Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C@H:6]([NH:8][C@H:9]([C:16]([OH:18])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][NH:14][CH:15]=1)[CH3:7])[C:3]([OH:5])=[O:4].C([N:21]([CH2:24][CH3:25])CC)C.[O:26]1CCOC[CH2:27]1>O>[NH2:21][C@@H:24]([CH3:25])[C:27]([NH:1][C@@H:2]([C@H:6]([NH:8][C@H:9]([C:16]([OH:18])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][NH:14][CH:15]=1)[CH3:7])[C:3]([OH:5])=[O:4])=[O:26]
Reactant: C1COCCO1
Reactant: C[C@@H](N[C@@H](Cc1c[nH]cn1)C(=O)O)[C@H](N)C(=O)O
Reactant: CCN(CC)CC
Solvent: O
Product: C[C@H](N)C(=O)N[C@H](C(=O)O)[C@@H](C)N[C@@H](Cc1c[nH]cn1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of (2S,3R)-2-amino-3-[[(1S)-1-carboxy-2-(4-imidazolyl)ethyl]amino]butyric acid (700 mg) and triethylamine (1.29 ml) in a mixture of water (10 ml) and dioxane was added t-butoxycarbonyl-L-alanine N-hydroxysuccinimide ester and the mixture was stirred for 4 hours at room temperature. The solvent was evaporated in vacuo and the residue was dissolved in 75% aqueous trifluoroacetic acid (20 ml). The solution was stored overnight at room temperature and the solvent was evaporated in vacuo. The residue was subjected to a column of Dowex 50W x 8 (30 ml) and the column was washed with water. The elution was carried out with 2.8% aqueous ammonia. The object fractions were collected and evaporated in vacuo. The residue was subjected to a column of Whatman CM52 (150 ml) and the elution was carried out with pyridine-acetic acid buffer (0.01M-0.14M, pH 4.9). The object fractions were collected and evaporated in vacuo. The residue was dissolved in water and lyophilized to give (2S,3R)-2-[[(2S)-2-aminopropionyl]amino]-3-[[(1S)-1-carboxy-2-(4 -imidazolyl)ethyl]amino]butyric acid (580 mg).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:22])[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][N:12]2[CH2:15][CH3:16])=[CH:7][C:6]=1[F:23])=O.[C:24]([NH:27][CH2:28][C:29]([NH2:31])=[S:30])(=[O:26])[CH3:25].C(N(CC)CC)C>CN(C)C=O>[C:24]([NH:27][CH2:28][C:29]1[S:30][CH:2]=[C:3]([C:5]2[CH:14]=[C:13]3[C:8]([C:9](=[O:22])[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][N:12]3[CH2:15][CH3:16])=[CH:7][C:6]=2[F:23])[N:31]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)NCC(N)=S
Reactant: CCOC(=O)c1cn(CC)c2cc(C(=O)CBr)c(F)cc2c1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(CC)c2cc(-c3csc(CNC(C)=O)n3)c(F)cc2c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 57.6 %

Procedure:
A suspension of 0.59 g (1.54 mmol) ethyl 7-bromoacetyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 4 ml N,N-dimethylformamide was treated with 0.22 g (1.67 mmol) acetamidothioacetamide [prepared according to J. Am. Chem. Soc. 51, 1817 (1929)]. After stirring three hours the mixture was treated with 0.22 ml (1.58 mmol) triethylamine, stirred one hour more and poured into 40 ml ice water. The precipitate was filtered, washed with water and dried to afford 0.45 g crude solid. Chromatography on a column of 20 g silica gel with chloroform-methanol (9:1) and crystallization from ethanol gave 0.37 g ethyl 7-[2(acetamidomethyl)-4-thiazolyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, mp 230°-233° C. (dec).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[N:12]1[C:16]2[C:17](=[O:28])[N:18]([C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=3)[CH2:19][CH2:20][C:15]=2[C:14]([C:29]([F:32])([F:31])[F:30])=[N:13]1.[CH3:34][N:35]1[CH2:39][CH2:38][CH2:37][CH:36]1[CH2:40][CH2:41][NH2:42].O>C(O)CO>[I:27][C:24]1[CH:23]=[CH:22][C:21]([N:18]2[CH2:19][CH2:20][C:15]3[C:14]([C:29]([F:32])([F:30])[F:31])=[N:13][N:12]([C:5]4[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:4]=4[C:3]([NH:42][CH2:41][CH2:40][CH:36]4[CH2:37][CH2:38][CH2:39][N:35]4[CH3:34])=[O:2])[C:16]=3[C:17]2=[O:28])=[CH:26][CH:25]=1
Reactant: COC(=O)c1cc(OC)ccc1-n1nc(C(F)(F)F)c2c1C(=O)N(c1ccc(I)cc1)CC2
Reactant: CN1CCCC1CCN
Solvent: O
Solvent: OCCO
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(I)cc2)CC3)c(C(=O)NCCC2CCCN2C)c1
Temperature: 85 °C
Yield: 32 %

