Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:26][C@@H:25]2[C@:20]([CH3:31])([CH2:21][CH2:22][C@H:23]([O:27][CH2:28][CH2:29][OH:30])[CH2:24]2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:33])([C@@H:17]([OH:32])[CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[OH:1][C@@H:2]1[CH2:26][C@H:25]2[C@:20]([CH3:31])([CH2:21][CH2:22][C@H:23]([O:27][CH2:28][CH2:29][O:30][S:40]([C:37]3[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=3)(=[O:42])=[O:41])[CH2:24]2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:33])([C@@H:17]([OH:32])[CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@H]4C[C@@H](OCCO)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](OCCOS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reaction time: 8 h

Procedure:
The compound of Example 1B (1.50 g, 3.2 mmol) was dissolved in 15 ml of chloroform and 15 ml of pyridine; p-toluenesulfonyl chloride (920 mg, 4.83 mmol) was added, and the mixture was stirred overnight. Chloroform (250 ml) was added, the resultant solution was washed with 5% HCI solution and sat. Na2SO4. After solvent removal in vacuo, the crude product was purified by column chromatography on silica gel (40%->60% ethyl acetate/hexanes. The yield of the title compound was 1.40 g (71%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:16])=[C:13]([OH:15])[CH:14]=1>CCO>[Cl:16][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][C:13]=1[OH:15]
Reactant: Nc1ccc(Cl)c(O)c1
Reactant: Brc1ccccn1
Solvent: CCO
Product: Oc1cc(Nc2ccccn2)ccc1Cl
Temperature: 90 °C
Yield: 24 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(heteroaryl-2-ylamino)phenol, 2-bromopyridine (0.13 mL, 1.4 mmol) and 5-amino-2-chlorophenol (100 mg, 0.7 mmol) in 10% aqueous EtOH (2 mL) was heated at 90° C. for 18 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 24% yield (36 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([Mg]Br)=[CH:30][CH:29]=1>CCOCC.C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=2)[N:3]=1)[Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)[Si](OCc1cccc(Br)n1)(c1ccccc1)c1ccccc1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](OCc1cccc(-c2ccc(F)cc2)n1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 2-bromo-6-(tert-butyldiphenylsiloxy)methylpyridine (1 g; WO 94/00444), 4-fluorophenylmagnesium bromide (3.5 mL of a 2M solution in Et2O) and tetrakis (triphenylphosphine) palladium (200 mg) in THF (20 mL) was refluxed for 4 h. To the mixture was added NH4OAc buffer and the mixture was extracted with EtOAc. The organics were dried (MgSO4), concentrated and chromatographed (silica gel; hexane/EtOAc (30:1)) to provide the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]([CH:9]2[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH3:8])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH:9]2[CH2:10][NH:11][CH2:12]2)[CH3:8])=[CH:20][CH:21]=1
Reactant: CC(Oc1ccc(Cl)cc1)C1CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(Oc1ccc(Cl)cc1)C1CNC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.9 %

Procedure:
To a flask charged with tert-butyl 3-(1-(4-chlorophenoxy)ethyl)azetidine-1-carboxylate (140 mg, 0.449 mmol) was added CH2Cl2 (1796 μL) followed by TFA (242 μL, 3.14 mmol). The reaction mixture was stirred at RT for 72 h. The yellow solution was dried under reduced pressure and purified with a 2 g SCX-2 column loading and washing with MeOH, then washing with 2M NH3 in MeOH to afford 3-(1-(4-chlorophenoxy)ethyl)azetidine (57 mg, 0.269 mmol, 60.0% yield, about 10% impurity present) as a light pink oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=O.N1C=CC=CC=1.[N:19]#[C:20][C:21]#[N:22]>C1(C)C=CC=CC=1>[C:20]([C:21]1[NH:2][CH:3]=[C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)[N:22]=1)#[N:19]
Reactant: N#CC#N
Reactant: Cc1ccc(C(=O)CN)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2c[nH]c(C#N)n2)cc1
Temperature: -78 °C
Yield: 52.4 %

