, 4 g, 10 mmol). After 15 minutes the mixture was filtered, washing with dichloromethane then methanol (twice) followed by evaporation affording the free base of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[O:10][CH:11]=[CH:12][C:4]=2[CH2:3]1.[Br:13][C:14]1[CH:15]=[C:16](F)[CH:17]=[CH:18][C:19]=1[Br:20]>>[Br:13][C:14]1[CH:15]=[C:16]([O:9][CH:6]2[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]3[CH:12]=[CH:11][O:10][C:5]2=3)[CH:17]=[CH:18][C:19]=1[Br:20]
Reactant: Fc1ccc(Br)c(Br)c1
Reactant: CN1CCC(O)c2occc2C1
Product: CN1CCC(Oc2ccc(Br)c(Br)c2)c2occc2C1

Procedure:
The same method as in Example 1 was conducted using 5-methyl-5,6,7,8-tetrahydro-4H-furo[3,2-c]azepin-8-ol (Reference Example 21) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dibromo-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[N+:8]([C:11]1[CH:29]=[CH:28][CH:27]=[CH:26][C:12]=1[CH2:13][C:14]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18][CH2:17][NH:16][C:15]1=[O:20])([O-:10])=[O:9].[CH2:30](I)[CH2:31][CH3:32]>O>[N+:8]([C:11]1[CH:29]=[CH:28][CH:27]=[CH:26][C:12]=1[CH2:13][C:14]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18][CH2:17][N:16]([CH2:30][CH2:31][CH3:32])[C:15]1=[O:20])([O-:10])=[O:9]
Reactant: CCOC(=O)C1(Cc2ccccc2[N+](=O)[O-])CCCNC1=O
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN1CCCC(Cc2ccccc2[N+](=O)[O-])(C(=O)OCC)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in oil, 1.59 g) was added to a DMF solution (100 ml) of ethyl 3-(2-nitrobenzyl)-2-oxo-3-piperidinecarboxylate (11.0 g) and propyl iodide (5.79 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and extracted with a mixture of ethyl acetate and diethyl ether. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/4 to 1/2) to obtain the entitled compound (10.6 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]#[N:8].[F:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14]>N1C=CC=CC=1>[C:7]([C:6]1[NH:5][CH:4]=[N:3][C:2]=1[NH:1][C:13](=[O:14])[C:12]1[CH:16]=[CH:17][CH:18]=[C:10]([F:9])[CH:11]=1)#[N:8]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: N#Cc1[nH]cnc1N
Solvent: c1ccncc1
Product: N#Cc1[nH]cnc1NC(=O)c1cccc(F)c1

Procedure:
Under a nitrogen atmosphere a stirred solution of 4-amino-1H-imidazole-5-carbonitrile (1.1 g, 0.01 mole) and 3-fluorobenzoyl chloride (1.8 g, 0.011 mole) in 25 ml of dry pyridine was heated at reflux for one hour. The reaction mixture was cooled and the pyridine removed under reduced pressure. The residue was washed with saturated aqueous sodium bicarbonate and water. The residual solid was collected by filtration and washed sequentially with two portions of water, diethyl ether, and ethyl acetate. The solid was dried under reduced pressure; mp, 222°-240°. The solid was dissolved in ethanol and precipitated with petroleum ether, then collected by filtration and washed with diethyl ether to give after drying N-(5-cyano-1H-imidazol-4-yl)-3-fluorobenzamide (2.0 g; mp, 242°-46°).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][NH:9][CH2:8][CH2:7]2.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([S:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][N:9]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[S:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:8][CH2:7]2
Reactant: BrCCCCCCC(Sc1ccccc1)c1ccccc1
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1OC)CN(CCCCCCC(Sc1ccccc1)c1ccccc1)CC2
Yield: 36.4 %

