Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:39][C:40]1[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[C:41]=1[C:42](Cl)=[O:43]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:42](=[O:43])[C:41]1[C:40]([Cl:39])=[CH:48][CH:47]=[CH:46][C:45]=1[Cl:49])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(c1c(Cl)cccc1Cl)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Yield: 20.6 %

Procedure:
200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 35a with 91 μl (0.655 mmol) of triethylamine and 80 μl (0.561 mmol) of 2,6-dichlorobenzoyl chloride to give the title compound (I 58 mg, 56%). TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.62, FD-MS: M+ =599,601.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[Br:15]Br.O.[OH-].[Na+]>CO>[Br:15][C:4]1[CH:3]=[C:2]([CH3:1])[S:6][C:5]=1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)s1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(Br)c(NC(=O)OC(C)(C)C)s1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 75.9 %

Procedure:
To a solution of tert-butyl 5-methylthiophen-2-ylcarbamate (5.1 g, 23.91 mmol) in MeOH (478 mL) at 0° C. was added drop wise a solution of bromine (1.232 mL, 23.91 mmol) in MeOH (478 mL) during 1.5 h. The reaction mixture was then stirred at 0° C. for 0.5 h and at ambient temperature for 45 min. The reaction was poured into water (400 mL) and the solution was neutralized with 2 M NaOH (aq). MeOH was removed under reduced pressure and the cloudy aqueous phase was extracted with DCM (3×200 mL). The combined organic phases were dried over MgSO4. The solvent was removed under reduced pressure to give (5.3 g, 76%) of the title compound that was used in the next step without further purification: LC/MS (Table 1, Method a) Rt=2.48 min; m/z: 292.1 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[C:27]([Br:28])=[CH:26][C:25](I)=[C:24]([N:30]([CH3:32])[CH3:31])[N:23]=4)[CH2:20][CH2:21][C@@H:14]23)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:35](B1OC(C)(C)C(C)(C)O1)([CH3:37])=[CH2:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[C:27]([Br:28])=[CH:26][C:25]([C:35]([CH3:37])=[CH2:36])=[C:24]([N:30]([CH3:32])[CH3:31])[N:23]=4)[CH2:20][CH2:21][C@@H:14]23)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: CN(C)c1nc([C@@H]2CC[C@H]3[C@@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)OC(=O)N23)c(Br)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)c1cc(Br)c([C@@H]2CC[C@H]3[C@@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)OC(=O)N23)nc1N(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To (1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[3-bromo-6-(dimethylamino)-5-iodopyridin-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one (50 mg, 0.075 mmol) in DMF (1 mL) was added isopropenylboronic acid pinacol ester (13.9 mg, 0.083 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (1.84 mg, 2.26 mmol) and potassium carbonate (0.5 M in water, 0.30 mL, 0.151 mmol). The system was stirred at 50° C. overnight before cooling and partitioning with water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated before purifying by column chromatography to yield (1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[3-bromo-6-(dimethylamino)-5-(prop-1-en-2-yl)pyridin-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one (19 mg, 0.033 mmol). MS ESI calc'd. for C24H23BrF6N3O2 [M+H]+ 580.1. found 580.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][OH:15])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][O:15][S:25]([CH3:24])(=[O:27])=[O:26])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: O=C1OC(CO)CN1c1ccc(I)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
A solution of iodo-alcohol 104 (25.2 g, 74.8 mmol) in methylene chloride (CH2Cl2, 150 mL) was treated with triethylamine (TEA, 15.15 g, 20.9 mL, 150 mmol, 2.0 equiv) at 25° C., and the resulting mixture was cooled to 0-5° C. before methanesulfonyl chloride (MsCl, 10.28 g, 6.95 mL, 89.7 mmol, 1.2 equiv) was dropwise introduced into the reaction mixture at 0-5° C. under N2. The resulting reaction mixture was subsequently stirred at 0-5° C. for 1 h under N2. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was quenched with H2O (100 mL) and CH2Cl2 (100 mL). The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (100 mL). The combined organic extracts were washed with H2O (2×100 mL) and saturated aqueous NaCl (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the desired (5R)-methanesulfonic acid 3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl ester 105 (30.71 g, 98.9% yield) as an off-white powder. This product was directly used in subsequent reactions without further purification. C11H11FINO5S, LCMS (EI) m/e 416 (M++H).
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[C:12]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=CC=C[CH:13]=1.CC(O)C.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:12]([CH3:17])[CH3:13])=[C:4]([Cl:11])[N:3]=1
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)n1cnc2c(Cl)nc(F)nc21
Temperature: -10 °C
Reaction time: 18 h