Procedure:
0.93 g (5 mmol) of 2-amino-4'-methylacetophenone hydrochloride was suspended in 30 ml of toluene in a 50-ml stainless steel autoclave. To the suspension was then added 0.79 g (10 mmol) of pyridine. The suspension was then cooled to a temperature of -78° C. To the suspension was then added about 0.5 g (9.6 mmol) of cyanogen which had been cooled and solidified at a temperature of -78° C. The autoclave was then sealed. The suspension was heated at a temperature of 100° C. for 2.5 hours, and then allowed to cool. The content was then taken out of the autoclave. The reaction mixture was then extracted with ethyl acetate and water. The resulting organic phase was dried over anhydrous sodium sulfate, and then subjected to silica gel column chromatography to obtain 0.48 g (yield: 52 %) of 2-cyano-4-(p-tolyl)imidazole.
Reaction SMILES: O/[C:2](/[C:9]([O:11][CH3:12])=[O:10])=[C:3](/O)\[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.Cl>CO>[CH3:7][O:6][C:4](=[O:5])[C:3]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([F:13])=[CH:15][CH:16]=1)=[C:2]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([F:13])=[CH:15][CH:16]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)/C(O)=C(\O)C(=O)OC
Reactant: Nc1ccc(F)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)C(Nc1ccc(F)cc1)=C(Nc1ccc(F)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
In a round bottom flask with a teflon stirbar, 25 g (142 mmol) of dimethyl dihydroxyfumarate (prepared according to a procedure described in U.S. Pat. No. 3,334,102), 34.7 g (312.5 mmol) of 4-fluoroaniline, 0.1 mL of concentrated HCl, and 90 ml of methyl alcohol were mixed and heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and left overnight in a refrigerator. The next morning, the resulting thick paste was filtered on a coarse frit, washed with a 50% (v:v) methanol-water mixture, and dried in a vacuum oven, yielding 32.4 g (63% yield) which, according to NMR analysis, was a mixture of E/Z isomers (E:Z˜1:2).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=O)[CH2:24][C:25]([CH:27]1[CH2:29][CH2:28]1)=[O:26])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=[S:40])[CH2:24][C:25]([CH:27]1[CH2:29][CH2:28]1)=[O:26])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)CC(=O)C1CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(=O)C1CC1

Procedure:
In analogy to the procedure described in example 192f, (2S,4R)-1-(3-cyclopropyl-3-oxo-propionyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 363a) was reacted with Lawesson's reagent to give the title compound as brown oil. MS (ESI): m/z=364.1 [M+H]
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[NH:5][CH:6]=1.[N+:19]([O-])([OH:21])=[O:20].S(=O)(=O)(O)O>O>[Br:1][C:2]1[N:3]=[C:4]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[NH:5][C:6]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: FC(F)(F)c1cc(Cl)c(-c2nc(Br)c[nH]2)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1[nH]c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1Br
Temperature: 70 °C

Procedure:
A mixture of 4-bromo-2-(2,6-dichloro-4-trifluoromethyl-phenyl)-imidazole (0.9 g, 0.025 mol), nitric acid (70% w/w, 1 ml) and sulphuric acid (98%w/w, 1 ml) was stirred and heated at 70° C. for 7.5 hours. After cooling it was added to a mixture of ice and water (50 ml). The precipitated solid was filtered off and purified by mplc on silica eluted with a mixture of ethyl acetate and petroleum spirit (b.p. 60°-80° C.) (1:5) to give 4-bromo-2-(2,6-dichloro-4-trifluoromethylphenyl)-5-nitro-imidazole (0.2 g), m.p. 292°-293° C., as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([O:13][CH3:14])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[N:21]1([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.O>CS(C)=O>[CH3:9][O:8][C:7]1[CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:4]([O:13][CH3:14])=[CH:3][C:2]=1[N:30]1[CH2:31][CH2:32][CH:27]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:28][CH2:29]1
Reactant: COc1cc([N+](=O)[O-])c(OC)cc1Cl
Reactant: C1CCN(C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc([N+](=O)[O-])c(OC)cc1N1CCC(N2CCCCC2)CC1
Temperature: 80 °C
Yield: 37.3 %

Procedure:
4-Chloro-2,5-dimethoxynitrobenzene (5.0 g, 23 mmol) was dissolved in DMSO (50 mL). K2CO3 (4.8 g, 34 mmol) and 4-piperidinopiperidine (3.9 g, 23 mmol) were added and the reaction mixture was heated to 80° C. and allowed to stir over the weekend. The mixture was then poured into H2O and extracted with EtOAc (2×). The combined organics were dried with MgSO4, filtered, and concentrated in vacuo. The resulting residue was adsorbed onto silica gel and flash chromatographed to give the title compound of step A (3.0 g, 37%). MS (M+H, ES+) 350.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:8][C:9]=1[CH2:10]Cl)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:28][C:29]1[CH:30]=[C:31]([CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH:32]=[CH:33][CH:34]=1.O>CN(C=O)C>[CH3:40][O:39][C:37](=[O:38])[CH2:36][CH2:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH2:10][C:9]2[S:8][C:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[N:6][C:5]=2[CH2:1][CH2:2][CH2:3][CH3:4])[CH:30]=1
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reactant: COC(=O)CCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1cccc(CCC(=O)OC)c1
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of 4-butyl-5-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole (300 mg, 0.90 mmol) in anhydrous DMF (5 mL) add cesium carbonate (586 mg, 1.80 mmol) and methyl 3-(3-hydroxyphenyl)propionate (178 mg, 0.99 mmol). Stir the resulting mixture overnight then pour into water and extract twice with ethyl acetate. Wash the combined extracts with water, dry over MgSO4, filter and concentrate under vacuum. Purify the residue by flash chromatography on silica gel (eluting with 5% ethyl acetate in heptane) to give the title compound (290 mg) as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[O:7][C:8]2[CH:14]=[C:13]([C:15]([O:17]CC)=O)[CH:12]=[CH:11][C:9]=2[CH:10]=1.[CH3:20][NH:21][CH3:22].[O-]CC.[Na+]>C(O)C>[CH3:20][N:21]([CH3:22])[C:15]([C:13]1[CH:12]=[CH:11][C:9]2[CH:10]=[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH2:1])[O:7][C:8]=2[CH:14]=1)=[O:17]
Reactant: CNC
Reactant: CCOC(=O)c1ccc2cc(CCCCN)oc2c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)C(=O)c1ccc2cc(CCCCN)oc2c1

Procedure:
A solution of ethyl 2-(4-aminobutyl)benzofuran-6-carboxylate (13.0 g., 0.05 mole), dimethylamine (35 g.), and a catalytic amount of sodium ethoxide (approximately 100 mg.) in ethanol (100 ml.) is heated in a sealed pressure bottle at 65° C. for 18 hours. Evaporation of the solvent provides N,N-dimethyl-2-(4-aminobutyl)benzofuran-6-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2([CH:14]3[CH2:16][CH2:15]3)[CH2:12][O:11]C(=O)[NH:9]2)[CH:7]=1.O.[OH-].[Li+]>C(O)C.O>[NH2:9][C:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:17])([CH:14]1[CH2:16][CH2:15]1)[CH2:12][OH:11]
Reactant: O=C1NC(c2cc(Br)ccc2F)(C2CC2)CO1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(CO)(c1cc(Br)ccc1F)C1CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of the crude (RS)-4-(5-bromo-2-fluoro-phenyl)-4-cyclopropyl-oxazolidin-2-one (4.802 g) in ethanol (25 ml) and water (125 ml) was treated with lithium hydroxide monohydrate (6.7 g, 160 mmol) and the reaction mixture was stirred at 100° C. overnight. For the workup, the reaction mixture was extracted with dichloromethane, the combined organic layers were washed with water, then dried over sodium sulfate and evaporated. The crude product was purified by chromatography on an Isolute flash NH2 column using a gradient of heptane/ethyl acetate as the eluent. (RS)-2-amino-2-(5-bromo-2-fluoro-phenyl)-2-cyclopropyl-ethanol was obtained as a yellow oil (2.27 g, 52% of theory). Mass (calculated) C11H13BrFNO [274.132]; (found) [M+H]+=274, [M+2-H]+=276.
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]([C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[C:1]([NH:9][CH:10]([C:11]([C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)=[O:12])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(CNC(=O)c1ccccc1)c1ccsc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1ccccc1)C(=O)c1ccsc1
Yield: 66.1 %