Procedure:
The free base from 4.60 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, 3.63 g of [(7-bromo-1-phenylheptyl)thio]benzene, 50 ml of acetonitrile and 2.61 ml of ethyl diisopropylamine is heated at reflux temperature for 29 hours. The solvent is evaporated over night and the residue is partitioned between chloroform and aqueous ammonium hydroxide. The organic layer is dried and concentrated in vacuo to give 5.81 g of crude product. The residue is purified by chromatography (silica gel: chloroform/methyl alcohol) to give 1.73 g of the desired product.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:17][C:18]([C:28]([F:31])([F:30])[F:29])=[CH:19][C:20]=2[S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:12][CH:11]=1>O1CCCC1>[Cl:1][C:19]1[C:20]([S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)[NH:17][C:18]=1[C:28]([F:29])([F:31])[F:30]
Reactant: FC(F)(F)c1cc(Sc2ccccc2)c(-c2ccc(Cl)cc2)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: FC(F)(F)c1[nH]c(-c2ccc(Cl)cc2)c(Sc2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Chlorosuccinimide (0.734 g, 5.5 mmol) is added to a solution of 2-(p-chlorophenyl)-3-(phenylthio)-5-(trifluoromethyl)pyrrole (1.77 g, 5 mmol) in tetrahydrofuran. The reaction mixture is stirred overnight at room temperature, concentrated in vacuo, diluted with carbon tetrachloride and filtered. The resultant filtrate is concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and a 1:10 ethyl acetate/hexanes solution gives the title product as a yellow syrup which is identified by 1H NMR spectral analysis.
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[C:7]1([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][C:14]2=[O:22])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OCC)=O.Cl>O.C(O)C>[C:7]1([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[CH:2][OH:4])[C:14]2=[O:22])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1Cc2ccccc2N1c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCOC=O
Product: O=C1C(=CO)c2ccccc2N1c1ccccc1

Procedure:
Potassium t-butoxide (1.63 g, 14.5 mmoles) and 5 ml absolute ethanol were heated to 80°. 1-Phenyl-2(1H,3H)-indolone (2.09 g, 10 mmoles) was added, followed by ethyl formate (1.09 ml, 13.5 mmoles). The mixture was heated 5 minutes, cooled to 25°, and the nearly solid mass diluted with 50 ml H2O and crushed ice, acidified to pH 3 with 3N HCl and title product recovered by filtration, 2.2 g, m.p. 192°-195°; m/e 237. cf J. Prakt. Chem. 135:345-360 (1932); J. Med. Chem. 8:637 (1965).
Reaction SMILES: O=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH3:12].S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)C>[NH2:12][C:2]([CH2:9][CH2:10][CH3:11])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: N
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CCCC(N)=CC(=O)OCC
Yield: 76 %

Procedure:
Ethyl 3-oxo-hexanoate (100 g, 0.63 mmol) was dissolved in 400 ml of diethyl ether and ammonia was bobbled through the solution for 8 hours. During the reaction magnesium sulfate was added in portions as a drying agent. When no starting material was detected on TLC, the mixture was filtered, and the solvent was evaporated to afford 75 g (76%) of ethyl 3-amino-hex-2-enoate as an oil. 1H--NMR (CDCl3, 200 MHz) δ: 0.95 (t, 3 H); 1.25 (t, 3 H); 1.58 (sextet, 2 H); 2.09 (t, 2 H); 4.11 (q, 2 H); 4.52 (s, 1 H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:26]=[C:27]([O:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=2)[CH:28]=1)[C:8]([NH:10][C:11]1[CH:16]=[N:15][C:14]([CH2:17][P:18](=[O:25])([O:22]CC)[O:19]CC)=[CH:13][N:12]=1)=[O:9])([CH3:3])[CH3:2].[Br:40][Si](C)(C)C>C(Cl)Cl>[BrH:40].[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:26]=[C:27]([O:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=2)[CH:28]=1)[C:8]([NH:10][C:11]1[N:12]=[CH:13][C:14]([CH2:17][P:18](=[O:19])([OH:22])[OH:25])=[N:15][CH:16]=1)=[O:9])([CH3:3])[CH3:2]
Reactant: CCOP(=O)(Cc1cnc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC(C)C)c2)cn1)OCC
Reactant: C[Si](C)(C)Br
Solvent: ClCCl
Product: Br
Product: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2cnc(CP(=O)(O)O)cn2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
In a similar manner to Example 1, a mixture of diethyl {2-[3-isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoylamino]-pyrazin-5-ylmethyl}phosphonate (29 mg, 0.05 mmol) and bromotrimethylsilane (0.13 mL, 1.0 mmol) in 1 mL of CH2Cl2 was stirred for 16 h at rt and the solvents evaporated. The residue was sonicated in 1 mL of CH3CN, the solvent evaporated, the residue sonicated in 1 mL CH3CN and 2 mL water, the solution concentrated by evaporation followed by lyophilization to provide 28 mg (76%) of the title compound as an amorphous solid. 1H NMR (500 MHz, DMSO-d6): δ 1.31 (d, 6H, J=6 Hz), 3.21 (s, 3H), 3.23 (d, 2H, J=22 Hz), 4.78 (septet, 1H, J=6 Hz), 6.97 (t, 1H, J=2 Hz), 7.25 (d, 2H, J=8 Hz), 7.36 (t, 1H, J=2 Hz), 7.52 (t, 1H, J=2 Hz), 7.95 (d, 2H, J=8 Hz), 8.39 (t, 1H, J=2 Hz), 9.25 (d, 1H, J=1 Hz), 11.13 (s, 1H); LCMS (m/z): 522.4 [C22H24N3O8PS+H]+. Anal. calcd. for (C22H24N3O8PS+2HBr+3H2O): C, 35.84; H, 4.37; N, 5.70. Found: C, 35.59; H, 4.19; N, 5.41.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[CH3:45][O:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CN(C=O)C>[CH3:45][O:46][CH:47]1[CH2:52][CH2:51][N:50]([C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:13]([CH3:15])[CH3:14])[CH2:49][CH2:48]1
Reactant: COC1CCNCC1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC1CCN(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 60.4 %