Procedure:
The title compound was prepared from 2-[6-(4-iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzoic acid methyl ester as obtained in Example 1. The ester (159 mg, 0.278 mmol) was dissolved in ethylene glycol (2 mL) containing 2-(1-methyl-pyrrolidin-2-yl)-ethylamine (400 μL, 2.78 mmol) and heated to 85° C. for 12 h. The reaction was poured into water and extracted with ethyl acetate (3×10 mL). The combined extracts were washed with water (5×10 mL), dried over sodium sulfate, filtered, and evaporated. The residue was purified by preparative thin layer chromatography to give 2-[6-(4-iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-N-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-benzamide (60 mg, 32%) as a faint yellow solid. MS (ES+) 668.4 (M+H)+(100%). This material (60 mg, 0.089 mmol) was combined with 2-pyridone (17 mg, 0.18 mmol), anhydrous potassium carbonate (49 mg, 0.36 mmol), copper(I) iodide (3.4 mg, 0.018 mmol), 1,10-phenanthroline (3.2 mg, 0.018 mmol), and dry-degassed dimethylsulfoxide (1.0 mL) and heated to 140° C. for 6 h. The mixture was cooled to ambient temperature and diluted with 6N ammonium hydroxide and ethyl acetate. The phases were separated, and the aqueous phase extracted once with ethyl acetate. The combined organic extracts were washed successively with water (2×) and 3N ammonium hydroxide, dried over sodium sulfate, filtered, and evaporated. The residue was purified by preparative HPLC to give the title compound as a colorless solid. MS (ES+) 635.5 (M+H)+(100%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.O=[C:12]([C:18](OCC)=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[N:9]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18](=[O:19])[NH:10]2
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: CCO
Product: CCOC(=O)c1nc2cc(Cl)c(Cl)cc2[nH]c1=O

Procedure:
A solution of 17.7 g. of 4,5-dichloro-o-phenylenediamine in 200 ml. of anhydrous ethanol was prepared. A 17.4 g. batch of diethyl 2-ketomalonate were added to this solution and the mixture was heated to refluxing temperature for about 17 hours. The volatile constituents were removed by evaporation in vacuo. Recrystallization of the residue from ethanol yielded 20 g. of ethyl 6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxaline carboxylate formed in the above reaction, melting in the range 226°-227° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:29]([O:36][C:37](=[O:44])[C@H:38]([CH2:40][CH:41]([CH3:43])[CH3:42])[NH2:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.C(Cl)Cl.O1CCCC1>[CH2:29]([O:36][C:37](=[O:44])[C@H:38]([CH2:40][CH:41]([CH3:42])[CH3:43])[NH:39][C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
To a solution of N-tert-butoxycarbonylalanine (0.06 mole) and N-methylmorpholine (0.06 mole) in dry tetrahydrofuran (100 ml) at -20° to -25° is added isobutyl chloroformate (0.06 mole) with stirring. After 10-15 minutes, a solution of leucine benzyl ester (0.06 mole) and N-methylmorpholine (6.8 ml) in methylene chloride-tetrahydrofuran (1:1, 100 ml) is added over a period of 1/2 hour. The mixture is allowed to warm to room temperature and stirred at room temperature overnight. The resulting mixture is concentrated in vacuo and the residue extracted between chloroform and dilute hydrochloric acid. The chloroform layer is separated, washed with water, dried over sodium sulfate and concentrated to give the crude N-tert-butoxycarbonylalanylleucine benzyl ester to be used as in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([C:8](=[O:21])/[CH:9]=[C:10]2\[S:11][CH:12]=[C:13]([CH3:20])[N:14]\2[CH2:15][CH:16]2[CH2:19][CH2:18][CH2:17]2)[CH:7]=1.[Br:24]N1C(=O)CCC1=O>C(#N)C>[Br:24][C:12]1[S:11]/[C:10](=[CH:9]\[C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:22][CH3:23])=[O:21])/[N:14]([CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19]2)[C:13]=1[CH3:20]
Reactant: COc1ccc(Cl)cc1C(=O)/C=C1\SC=C(C)N1CC1CCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1ccc(Cl)cc1C(=O)/C=C1\SC(Br)=C(C)N1CC1CCC1
Reaction time: 16 h