Procedure:
4.7 g of N-benzoyl-N-[(3-thienylcarbonyl)methyl]amine, 1.1 g of 50% sodium hydride and 3.9 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(4). 4.2 g of ethyl 3-benzoylamino-3-(3-thienylcarbonyl)propionate are thereby obtained.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]#[N:8].[CH:9]1([C:15](OC)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>C1COCC1>[CH:9]1([C:15](=[O:16])[CH2:6][C:7]#[N:8])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC#N
Reactant: COC(=O)C1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCCCC1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To 700 mL of THF cooled at −78° C. under inert atmosphere was added n-butyllithium (56 mL, 2.5 M in hexane) followed by CH3CN (7.3 mL, 0.14 mol) maintaining the temperature below −70° C. The mixture was stirred at −78° C. for 20 min then a solution of methyl cyclohexane carboxylate (10 g, 0.07 mol) in dry THF (300 mL) was added dropwise, maintaining the temperature under −60° C. The reaction was stirred an additional 20 min at −78° C., warmed to −20° C. and quenched by addition of saturated aq. NH4Cl. The reaction mixture was diluted with H2O and extracted with t-BuOMe. The solvents were removed under vacuum to give 3-cyclohexyl-3-oxopropanenitrile as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:7]2=[O:22])([O-])=O>C(OCC)(=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[C:7]2=[O:22]
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)CN1C(=O)c2ccc(N)cc2C1=O
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of tert-butyl 2-(5-nitro-1,3-dioxoisoindolin-2-yl)acetate (15.7 g, 51.3 mmol) in a mixture of ethyl acetate (400 ml) and MeOH (200 ml), 10% w/w Pd/C (0.900 g) was added, and the mixture was hydrogenated in a Parr apparatus at 30 psi for 2 hours. The catalyst was filtered off, and the filtrate was evaporated to dryness affording tert-butyl 2-(5-amino-1,3-dioxoisoindolin-2-yl)acetate (14 g, 50.7 mmol, 99% yield, MS/ESI+ 276.9 [MH]+). This product was used in the following step without any further purification.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4].[F:8][C:9]([F:16])([F:15])[C:10](OCC)=[O:11]>C1COCC1>[F:8][C:9]([F:16])([F:15])[C:10]([N:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4])=[O:11]
Reactant: CCOC(=O)C(F)(F)F
Reactant: OC[C@@H]1CCCN1
Solvent: C1CCOC1
Product: O=C(N1CCC[C@H]1CO)C(F)(F)F
Reaction time: 12 h
Yield: 97 %

Procedure:
L-prolinol (2.0 g, 20 mmol) was dissolved in 20 ml of THF. On the other hand, ethyl trifluoroacetate (3.0 g, 21 mmol) was dissolved in 20 ml of THF. Then, the latter THF solution was instilled in the former THF solution containing the L-prolinol, and this was stirred for 12 hours. This reaction solution was vacuum concentrated. Thus, Compound 1 was obtained (3.7 g, yield: 97%). The result of NMR analysis with respect to this compound is shown below.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([NH:20][CH2:21][CH2:22][OH:23])=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:24][S:25]([O:23][CH2:22][CH2:21][NH:20][C:19]1[C:15]([C:10]2[N:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=3)[C:13](=[O:14])[O:12][N:11]=2)=[N:16][O:17][N:18]=1)(=[O:27])=[O:26]
Reactant: O=c1onc(-c2nonc2NCCO)n1-c1ccc(F)c(Br)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 35 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(3-bromo-4-fluorophenyl)-3-{4-[(2-hydroxyethyl)amino]-1,2,5-oxadiazol-3-yl}-1,2,4-oxadiazol-5(4H)-one (1.5 kg, 3.9 mol, containing also some of the corresponding bromo-compound) in ethyl acetate (12 L) was added methanesulfonyl chloride (185 mL, 2.4 mol) dropwise over 1 h at room temperature. Triethylamine (325 mL, 2.3 mol) was added dropwise over 45 min, during which time the reaction temperature increased to 35° C. After 2 h, the reaction mixture was washed with water (5 L), brine (1 L), dried over sodium sulfate, combined with 3 more reactions of the same size, and the solvents removed in vacuo to afford the desired product (7600 g, quantitative yield) as a tan solid. LCMS for C13H11BrFN5O6SNa (M+Na)+: m/z=485.9, 487.9. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (dd, J=6.2, 2.5 Hz, 1H), 7.72 (m, 1H), 7.58 (t, J=8.7 Hz, 1H), 6.75 (t, J=5.9 Hz, 1H), 4.36 (t, J=5.3 Hz, 2H), 3.58 (dd, J=11.2, 5.6 Hz, 2H), 3.18 (s, 3H).
Reaction SMILES: C([O:3]C(=O)CN(CCC)CCC)C.[CH2:14]([C:17]([C:26]#[N:27])([CH2:23][CH2:24][CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:15][CH3:16]>>[CH2:21]([O:20][C:18](=[O:19])[C:17]([CH2:23][CH2:24][CH3:25])([CH2:14][CH2:15][CH3:16])[C:26]([NH2:27])=[O:3])[CH3:22]
Reactant: CCCN(CCC)CC(=O)OCC
Reactant: CCCC(C#N)(CCC)C(=O)OCC
Product: CCCC(CCC)(C(N)=O)C(=O)OCC
Yield: 81 %

Procedure:
The synthesis of this compound, which can also be called di-n-propylglycine ethyl ester, was later optimized (P. M. Hardy, l. N. Lingham, Int. J. Peptide Protein Res. 21, 392-405 (1983)). The synthesis of ethyl 2,2-di-n-propylcyanoacetate 2 gave a yield of 81%, while the subsequent reaction to give the 2,2-di-n-propylmalonic acid monoamide ethyl ester 3 gave a yield of 82%. Following further reaction with bromine and NaOH in CHCl3 at low temperature, the N-bromoamide 4 was not isolated, but, following treatment with a 4-fold excess of sodium hydroxide solution, the corresponding isocyanate 6 in a distillative yield of 81% was obtained. The latter was then refluxed with an excess of 3M HCl. Subsequent alkalinization with sodium hydroxide solution gave the amino ester 5 in a yield of 87%. The overall yield of this synthesis was about 47% starting from cyanoacetic ester 1.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([C:18]([NH:21][CH2:22][CH2:23][CH2:24][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)([CH3:20])[CH3:19])[CH:14]=[CH:15][C:16]=1[Cl:17].Cl>ClCCl.C(N(CC)CC)C>[Cl:17][C:16]1[CH:15]=[CH:14][C:13]([C:18]([NH:21][CH2:22][CH2:23][CH2:24][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)([CH3:19])[CH3:20])=[CH:12][C:11]=1[NH:10][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(NCCCn1ccnc1)c1ccc(Cl)c(N)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NCCCn1ccnc1)c1ccc(Cl)c(NC(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Benzoyl chloride (0.21 ml) was added to a solution of N-[1-(3-amino-4-chlorophenyl)-1-methylethyl]-3-(imidazol-1-yl)propylamine (0.50 g) in dichloromethane (50 ml) and triethylamine (0.25 ml) with stirring at 0° C. The mixture was allowed to warm up to ambient temperature and stirred at this temperature for 18 hours. The mixture was washed with water, dried and evaporated. The residue was purified by flash column chromatography on silica using ethyl acetate/methanol/triethylamine (8:1:1) as the mobile phase. The product was obtained as an oil which was added to ethereal hydrogen chloride to produce a gum. The gum was triturated and then left standing for 18 hours. The resulting solid was ground up, filtered and dried to give 2'-chloro-5'-{1-[3-(imidazol-1-yl)propylamino]-1-methylethyl}benzanilide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:34]I)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:34][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(Cl)cc2)C1
Reactant: Oc1ccc(-c2ncc(Cl)cn2)cc1
Product: CCOC(=O)C1(COc2ccc(-c3ncc(Cl)cn3)cc2)CCN(C(=O)c2ccc(Cl)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4-(5-chloro-pyrimidin-2-yl)-phenol (Preparation 19) and 1-(4-chloro-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 13) to afford the racemate as a white solid (153 mg, 65.7%)
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1([C:24]([O:26]O)=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)C.ClCCl.C(OCC)C>[C:1]([O:5][C:6]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([O:13][O:26][C:24](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Oc1ccccc1C(=O)O
Reactant: O=C(OO)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Oc1ccccc1C(=O)OOC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 47.2 %

Procedure:
3 g (13 mmol) of 2-(tert-butoxycarbonyloxy)benzoic acid and 1.8 g (13 mmol) of benzenecarboperoxoic acid (prepared as described in Example 1-3) are dissolved in a diethyl ether/dichloromethane 6/4 mixture. The solution is cooled to 0° C. and then 2.6 g (13 mmol) of N,N′-dicyclohexylcarbodiimide dissolved in 50 ml of diethyl ether are added dropwise. After stirring at 0° C. for 3 hours, the reaction medium is filtered and then concentrated to dryness. The residue is purified by chromatography on silica gel eluted with a pentane/dichloromethane 4/6 mixture. 2.2 g of (2-(tert-butoxycarbonyloxy)benzoyl)benzoyl peroxide are obtained in the form of a white solid with a yield of 49%.