Procedure:
Anhydrous tetrahydrofuran (60 mL) is added to a flame-dried flask under N2 containing 2-fluoro-6-chloropurine (1.8 g, 10.4 mmol) and triphenylphosphine (6 g, 20.8 mmol). To this anhydrous 2-propanol (1.6 ml, 20.8 mmol) is added, and the mixture is then cooled to −10° C. After dropwise addition of 40% (W/V) diethyl azodicarboxylate in tetrahydrofuran (9 ml, 20.8 mmol), the mixture is warmed gradually to room temperature. After 18 h, the reaction mixture is quenched with 1 ml of water and the solvent is removed in vacuo. The resulting yellow oil is purified by column chromatography. The resulting solid is triturated with methanol (to remove the diethyl hydrazine-N,N′-dicarboxylate ester by-products) to yield 1.1 g (49%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[C:11](O)(=[O:13])C.C1N2CN3CN(C2)CN1C3>O>[Br:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[C:10]([CH:11]=[O:13])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Brc1ccc2cc[nH]c2n1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: O=Cc1c[nH]c2nc(Br)ccc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
6-Bromo-1H-pyrrolo[2,3-b]pyridine (0.028 g, 0.14 mmol) was successively added with acetic acid (0.1 mL), water (0.2 mL), and hexamethylenetetramine (0.028 g, 0.20 mmol), and then the mixture was stirred overnight at 120° C. in a sealed tube. The reaction mixture was added with water, and the precipitated solid was collected by filtration to obtain 6-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.008 g, 25%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH2:9][CH2:10][C:11]([O:13]C)=[O:12])=[O:8])=[CH:5][C:4]=1[OH:17].[OH-:18].[K+]>>[OH:17][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:3]=1[CH2:2][OH:18])[C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8]
Reactant: COC(=O)CCC(=O)c1ccc(CCl)c(O)c1
Reactant: [OH-]
Agent: [K+]
Product: O=C(O)CCC(=O)c1ccc(CO)c(O)c1

Procedure:
A mixture of methyl 3-(4-chloromethyl-3-hydroxybenzoyl)-propionate and 3N potassium hydroxide solution was heated under reflux for 4 hours to give 3-(3-hydroxy-4-hydroxymethylbenzoyl)propionic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li:14])CCC>CCCCC.CCCCCC>[Li:14][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: [Li]CCCC
Reactant: COc1ccccc1Br
Solvent: CCCCCC
Solvent: CCCCC
Product: [Li]c1ccccc1OC
Reaction time: 9 h

Procedure:
2-Bromoanisole (97.0 g, 0.52 mol, 1.0 eq) was dissolved in 150 ml pentane. A 1.6M solution of n-butyllithium (0.52 mol, 1.0 eq) in 325 ml hexane was slowly added drop wise with vigorous stirring and cooling with an ice bath. A white suspension formed which was stirred for a further 3 hours at 0° C., then for 9 hours at room temperature. The white solid was filtered off and washed with pentane (4×30 ml). After drying under vacuum, 2-lithioanisole was isolated as a fine white powder.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C@@H:10]2[CH2:14][S:13][CH2:12][C@H:11]2[C:15]([OH:17])=O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[F:58][C:59]1[CH:71]=[CH:70][C:62]([CH2:63][C@@H:64]2[CH2:69][CH2:68][CH2:67][NH:66][CH2:65]2)=[CH:61][CH:60]=1>ClCCl>[F:58][C:59]1[CH:60]=[CH:61][C:62]([CH2:63][C@@H:64]2[CH2:69][CH2:68][CH2:67][N:66]([C:15]([C@H:11]3[C@H:10]([NH:9][C@@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH3:8])[CH2:14][S:13][CH2:12]3)=[O:17])[CH2:65]2)=[CH:70][CH:71]=1
Reactant: C[C@@H](N[C@@H]1CSC[C@H]1C(=O)O)c1ccccc1
Reactant: Fc1ccc(C[C@@H]2CCCNC2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](N[C@@H]1CSC[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1)c1ccccc1
Reaction time: 0.08 h
Yield: 94 %

Procedure:
A cloudy solution of (3R,4S)-4-[(R)-1-phenyl-ethylamino]-tetrahydrothiophene-3-carboxylic acid (containing sodium chloride; 928 mg, 2.54 mmol) in dichloromethane (20 mL) was treated with benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (1.59 g, 3.05 mmol) and triethylamine (814 μL, 5.84 mmol) and stirred for 5 minutes. A solution of the (S)-3-(4-fluorobenzyl)-piperidine prepared above in dichloromethane (5 mL) was added and the mixture was stirred at room temperature. After 21.5 h, the mixture was diluted with dichloromethane, washed with water and saturated NaHCO3, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (55% ethyl acetate/hexanes) to provide the product as a gum (1.05 g, 94%).
Reaction SMILES: [C:1]([C:4]1[CH2:5][CH2:6][O:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=1)([OH:3])=[O:2].[CH2:15](O)[CH3:16]>S(=O)(=O)(O)O>[CH2:15]([O:2][C:1]([C:4]1[CH2:5][CH2:6][O:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:3])[CH3:16]
Reactant: O=C(O)C1=Cc2ccccc2OCC1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=Cc2ccccc2OCC1

Procedure:
A mixture of 8.2 g (0.043 mol) of 2,3-dihydro-4-carboxybenzoxepine in 150 ml of ethanol and 5 ml of concentrated sulphuric acid is brought to reflux for 6 hours. The reaction mixture is subsequently concentrated under reduced pressure and the residue is taken up in water. The combined mixture is extracted with ethyl acetate. The organic phase is then washed with sodium bicarbonate and then with water and dried over anhydrous sodium sulphate before being concentrated under reduced pressure. 8.5 g of an orange oil are thus obtained.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[F:15][C:16]1[C:17](=O)[NH:18][C:19](=[O:22])[NH:20][CH:21]=1.C(=O)([O-])O.[Na+].C(=O)=O>COCCOCCOC.O>[F:15][C:16]1[C:17](=[S:2])[NH:18][C:19](=[O:22])[NH:20][CH:21]=1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: O=c1[nH]cc(F)c(=S)[nH]1
Temperature: 110 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
To a solution of phosphorus pentasulfide (102.6 g, 0.46 mol) in diglyme (1 L) was added 5-fluoropyrimidine-2,4(1H,3H)-dione (30 g, 0.23 mol). Solid sodium hydrogen carbonate (NaHCO3; 77.3 g, 1.04 mol) was added at a rate determined by the evolution of carbon dioxide. The reaction mixture was stirred overnight at 110° C. The yellow mixture was cooled and poured into 1 L of cold water. The precipitated solid product was isolated by filtration and purified by normal phase chromatography (gradient, 10 to 50% EtOAc/Petroleum ether) to give 5-fluoro-4-thioxo-3,4-dihydropyrimidin-2(1H)-one (13.4 g, 40%) as a yellow solid: mp 254-255° C.; 1H NMR (301 MHz, DMSO-d6) δ 7.81 (d, J=4.0 Hz, 1H); ESIMS m/z 145 ([M−H]−).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]([C:15](=[O:49])[CH:16]([C:21]1[CH:48]=[CH:47][C:24]([C:25]([NH:27][C:28]2[CH:33]=[C:32]([C:34]3[CH:38]=[CH:37][S:36][CH:35]=3)[CH:31]=[CH:30][C:29]=2[NH:39]C(=O)OC(C)(C)C)=[O:26])=[CH:23][CH:22]=1)[CH2:17][N:18]([CH3:20])[CH3:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[NH2:39][C:29]1[CH:30]=[CH:31][C:32]([C:34]2[CH:38]=[CH:37][S:36][CH:35]=2)=[CH:33][C:28]=1[NH:27][C:25](=[O:26])[C:24]1[CH:47]=[CH:48][C:21]([CH:16]([CH2:17][N:18]([CH3:20])[CH3:19])[C:15]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:49])=[CH:22][CH:23]=1
Reactant: CN(C)CC(C(=O)Nc1ccccc1)c1ccc(C(=O)Nc2cc(-c3ccsc3)ccc2NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CC(C(=O)Nc1ccccc1)c1ccc(C(=O)Nc2cc(-c3ccsc3)ccc2N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the trifluoroacetic acid salt of tert-butyl [2-[(4-{2-anilino-1-[(dimethylamino)methyl]-2-oxoethyl}benzoyl)amino]-4-(3-thienyl)phenyl]carbamate (374 mg, 0.54 mmol) in CH2Cl2 (8 mL) was added trifluoroacetic acid (2 mL), and the reaction was stirred at room temperature for 1 h. Concentration yielded a yellow residue that was purified by reverse phase HPLC (10-70% MeCN/water). The resulting solid was dissolved in CH2Cl2 (with a small amount of MeOH), neutralized with sat. NaHCO3, washed with brine, dried (MgSO4), and evaporated to yield N-[2-amino-5-(3-thienyl)phenyl]-4-{2-anilino-1-[(dimethylamino)methyl]-2-oxoethyl}benzamide as an off-white solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([Cl:21])[CH:14]=1)[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:22][C:23](C)(O)[C:24]#N>CCO>[Cl:21][C:15]1[CH:14]=[C:13]([NH:12][C@H:3]([CH2:2][NH:1][CH:23]([CH3:24])[CH3:22])[CH2:4][C:5]([O:7][C:8]([CH3:10])([CH3:9])[CH3:11])=[O:6])[CH:18]=[CH:17][C:16]=1[C:19]#[N:20]
Reactant: CC(C)(C)OC(=O)C[C@@H](CN)Nc1ccc(C#N)c(Cl)c1
Reactant: CC(C)(O)C#N
Solvent: CCO
Product: CC(C)NC[C@H](CC(=O)OC(C)(C)C)Nc1ccc(C#N)c(Cl)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 93.8 %

Procedure:
A mixture of 1,1-dimethylethyl (3S)-4-amino-3-[(3-chloro-4-cyanophenyl)amino]butanoate (0.309 g, 1 mmol), acetone cyanohydrin (0.1 g, 1.18 mmol) and crushed 4 Å molecular sieves in EtOH (5 mL) was stirred at 60° C. for 6 h. After cooled down, the reaction mixture was filtered. The filtrate was treated with NaBH4 (excess amount) and stirred for 2.5 h. The reaction was diluted with H2O and extracted with Et2O (2×). The organic extracts were washed with H2O (2×), dried over Na2SO4, filtered, and concentrated to yield the titled product (0.33 g, 94%). LC-MS (ES) m/e 352.5 (M+H)+.
Reaction SMILES: [CH3:1][P:2](=[O:14])([CH3:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[CH:5]=1>CO.[Pd]>[CH3:13][P:2]([CH2:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[NH2:10])([CH3:1])=[O:14]
Reactant: CP(C)(=O)Cc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CP(C)(=O)Cc1cccc(N)c1
Yield: 97.4 %

Procedure:
The dimethyl(3-nitrobenzyl)phosphane oxide (153 mg) produced as described above was hydrogenated in the presence of 10% Pd/C (100 mg) in MeOH (5 mL) overnight. The mixture was filtered and the filtrate concentrated in vacuo to afford 128 mg of the desired 3-[(dimethylphosphoryl)methyl]aniline (yield: 96%), which was used in further chemistries without purification. 1H-NMR (CDCl3, 400 MHz): δ=1.44 (d, J=12.8 Hz, 6 H), 3.06 (d, J=15.6 Hz, 2 H), 3.81 (s, br, 2 H), 6.55-6.58 (m, 3 H), 7.08 (t, J=7.6 Hz, 1 H). MS (ES+): m/z 184.02 (MH+). HPLC: tR=0.58 and 0.90 min (ZQ3, polar—5 min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:19])[CH2:15][C:16]([OH:18])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:21]1([CH2:27][CH2:28][CH2:29][CH:30]([NH2:40])[CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:34]1([CH2:33][CH2:32][CH2:31][CH:30]([NH:40][C:16](=[O:18])[CH2:15][C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:19])[CH2:29][CH2:28][CH2:27][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CC(=O)O)CC1
Reactant: NC(CCCc1ccccc1)CCCc1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CC(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-3-oxopropionic acid (36) (1.20 g; 4.41 mmol) is dissolved in methylene chloride (40 mL) at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) (1.61 g; 5.29 mmol), N,N-diisopropylethylamine (1.82 g; 14.1 mmol) and PyBOP (2.75 g; 5.29 mmol) are added sequentially. The reaction is stirred for 14 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (40%→70% ethyl acetate in hexanes) affording the desired product as a solid. ESMS: MH− 522.4
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([CH2:34][CH2:35][CH2:36][CH3:37])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([CH2:34][CH2:35][CH2:36][CH3:37])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2,6-di-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:10][CH:11]=[CH:12][C:5]=12.Cl[Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16]>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH:11]=[CH:12][C:5]=12
Reactant: Brc1ccnc2[nH]ccc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Br)ccnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.7 %

Procedure:
Sodium hydride (8.37 g, 209 mmol; 60% oil dispersion) was slowly added to 4-bromo-1H-pyrrolo[2,3-b]pyridine (33.0 g, 167 mmol) in THF (500 mL) at 0° C. The reaction was stirred for 15 minutes. Chlorotriisopropylsilane (38.7 g, 201 mmol) was then added in one portion. The suspension was warmed to room temperature and stirred for 30 minutes. The suspension was then cooled to about 0-5° C. and quenched with saturated aqueous NH4Cl (about 200 mL). The aqueous phase was extracted with hexanes (3×300 mL), and the combined organic phases were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with hexanes to yield 4-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (50 g, 84% yield) as an oil, which solidified upon standing. 1H NMR (400 MHz, CDCl3) δ 8.05 (d, 1H), 7.34 (d, 1H), 7.22 (d, Hz, 2H), 6.59 (d, 1H), 1.88-1.80 (m, 3H), 1.11 (d, 18H).
Reaction SMILES: [O:1]1[CH2:23][CH:2]1[CH2:3][N:4]([CH:15]([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[H-].[Na+].[Na].[CH3:27][N:28]([CH3:32])[C:29](Cl)=[O:30]>CN(C)C=O>[O:1]1[CH2:23][CH:2]1[CH2:3][N:4]([CH:15]([CH3:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[S:5]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:29](=[O:30])[N:28]([CH3:32])[CH3:27])=[CH:12][CH:13]=1)(=[O:7])=[O:6]
Reactant: CN(C)C(=O)Cl
Reactant: CC(c1ccccc1)N(CC1CO1)S(=O)(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(c1ccccc1)N(CC1CO1)S(=O)(=O)c1ccc(OC(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
1 g (3 mmol) of N-(2,3-epoxypropyl)-N-α-methylbenzyl-4-hydroxybenzenesulfonamide and 180 mg (3.75 mmol) of 50% sodium hydride were added to 15 ml of dry N,N-dimethylformamide, followed by agitating at room temperature for 30 minutes. To the resulting sodium salt was added 400 mg (3.83 mmol) of N,N-dimethylcarbamoyl chloride for reaction at 60° C. for 1 hour. After completion of the reaction, the excess of the solvent and N,N-dimethylcarbamoyl chloride were removed by distillation under reduced pressure. The residue was dissolved in chloroform and sufficiently washed with water and the chloroform solution was dehydrated over anhydrous magnesium sulfate, followed by distilling off the solvent to obtain a crude product. The crude product was purified by the silica gel chromatography to obtain 980 mg of N-(2,3-epoxypropyl)-N-α-methylbenzyl-4-(N,N-dimethylcarbamoyloxy)-benzenesulfonamide (Compound No. 57). The nD26.0 value was found to be 1.5320. The results of the elemental analysis are shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[CH3:11][C:12]([CH3:14])=[O:13].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1/[CH:4]=[CH:11]/[C:12](=[O:13])/[CH:14]=[CH:4]/[C:3]1[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1]
Reactant: O=Cc1c(F)cccc1Cl
Reactant: CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(/C=C/c1c(F)cccc1Cl)/C=C/c1c(F)cccc1Cl
Temperature: 25 °C
Yield: 51.8 %

Procedure:
(72) To a solution of the 2-chloro-6-fluoro-benzaldehyde (1.59 g, 10.0 mmol) and acetone (290 mg, 5.00 mmol) in 15 ml of ethanol was added 5 ml of 40% potassium hydroxide at 10° C. After stirring for several hours at room temperature, the solution was filtered. The precipitate was recrystallized from ethanol to afford 879 mg (51.7%) of a light-yellow powder: mp 143.5-144.3° C. 1H NMR (250 MHz) δ 7.98-7.91 (d, 2 H), 7.36-7.22 (m, 6 H), 7.13-7.03 (m, 2 H); 13C NMR (62.7 MHz) 189.6, 134.0, 132.1, 131.8, 131.2, 131.0, 126.3, 115.4, 115.0 ppm. Elemental Analysis. Calculated for C17 H10Cl2F2O5: C, 60.20; H, 2.98. Found: C, 60.07; H, 2.99.