Procedure:
(S)-2-(Tert-butoxycarbonylamino)-3-methylbutanoic acid (2.0 g, 9.21 mmol) and TBTU (2.96 g, 9.21 mmol) were mixed in DMF (20 mL). The mixture was cooled to 0° C. and NMM (1.518 mL, 13.81 mmol) was dropwise added. After stirring for 10 min was 4-methoxypiperidine (1.272 g, 11.05 mmol) added. The resultant mixture was stirred at rt over night. The mixture was concentrated and the residue dissolved in DCM (50 mL). The organic layer was washed with HCl (1M aq. solution, 100 mL), NaHCO3 (saturated, 2×100 mL) and brine (100 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified via Biotage (isocratic; DCM/MeOH, 95:5, KP-SIL 100 g column). The solvent was removed under reduced pressure to give the title compound (1.75 g, 60%). 1H NMR (400 MHz, CD3OD) δ 0.69-1.09, 1.24-1.71, 1.72-2.10, 3.09-3.27, 3.36, 3.39-3.60, 3.60-4.15, 4.20-4.49. Total no of protons: 30.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[C:7]([OH:11])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc([N+](=O)[O-])c(O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
To a mixture of 5 g of 3-tert-butylphenol and 30 ml of acetic acid, a mixture of 3.0 g of 70% nitric acid and 10 ml of acetic acid was added dropwise with the temperature kept at 10-15° C. and stirred for two hours. The reaction mixture was poured into ice water and extracted with ethyl acetate twice. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.82 g of 5-tert-butyl-2-nitrophenol.
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:22](O)=[O:23])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:21])[NH:8][S:9]([C:12]1[C:19]([CH3:20])=[CH:18][C:16]([CH3:17])=[CH:15][C:13]=1[CH3:14])(=[O:11])=[O:10].C[N:33]1CCOCC1.N>C1COCC1>[NH:1]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[C@H:2]([C:22]([NH2:33])=[O:23])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:21])[NH:8][S:9]([C:12]1[C:13]([CH3:14])=[CH:15][C:16]([CH3:17])=[CH:18][C:19]=1[CH3:20])(=[O:11])=[O:10]
Reactant: Cc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)c(C)c1
Reactant: CN1CCOCC1
Agent: N
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(N)=O)c(C)c1
Reaction time: 0.25 h

Procedure:
Boc-Arg(Mts)-OH prepared from 1.3 kg of Boc-Arg(Mts)-OH·CHA are dissolved at ambient temperature in 6.2 kg of THF, and 280 g of NMM are added. To this solution 380 g of SBCF are added at -10° C., and stirring is continued at -10° C. for 15 minutes, and then 0.69 kg of 29% aqueous ammonia are added at -10° C. The medium is stirred at -10° C. for 30 mins. and then at 5° C., and the development of the reaction is followed by HPLC. The reaction is terminated after 30 mins. The medium is poured into 31.5 kg of water, and then 19.2 kg of AcOEt are added. After stirring for 15 mins, the organic phase is washed by: