Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][O:14][CH3:15].N(C(OC(C)C)=O)=NC(OC(C)C)=O.FC1C=CC([N+]([O-])=O)=CC=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCO>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: COCCOc1cc([N+](=O)[O-])ccc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=[N+]([O-])c1ccc(F)c(O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCO
Solvent: C1CCOC1
Product: COCCOc1cc(N)ccc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
1-Fluoro-2-(2-methoxyethoxy)-4-nitrobenzene. Diisopropyl azodicarboxylate (1.356 mL, 7.00 mmol) was added dropwise to a stirred solution of 2-fluoro-5-nitrophenol (1.00 g, 6.37 mmol), triphenylphosphine (1.837 g, 7.00 mmol), and 2-methoxyethanol (0.533 g, 7.00 mmol) in tetrahydrofuran (10 mL) cooled with a water bath. The resulting dark red mixture was stirred at room temperature under nitrogen for 1.5 h. The resulting mixture was purified using flash chromatography (Biotage) (0-30% ethyl acetate in hexane). Fractions containing the desired product were combined and washed twice with water and once with brine. The organics were dried over magnesium sulfate, filtered, and concentrated on a rotary evaporator nearly to dryness. The residue was diluted with cold hexane. Solids were collected by vacuum filtration, washed with cold hexane, and dried under high vacuum to give the desired product (0.865 g, 4.02 mmol, 63% yield) as slightly yellow needles. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.01 (dd, J=2.73, 7.42 Hz, 1H), 7.91 (ddd, J=2.73, 3.90, 8.98 Hz, 1H), 7.54 (dd, J=8.98, 10.93 Hz, 1H), 4.31-4.39 (m, 2H), 3.67-3.76 (m, 2H), 3.32 (s, 3H); MS (ESI) m/z 216.3 [M+1]+.
Reaction SMILES: C[Al](C)C.[CH2:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=O)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)[CH3:6].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][C:35]2[CH:36]=[C:37]([NH2:40])[NH:38][N:39]=2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>C1(C)C=CC=CC=1>[CH3:32][O:31][C:29]1[CH:28]=[C:27]([CH2:33][CH2:34][C:35]2[CH:36]=[C:37]([NH:40][C:17](=[O:19])[C:16]3[CH:15]=[CH:14][C:13]([CH:10]4[CH2:9][CH2:8][N:7]([CH2:5][CH3:6])[CH2:12][CH2:11]4)=[CH:22][CH:21]=3)[NH:38][N:39]=2)[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=1
Reactant: CCN1CCC(c2ccc(C(=O)OC)cc2)CC1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCN1CCC(c2ccc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cc2)CC1
Temperature: 60 °C
Yield: 38 %

Procedure:
A 2M solution of trimethylaluminium in toluene (0.413 mL, 0.83 mmol), was added drop-wise to a suspension of methyl 4-(1-ethylpiperidin-4-yl)benzoate (0.082 g, 0.33 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.082 g, 0.33 mmol) in toluene (2 mL) at room temperature. The solution was then heated at 60° C. for 18 h. The reaction mixture was cooled, quenched with methanol (2 ml) and 2N hydrochloric acid (1 ml). The reaction mixture was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.058 g, 38.0%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].O1CCCC1.B>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Br
Agent: B
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Br)c(CO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-bromo-5-nitrobenzoic acid (5 g, 20 mmol) at 0° C. was added borane tetrahydrofuran complex (1 M in THF; 200 mL, 200 mmol), and the reaction was stirred at room temperature overnight. The mixture was quenched with 1N aqueous HCl to give the title compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:29])([F:28])[C:5]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:7]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])=[CH:16][CH:15]=2)[N:6]=1.[CH3:30]I>CN(C=O)C>[CH3:30][N:20]([C:17]1[CH:16]=[CH:15][C:14]([N:7]2[C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=3[C:5]([C:4]([F:3])([F:28])[F:29])=[N:6]2)=[CH:19][CH:18]=1)[C:21]([N:23]1[CH2:24][CH2:25][CH2:26][CH2:27]1)=[O:22]
Reactant: CI
Reactant: O=C(Nc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)N1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)N1CCCC1)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
Under an inert atmosphere (Ar), NaH (60% in mineral oil, 3.8 mg; 95 μmol) was added in one portion to a stirring solution of N-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-1-pyrrolidinecarboxamide (17.7 mg; 44 μmol) in anhydrous DMF (1.5 mL). After stirring at room temperature for 1 hour, MeI (20 μL; 0.32 mmol) was added in one portion, and the reaction stirred at this temperature for 2 hours 10 minutes. The reaction was quenched with methanolic ammonia (1M, 1 mL), concentrated in vacuo and purified by column chromatography, giving the desired material as a yellow oil (15.4 mg; 84%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].[Br:27][C:28]1[CH:29]=[C:30]([OH:37])[CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[Br:27][C:28]1[CH:29]=[C:30]([CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=1)[O:37][C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: O=[N+]([O-])c1cc(O)cc(Br)c1
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cc(Br)cc([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
A mixture of 5-chloro-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (250 mg), 3-bromo-5-nitrophenol (170 mg), potassium carbonate (138 mg), and N-methylpyrrolidone (5 mL) was stirred at 100° C. for 4 hours. To the reactant was added water, followed by extraction with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=1:0-9:1) to obtain 5-(3-bromo-5-nitrophenoxy)-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (336 mg) as a yellow solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)O1.[Cl:19][C:20]1[CH:38]=[CH:37][C:23]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:25])=[CH:22][C:21]=1I.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O.C(O)C>[Cl:19][C:20]1[C:21]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)=[CH:22][C:23]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=2)=[O:25])=[CH:37][CH:38]=1
Reactant: CC1(C)OB(c2cccc([N+](=O)[O-])c2)OC1(C)C
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(Cl)c(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(Cl)c(-c2cccc([N+](=O)[O-])c2)c1
Yield: 146.6 %

Procedure:
4,4,5,5-Tetramethyl-2-(3-nitrophenyl)-1,3,2-dioxaborolane (0.40 g, 0.0016 mol) was mixed with 4-chloro-3-iodo-N-[3-(trifluoromethyl)phenyl]benzamide (0.600 g, 0.00141 mol), potassium carbonate (0.39 g, 0.0028 mol), toluene (10 mL), ethanol (1.7 mL), and water (1.1 mL). The mixture was degassed by bubbling nitrogen through it. To the reaction was added tetrakis(triphenyl-phosphine)palladium(0) (0.078 g, 0.000068 mol). The reaction was heated to reflux for 16 hours. LCMS showed about 80% conversion to M+H 421/423 (3:1). The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, then dried (Na2SO4). Solvent was removed under vacuum to give 0.87 g oil. The product was purified by automatic flash chromatography on silica gel. Used a 40 g column; flow 40 mL/min; [A=hexane] [B=EtOAc]. A, 4 min; Gradient to 20% B in 30 min. The product eluted in 23-28 min (starting material at 16-18 min). Removal of solvent under vacuum gave 0.46 g white solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=O)[CH:4]=[CH:5][C:6](=[CH:11][N:12]1CCCC1)[CH:7]([S:9][CH3:10])[CH3:8].C(N(CC)CC)C.Cl.N[OH:29]>C1(C)C=CC=CC=1>[CH3:10][S:9][CH:7]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:18])[F:1])=[N+:12]([O-:29])[CH:11]=1)[CH3:8]
Reactant: NO
Reactant: CSC(C)C(C=CC(=O)C(F)(F)F)=CN1CCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CSC(C)c1ccc(C(F)(F)F)[n+]([O-])c1
Temperature: 12.800000190734863 °C
Reaction time: 1 h

Procedure:
403 mg (0.37 mmol) of the 27 wt % 1,1,1-trifluoro-6-(methylthio)-5-(pyrrolidine-1-ylmethylene)hept-3-en-2-one (4) in toluene was added to a 25 mL three-neck round bottom flask equipped with a reflux condenser and vented to a bleach scrubber. To this mixture was added 34 mg (0.34 mmol) of triethylamine in one portion. The reaction mixture was cooled to about 12.8° C. and then 24 mg (0.34 mmol) of hydroxylamine hydrochloride was added in one portion. The reaction mixture was slowly heated to 85° C. and stirred for one hour and forty-five minutes. The reaction mixture was then cooled to ambient temperature. This mixture was split into many fractions for instrumental analysis and purification. A portion of the reaction mixture was partitioned between toluene and water. Both the organic and aqueous layers were analyzed by LC/MS. Both layers were confirmed to have a peak with molecular consistency for 5-(1-(methylthio)ethyl)-2-(trifluoromethyl)pyridine N-oxide (C9H10F3NOS). Calculated m/z=237.04. Found m/z=237.04.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH2:27][C:28]#[CH:29])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:31]([O:38][CH2:39]I)(=[O:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(OCC)(=O)C.C(OC(C)C)(C)C>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH2:27][C:28]#[CH:29])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O:22][CH2:39][O:38][C:31](=[O:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=C)CS[C@H]12)c1csc(N)n1
Reactant: CCCCCC(=O)OCI
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)CCCCC)=C(C=C)CS[C@H]12)c1csc(N)n1
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To a solution of sodium 7-[2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2 g) in N,N-dimethylformamide (20 ml) was added a solution of iodomethyl hexanoate (1.28 g) in N,N-dimethylformamide (4 ml) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture was added ethyl acetate (80 ml), followed by washing twice with water, three times with 5% aqueous solution of sodium bicarbonate and twice with a saturated aqueous solution of sodium chloride. The resultant solution was dried over anhydrous magnesium sulfate and then evaporated to give a residue, which was pulverized with diisopropyl ether to obtain hexanoyloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (1.85 g), mp 98°-109° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[C:4]([CH2:10][O:11][CH3:12])[N:3]=1.[CH3:13][CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][NH:15]1>>[CH3:12][O:11][CH2:10][C:4]1[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([N:15]2[CH2:16][CH2:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]2[CH3:13])[C:5]=1[CH3:9]
Reactant: CC1NCCc2ccccc21
Reactant: COCc1nc(Cl)nc(Cl)c1C
Product: COCc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Yield: 59.9 %

Procedure:
The same procedures as in Step 1 of Example 25 were repeated using 2,4-dichloro-6-methoxymethyl-5-methylpyrimidine(1.3 g, 6.3 mmol) and 1-methyl-1,2,3,4-tetrahydroisoquinoline(1.02 g, 6.93 mmol) to afford 1.2 g of the titled compound. (Yield: 60%)
Reaction SMILES: [N:1]1([S:7]([C:10]2[NH:11][C:12](=[O:16])[CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[S:17](Cl)([CH3:20])(=[O:19])=[O:18].C(N(CC)CC)C>ClCCl.C(Cl)(Cl)Cl>[N:1]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[N:11]=2)(=[O:9])=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=c1cccc(S(=O)(=O)N2CCOCC2)[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Oc1cccc(S(=O)(=O)N2CCOCC2)n1
Reaction time: 0.08 h

Procedure:
A solution of the pyridone prepared in stage (v) (0.27 g) in dichoromethane (30 cm3) under nitrogen was cooled to 0° C. and a solution of mesyl chloride in chloroform was added (0.12 g in 5 cm3). The reaction mixture was stirred for 5 minutes then treated with triethylamine (0.1 g) in dichloromethane.
Reaction SMILES: [C:1]12([OH:13])[CH2:10][C:5]3([OH:11])[CH2:6][CH:7]([CH2:9][C:3]([OH:12])([CH2:4]3)[CH2:2]1)[CH2:8]2.C[N:15]([CH:17]=[O:18])[CH3:16]>>[CH3:16][NH:15][C:17]([O:13][C:1]12[CH2:10][C:5]3([O:11][C:17](=[O:18])[NH:15][CH3:16])[CH2:6][CH:7]([CH2:9][C:3]([O:12][C:17](=[O:18])[NH:15][CH3:16])([CH2:4]3)[CH2:2]1)[CH2:8]2)=[O:18]
Reactant: OC12CC3CC(O)(C1)CC(O)(C3)C2
Reactant: CN(C)C=O
Product: CNC(=O)OC12CC3CC(OC(=O)NC)(C1)CC(OC(=O)NC)(C3)C2
Temperature: 60 °C
Yield: 95 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1,3,5-adamantanetriol obtained by the method of Example 32 and one drop of pyridine were dissolved in 10 mL of DMF. To the mixture, 30 mmole of methylisocyanato was added dropwise with stirring. Cooling of the resultant mixture with ice was started at about the time exothermic reaction began. When the exothermic reaction is completed, the mixture was heated to 60° C. and then stirred for one hour. As a result, the conversion of 1,3,5-adamantanetriol was 99% and 1,3,5-tris(N-methylcarbamoyloxy)adamantane (yield 95%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH2:21][CH3:22])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:24][OH:25].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH2:21][CH3:22])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:24]\[OH:25])=[CH:4][CH:3]=1
Reactant: CCCC(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCC(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-hexanoyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=377.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1.C(OC1C=CC([NH:26][CH2:27][C:28]2[CH:41]=[CH:40][C:31]([C:32]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:29]=2)=CC=1)CCC.Cl[CH:43](Cl)[CH3:44]>>[CH2:32]([O:33][C:43]1[CH:44]=[CH:40][C:41]([CH:27]([NH:26][C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=2)=[O:12])[C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:40][CH:41]=2)=[CH:28][CH:27]=1)[CH2:31][CH2:30][CH3:29]
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CCCCOc1ccc(NCc2ccc(C(=O)NCCC(=O)O)cc2)cc1
Reactant: CC(Cl)Cl
Product: CCCCOc1ccc(C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)c2ccc(C(=O)NCCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
200 μmol 4-trifluoromethoxyphenylisocyanate dissolved in 500 μL dichloroethane was added to the above resin bound 3-{4-[(4-butoxyphenylamino)methyl]benzoylamino}propionic acid (50 mg). Shaking the mixture 5 hours at 25° C. followed by filtration and washing of the resin with 2×1 mL dichloromethane, 4×1 mL DMF, 2×1 mL H2O, 3×1 mL THF and 3×1 dichloromethane afforded the resin bound title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:12]([O-:14])=[O:13])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C:15]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([N+:12]([O-:14])=[O:13])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:8][CH3:15])=[O:7]
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(C(=O)O)c1[N+](=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cccc(OC)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-methoxy-2-nitrobenzoic acid (25.0 g, 126 mmol) and K2CO3 (35.0 g, 253 mmol) in DMF (126 mL) was added MeI (15.8 mL, 253 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. To the mixture was poured the water (200 mL) and then stirred at 5° C. for 30 min. The precipitated solid was collected by filtration, washed with water and hexane. The solid was dried under reduced pressure to afford the compound 52 in a crude form (26.2 g, 98%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[C:3]=1Cl.[Mg].II.C(O[C:18]([N:20]([C:39]([O:41]C(C)(C)C)=O)[C@H:21]([CH2:32][CH2:33]/[CH:34]=[CH:35]/[N+:36]([O-])=O)C(OCC1C=CC=CC=1)=O)=O)(C)(C)C.[CH2:46]([O:48][CH2:49]C)C>>[NH2:36][C@@H:35]1[CH2:34][CH2:33][C@@H:32]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:21][N:20]([CH2:18][CH2:46][O:48][CH3:49])[C:39]1=[O:41]
Reactant: Clc1cccc(Br)c1Cl
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC/C=C/[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: II
Agent: [Mg]
Product: COCCN1C[C@H](c2ccccc2)CC[C@@H](N)C1=O
Temperature: 25 °C

Procedure:
To a slurry of 1-bromo-2,3-dichlorobenzene (1.46 g, 6.46 mmol) in diethyl ether (10 mL) was added magnesium (0.157 g, 6.46 mmol) and a crystal of iodine. This mixture was refluxed for 3 h, and then cooled to room temperature. A solution of benzyl (2R,5E)-2-[bis(tert-butoxycarbonyl)amino]-6-nitrohex-5-enoate (0.50 g, 1.08 mmol) in diethyl ether (10 mL) was cooled to 0° C., and 2.0 mL of the Grignard solution prepared above was added. After 1 and 2 h, respectively, 2.0 and 1.0 mL of the Grignard solution was added. The reaction was quenched with a saturated aqueous solution of ammonium chloride, the phases separated and the organic phase washed with saturated aqueous sodium potassium tartrate and brine. The combined organics were dried over magnesium sulfate, filtered and concentrated to give a residue that was purified by silica gel chromatography (0%→3% methanol/dichloromethane) to give the title compound (0.52 g). MS 411.0 (M+1-2Boc).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15][O:16][CH2:17][CH2:18][NH2:19].[BH4-].[Na+]>CO.C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:19][CH2:18][CH2:17][O:16][CH3:15])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: COCCN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COCCNC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 16 h

Procedure:
Amine preparation: 1-BOC-4-piperidone (500 mg) and 2-methoxyethylamine (218 μL) were stirred in MeOH at room temperature. After 16 h, sodium borohydride was added (190 mg) carefully. After a further 3 h, the reaction mixture was diluted with DCM, washed with water, dried (MgSO4) and the solvent removed in vacuo to yield 4-(2-methoxy-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester (560 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][NH:6][C:5]1=[S:10].[CH3:11][S:12]([O:15]C)(=[O:14])=[O:13]>C(O)C.COC(C)(C)C>[S:12]([OH:15])(=[O:14])(=[O:13])[CH3:11].[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][NH:6][CH:5]1[S:10][CH3:11]
Reactant: OCCN1CCCNC1=S
Reactant: COS(C)(=O)=O
Solvent: CCO
Solvent: COC(C)(C)C
Product: CS(=O)(=O)O
Product: CSC1NCCCN1CCO
Temperature: 25 °C
Yield: 128.8 %

Procedure:
Then, 1-(2-hydroxyethyl)-3,4,5,6-tetrahydropyrimidine-2-thione (121.2 g) and methyl methanesulfonate (91.51 g) are heated at reflux in ethyl alcohol (200 ml) for about 2 hours and then allowed to cool to room temperature. The mixture was diluted with t-butyl methyl ether (2 liters). An oil separates which crystallizes on keeping in freezer at -20° C. Filtration and drying yields 145.7 g of 1-(2-hydroxyethyl)-2-methylthio-3,4,5,6-tetrahydropyrimidine mesylate, melting point 61.7°-62.2° C.
Reaction SMILES: C([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][CH2:8][CH:7]3CC(N(CCC)CCC)C[C:5]=1[C:6]=23)(=O)C.C([N:25]([CH2:28]C)CC)C.ClC(OCC(Cl)(Cl)Cl)=[O:32]>ClCl>[C:28]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:12][CH:11]=2)[CH2:7][CH2:8]1)(=[O:32])[NH2:25]
Reactant: CCCN(CCC)C1Cc2c(C(C)=O)ccc3c2C(CN3)C1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: ClCl
Product: NC(=O)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (±)-6-acetyl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (2.3 g, 7.7 mmol) and triethylamine (1.1 ml, 8 mmol) in 90 ml CH2 Cl2 under N2 was added dropwise a solution of 2,2,2-trichloroethyl chloroformate. The reaction mixture was stirred at room temperature for 1 hr. The CH2Cl2 solution was extracted with water and 1N HCl . The organic solution was washed with a saturated NaHCO3 solution and with a brine solution. The CH2Cl2 solution was dried (MgSO4) and concentrated in vacuo to give 3.3 g of the 1-carbamylindoline.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([N+:18]([O-:20])=[O:19])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+:22](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.Cl.[C:46]([O:50][C:51](=[O:63])[C@H:52]([CH2:54][CH2:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[NH2:53])([CH3:49])([CH3:48])[CH3:47]>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:22][NH:53][C@H:52]([C:51]([O:50][C:46]([CH3:48])([CH3:49])[CH3:47])=[O:63])[CH2:54][CH2:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])=[O:15])=[C:11]([N+:18]([O-:20])=[O:19])[CH:10]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC[C@H](NNC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-])C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
To a mixture of 4-(tert-butoxycarbonylamino)-2-nitrobenzoic acid in 60 ml of dichloromethane were added 4.8 g of N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)-uronium-hexafluorophosphate. After stirring for 15 min. a mixture of 3.8 g of L-glutamic acid-di tert.-butylester hydrochloride in 60 ml dichloromethane and 3 ml triethylamine was added dropwise. After stirring for 20 hours at room temperature, the mixture was filtered and the filtrate was washed five times with 10% aqueous citric acid, four times with 5% aqueous sodium carbonate solution and two times with water. The organic layer was dried over magnesium sulphate and concentrated in vacuum to give 6.3 g of di-tert-butyl N-(4-(tert-butoxycarbonylamino)-2-nitrobenzamido)-L-glutamate as a yellow foam. This was directly used in example 3.