Procedure:
In a 20 mL vial, a solution of Example 169B (620 mg, 1.772 mmol) was dissolved in acetonitrile (4 ml). N-bromosuccinimide (268 mg, 1.506 mmol) was added and the reaction was stirred for 16 hrs. The reaction was concentrated and purified by chromatography over silica gel (hex-EtOAc 4:1 as eluent) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.82-1.93 (m, 4 H) 1.95-2.06 (m, 2 H) 2.29 (s, 3 H) 2.71-2.84 (m, 1 H) 3.88 (s, 3 H) 4.06 (d, J=7.12 Hz, 2 H) 6.82 (s, 1 H) 7.14 (d, J=8.82 Hz, 1 H) 7.44 (dd, J=8.82, 2.71 Hz, 1 H) 7.66 (d, J=2.71 Hz, 1 H). MS (ESI) m/z 428 (M+H)+. Anal calcd for C19H22ClF2NO3S: C, 54.61; H, 5.31; N, 3.35. Found: C, 54.51; H, 5.26; N, 3.35.
Reaction SMILES: Cl[C:2]1C=CC(C2C=C3C(C(C4C(F)=C(NS(CCC)(=O)=O)C=CC=4F)=O)=CNC3=NC=2)=CC=1.[OH-].[K+].[C:36]([O:40][C:41]([NH:43][CH:44]([CH:50]([CH3:52])[CH3:51])[C:45]([O:47]CCl)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C>[C+4:2].[C:36]([O:40][C:41]([NH:43][CH:44]([CH:50]([CH3:52])[CH3:51])[C:45]([O-:47])=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37].[C:36]([O:40][C:41]([NH:43][CH:44]([CH:50]([CH3:52])[CH3:51])[C:45]([O-:47])=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37].[C:36]([O:40][C:41]([NH:43][CH:44]([CH:50]([CH3:52])[CH3:51])[C:45]([O-:47])=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37].[C:36]([O:40][C:41]([NH:43][CH:44]([CH:50]([CH3:52])[CH3:51])[C:45]([O-:47])=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OCCl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)[O-]
Product: [C+4]

Procedure:
The title compound was prepared according to the procedure as described in Example 14 Step 2 using N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.1 g, 0.2 mmol) in DMF (0.9 mL), KOH (23 mg, 0.4 mmol), a solution of chloromethyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (54 mg, 0.2 mmol) in DMF (100 μL). The title compound was purified by a silica gel column chromatography (PE/EtOAc (v/v)=4/1 to 3/1) and was obtained as a white solid (82 mg, 55.8%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [CH:1]([C:3]1[CH:39]=[CH:38][C:6]([C:7]([N:9]([CH2:24][C:25]2[N:26](COCC[Si](C)(C)C)[CH:27]=[CH:28][N:29]=2)[CH2:10][C:11]2[N:12](COCC[Si](C)(C)C)[CH:13]=[CH:14][N:15]=2)=[O:8])=[CH:5][CH:4]=1)=[O:2]>FC(F)(F)C(O)=O.ClCCl>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]([CH2:24][C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)[CH2:10][C:11]2[NH:15][CH:14]=[CH:13][N:12]=2)=[O:8])=[CH:38][CH:39]=1)=[O:2]
Reactant: C[Si](C)(C)CCOCn1ccnc1CN(Cc1nccn1COCC[Si](C)(C)C)C(=O)c1ccc(C=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1ccc(C(=O)N(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To the compound 40 (1.7 g), a 50% trifluoroacetic acid-dichloromethane solution (10 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and an aqueous 5N sodium hydroxide solution (15 mL) was added to the residue. The aqueous layer was extracted three times with 50 mL of dichloromethane. The combined organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was concentrated to obtain the title compound (compound B) (922 mg) having the following physical properties.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[N:10]([CH2:13][CH2:14][CH2:15][NH2:16])=[N+:11]=[N-:12]>>[N:10]([CH2:13][CH2:14][CH2:15][NH:16][C:2]1[N:4]=[C:5]([NH:16][CH2:15][CH2:14][CH2:13][N:10]=[N+:11]=[N-:12])[N:7]=[C:8]([NH:16][CH2:15][CH2:14][CH2:13][N:10]=[N+:11]=[N-:12])[N:1]=1)=[N+:11]=[N-:12]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: [N-]=[N+]=NCCCN
Product: [N-]=[N+]=NCCCNc1nc(NCCCN=[N+]=[N-])nc(NCCCN=[N+]=[N-])n1

Procedure:
FIG. 6 is a series of schemes showing the synthesis of the monomers used in the adhesives test. The first reaction to make 1 is an N-sulfonylation of the nitrogen mustard, N,N-di(2-chloroethyl) amine, followed by an SN2 displacement of the chlorides to obtain the diazide, 1. The second reaction is an N-propargylation of 4-methyl-benzenesulfonamide under mild conditions to give the diacetylene, 2. The last reaction is the displacement of the chlorides of cyanuric chloride with 3-azidopropylamine to give the triamino-1,3,5-triazine 5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:19](=[O:20])[C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[Cl:16])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccc1Cl

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-chlorobenzamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 2-chlorobenzoyl chloride in a similar manner as described above to give a white solid (30% yield). 1H-NMR (DMSO-d6): δ 10.98 (s, 1H), 8.89 (d, 1H), 7.54 (dd, 2H), 7.48-7.44 (m, 1H), 7.42 (dd, 1H), 7.40-7.34 (m, 1H), 7.28 (d, 1H), 7.13 (dd, 1H), 5.26 (m, 1H), 2.60 (m, 2H), 2.08-1.91 (m, 2H), 1.90-1.73 (m, 2H); MS m/z 403 (M−1).
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([CH:10](C(OCC)=O)[C:11]([O:13][C:14](C)(C)[CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N+:1]([C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])nc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of tert-butyl ethyl (6-nitropyridin-3-yl)propanedioate (1.4 g, 4.5 mmol) in a mixed solution of TFA/DCM (10 mL/10 mL) was stirred for 5 hours at room temperature. The mixture was concentrated under reduce pressure. The residue was dissolved with DCM, washed with sat. NaHCO3, dried over anhydrous Na2SO4 and concentrated to give ethyl (6-nitropyridin-3-yl)acetate. 1H-NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.27 (d, J=8.4 Hz, 1H), 8.03 (dd, J=2.4 Hz, 8.4 Hz, 1H), 4.22 (q, J=7.2 Hz, 2H), 3.81 (s, 2H), 1.30 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25](OCC)=[O:26])=[N:4][C:5]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16].OC1C=CC([NH:37]C2N=C(C(OCC)=O)C([N+]([O-])=O)=C(NC3C=CC=CC=3OC)N=2)=CC=1.[CH2:61]([OH:63])C>[Pd]>[OH:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:5]2[N:6]=[C:7]3[C:2]([NH:1][C:61](=[O:63])[N:8]3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:3]([C:25]([NH2:37])=[O:26])[N:4]=2)=[CH:19][CH:20]=1
Reactant: CCO
Reactant: CCOC(=O)c1nc(Nc2ccc(O)cc2)nc(Nc2ccccc2OC)c1N
Reactant: CCOC(=O)c1nc(Nc2ccc(O)cc2)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Agent: [Pd]
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(Nc3ccc(O)cc3)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Ethyl 5-amino-2-(4-hydroxyphenylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate. Ethyl 2-(4-hydroxyphenylamino)-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate (220 mg, 0.517 mmol) was dissolved in ethanol (10 mL) and 10% palladium on carbon (55 mg, 0.052 mmol) was added. The reaction mixture was stirred at room temperature under an atmosphere of hydrogen overnight. The reaction was then filtered through Celite, solvent was removed under reduced pressure and purified by column chromatography (60-100% ethyl acetate in hexanes). Fractions containing product were combined and the solvent evaporated to provide the title compound (201.3 mg, 0.509 mmol, 98% yield). MS (ESI) m/z 396.2 [M+1]+.
Reaction SMILES: [Br:1][CH2:2]/[CH:3]=[CH:4]/[C:5]([OH:7])=O.ClC(OCC(C)C)=O.CN1CCOCC1.[Cl:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]2[C:44]3[C:43]4[CH2:42][CH2:41][NH:40][CH2:39][C:38]=4[S:37][C:36]=3[N:35]=[CH:34][N:33]=2)[CH:27]=[CH:28][C:29]=1[F:30]>ClCCl.CO.C(Cl)Cl>[Br:1][CH2:2][CH:3]=[CH:4][C:5]([N:40]1[CH2:39][C:38]2[S:37][C:36]3[N:35]=[CH:34][N:33]=[C:32]([NH:31][C:26]4[CH:27]=[CH:28][C:29]([F:30])=[C:24]([Cl:23])[CH:25]=4)[C:44]=3[C:43]=2[CH2:42][CH2:41]1)=[O:7]
Reactant: Fc1ccc(Nc2ncnc3sc4c(c23)CCNC4)cc1Cl
Reactant: O=C(O)/C=C/CBr
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CO
Solvent: ClCCl
Product: O=C(C=CCBr)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Reaction time: 1 h

Procedure:
To a solution of 4-Bromo crotonic acid (2.07 g, 0.012 mol) in dichloromethane (48 ml) at 0-5° C. was added isobutyl chloroformate (1.70 ml, 0.013 mol) followed by 4-methylmorpholine (1.40 ml, 0.013 mol) under nitrogen. This mixture was stirred at this temp. for one hour. The resulting suspension was added to a cooled solution of (3-Chloro-4-fluoro-phenyl)-(5,6,7,8-tetrahydro-9-thia-1,3,7-triaza-fluoren-4-yl)-amine (4.0 g, 0.012 mol) in dichloromethane (200 ml) over a period of 10 min. This mixture was stirred at RT for 1.5 hours. TLC (10% MeOH/DCM) shows no starting material present. The mixture was used as such in further reaction. LCMS RT=3.55 min, [M+H]+=483.04.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][C:10]([OH:17])=[CH:11][CH:12]=3)[O:7][C:6]=2[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.[CH2:21]([N:23]([CH2:28][CH3:29])[CH2:24][CH2:25][NH:26][NH2:27])[CH3:22].C(N(C(C)C)CC)(C)C>CN(C)C=O>[ClH:1].[N+:18]([C:5]1[CH:4]=[CH:3][C:2]2[N:26]([CH2:25][CH2:24][N:23]([CH2:28][CH3:29])[CH2:21][CH3:22])[N:27]=[C:14]3[C:13]4[CH:12]=[CH:11][C:10]([OH:17])=[CH:9][C:8]=4[O:7][C:6]=1[C:15]=23)([O-:20])=[O:19]
Reactant: CCN(CC)CCNN
Reactant: O=c1c2ccc(O)cc2oc2c([N+](=O)[O-])ccc(Cl)c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCn1nc2c3c(c([N+](=O)[O-])ccc31)Oc1cc(O)ccc1-2
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6.0 g of 1-chloro-6-hydroxy-4-nitro-9H-xanthen-9-one and 5.4 g of [2-(diethylamino)ethyl]-hydrazine and 3.9 ml of diisopropylethylamine in 100 ml of N,N-dimethylformamide was stirred at 25° C. for three hours. The mixture was evaporated and the residue crystallized from 2-propanol to afford the title compound, a salt with one equivalent of hydrogen chloride, mp 285° C. (decomposition).
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:11].Cl.[NH:13]1[CH:17]=[C:16]([CH2:18][N:19]2[C:25]3[CH:26]=[C:27](N)[CH:28]=[CH:29][C:24]=3[CH2:23][N:22]([C:31]([C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=[CH:35][CH:34]=3)=[O:32])[CH2:21][CH2:20]2)[N:15]=[CH:14]1.C(N(CC)CC)C>C(Cl)Cl.C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>[ClH:11].[ClH:11].[NH:13]1[CH:17]=[C:16]([CH2:18][N:19]2[C:25]3[CH:26]=[C:27]([NH:10][S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:28]=[CH:29][C:24]=3[CH2:23][N:22]([C:31]([C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=[CH:35][CH:34]=3)=[O:32])[CH2:21][CH2:20]2)[N:15]=[CH:14]1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: Nc1ccc2c(c1)N(Cc1c[nH]cn1)CCN(C(=O)c1cccc3ccccc13)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2cc(NS(=O)(=O)c3ccccc3)ccc2C1
Reaction time: 16 h

Procedure:
Benzenesulphonamide (0.024 g, 0.13 mmol) was added to a solution of Example 26 (0.50 g, 0.12 mmol) and triethylamine (0.019 mL, 0.13 mmol) in CH2Cl2 (1 mL). After stirring for 16 hr, the reaction was diluted with CHCl3 (10 mL) and NaHCO3 (3 mL) and stirred for 30 min. The layers were separated and the aqueous layer was reextracted with CHCl3 (2×20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was treated with HCl/ether, a yellow solid was formed which was triturated with ether several times and dried under vacuum to afford Example 54 (0.64.2 g, 83%) as a light brown solid.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[C-:14]#[N:15].[K+].S(=O)(O)[O-].[Na+].CCN(S(F)(F)[F:28])CC>C1COCC1.O>[C:14]([C:2]1([F:28])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)#[N:15]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(F)(C#N)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 19.4 %

Procedure:
To a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (2.0 g, 10.8 mmol) in THF (10 mL) at 0° C. was added KCN (1.05 g, 16.2 mmol) followed by H2O (10 mL). To the homogeneous orange-brown reaction mixture was added a solution of sodium bisulfite (1.69 g, 16.2 mmol) in H2O (10 mL). The cloudy reaction mixture was stirred at 0° C. for 1 h then extracted with CHCl3 (3×). The combined organic layers were dried over MgSO4 and concentrated. The resultant light brown oil was dissolved in CH2Cl2 (30 mL) and cooled to −78° C. then DAST (90%) (1.74 ml, 11.9 mmol) was slowly added. The reaction mixture was stirred at −78° C. for 10 min then warmed to 0° C. and stirred for 1 h. Carefully quenched with saturated aqueous NaHCO3 then diluted with H2O and extracted with CH2Cl2. The combined organics were dried over MgSO4 and concentrated to a brown oil which was purified by SiO2 chromatography (10% to 25% EtOAc/hexanes) to afford 0.45 g (20%) of tert-butyl 3-cyano-3-fluoropyrrolidine-1-carboxylate as a white solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29]>CC#N>[Br-:23].[CH2:29]([N+:1]12[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([CH2:3][CH2:2]1)[CH2:7][CH2:8]2)[CH2:28][CH2:27][CH2:26][CH:25]=[CH2:24]
Reactant: C=CCCCCBr
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: C=CCCCC[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 67 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0637 g, 0.217 mmol) and 6-bromo-1-hexene (0.050 mL, 0.373 mmol) in 2 CH3CN/3 CHCl3 (5.0 mL) were reacted to give the desired product (0.0664 g, 67.1%). EI-MS m/z 376 (M+) Rt (1.90 min).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc([N+](=O)[O-])cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccc([N+](=O)[O-])cc1
Yield: 91.5 %

Procedure:
A mixture of 1-ethyl-4-nitro-benzene (3.4 mL, 25 mmol), N-bromosuccinimide (4.38 g, 24.6 mmol) and benzoylperoxide (0.04 g, 0.18 mmol) in carbon tetrachloride (30 mL) was refluxed 1 h, cooled and filtered, washing with 1:1 ethyl acetate:hexanes. The filtrate was evaporated and purified by flash chromatography (SiO2) eluted with 2:98 ethyl acetate:hexanes to provide 1-(1-bromo-ethyl)-4-nitro-benzene (5.18 g, 90% yield) as a yellow oil. 1H-NMR (CDCl3, 500 MHz) 8.22 (d, 2H), 7.62 (d, 2H), 5.22 (q, 1H), 2.08 (d, 3H) ppm; HPLC (Method A) 3.837 min.