Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH:30]([C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:20]=[C:2]([C:35]2[CH:36]=[N:37][C:32]([CH:30]=[O:31])=[CH:33][CH:34]=2)[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Reactant: O=Cc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 66.6 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (0.4 g, 0.86 mmol) and (6-formylpyridin-3-yl)boronic acid (0.3 g, 1.29 mmol) in dioxane/water mixture (10 mL+2 mL), Na2CO3 (0.32 g, 3.09 mmol) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.092 g, 0.086 mmol) was added and argon was purged again for 10 min. The reaction mixture was heated at 100° C. for 6 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(6-formylpyridin-3-yl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (0.28 g, 66%).
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH2:25][C:26]([OH:45])([CH2:31][C:32]([C:35]2[C:43]3[O:42][CH2:41][CH2:40][C:39]=3[CH:38]=[C:37]([Cl:44])[CH:36]=2)([CH3:34])[CH3:33])[C:27]([F:30])([F:29])[F:28])(=O)=O)C=CC=CC=1>CO.[OH-].[Na+].[Cl-].[Na+].O>[Cl:44][C:37]1[CH:36]=[C:35]([C:32]([CH3:34])([CH3:33])[CH2:31][C:26]([CH2:25][C:11]2[NH:10][C:18]3[C:13]([CH:12]=2)=[CH:14][C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:16][CH:17]=3)([OH:45])[C:27]([F:29])([F:28])[F:30])[C:43]2[O:42][CH2:41][CH2:40][C:39]=2[CH:38]=1
Reactant: CC(C)(CC(O)(Cc1cc2cc(-c3ccccn3)ccc2n1S(=O)(=O)c1ccccc1)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(CC(O)(Cc1cc2cc(-c3ccccn3)ccc2[nH]1)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Reaction time: 4 h
Yield: 42.2 %

Procedure:
A mixture of the above 2-(1-benzenesulfonyl-5-pyridin-2-yl-1H-indol-2-ylmethyl)-4-(5-chloro-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methylpentan-2-ol (30.1 mg, 0.046 mmol, theoretical maximum from above) in 5 mL of methanol and 5 mL of 10% aqueous sodium hydroxide solution was warmed at reflux. After 4 hours, the mixture was diluted with 7 mL of brine and extracted with three 5 mL portions of ethyl acetate. The combined organic layers were washed with three 5 mL portions of saturated aqueous sodium bicarbonate solution, 5 mL of brine, two 5 mL portions of saturated aqueous ammonium chloride solution, 5 mL of brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel preparative TLC using ethyl acetate-hexanes (1:1). The material from the preparative TLC plate when concentrated in vacuo from diethyl ether-hexanes afforded 10 mg (42% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][S:8][C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1.[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]([N:30]2[CH2:31][CH2:32][N:27]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:28][CH2:29]2)=[O:13])=[CH:18][CH:19]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COc1ccc(CSc2ccccc2C(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CSc2ccccc2C(=O)N2CCN(Cc3ccccc3)CC2)cc1

Procedure:
N1-(S-(4-methoxybenzyl)thiosalicyloyl)-N4-benzylpiperazine (compound 5) was prepared using the same procedure described above using: 10 mM(2.743 g) of S-(4-methoxybenzyl) thiosalicylic acid, 3 mM(728 mg) of 1-Benzylpiperazine and 20 mM (3.525 g) triethylamine. The product was dissolved in 5 ml of methylene chloride and purified by column chromatography on a silica gel column (eluent: Ethyl acetate) to give 870 mg (20.1%) of a white crystal. The product was then further purified by crystallization from hexane. The purified product had having a melting point of 84-85° C. and had the following specifications:
Reaction SMILES: [CH3:1][C:2](=[CH:5]N(C)C)[CH:3]=O.[NH:9]([C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)[NH2:10].O.Cl>CO>[CH3:5][C:2]1[CH:1]=[N:10][N:9]([C:11]2[NH:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:3]=1
Reactant: NNc1nc2ccccc2c(=O)[nH]1
Reactant: CC(C=O)=CN(C)C
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1cnn(-c2nc3ccccc3c(=O)[nH]2)c1
Reaction time: 1.5 h

Procedure:
149.2 g (1.32 moles) of 2-methyl-3-dimethylaminoacrolein are added all at once to a mixture, stirred at 40° C., of 211.2 g (1.2 moles) of 2-hydrazino-4(3H)-quinazolinone, 1.5 litres of water, 540 ml of methanol and 220 ml of concentrated hydrochloric acid. The suspension is stirred at 40° for a total of 4.5 hours and at 60° for 1.5 hours. The crude 2-(4-methyl-1H-pyrazol-1-yl)-4(3H)-quinazolinone isolated at room temperature is obtained in an amount of 245 g of melting point 169°-71°.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[N:15]=[C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.P(Br)(Br)[Br:25]>C(Cl)(Cl)Cl>[Br:25][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[N:15]=[C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: BrP(Br)Br
Reactant: O=C(Nc1nc2cccc(-c3ccc(CO)cc3)n2n1)C1CC1
Solvent: ClC(Cl)Cl
Product: O=C(Nc1nc2cccc(-c3ccc(CBr)cc3)n2n1)C1CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of cyclopropanecarboxylic acid [5-(4-hydroxymethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide (1.0 eq) in chloroform is slowly added phosphorus tribromide (1.0 eq.). The reaction mixture is stirred at room temperature for 20 h, quenched with ice and water (20 mL) and extracted with dichloromethane. The organic layer is dried over anhydrous MgSO4, filtered and concentrated to dryness. The resulting white residue is triturated in dichloromethane/diethyl ether 2:1 to afford the desired product.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([F:16])[CH:15]=1)[C:10]([OH:12])=[O:11].[CH2:17](O)[CH3:18]>C(OCC)C.O>[Br:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([F:16])[CH:15]=1)[C:10]([O:12][CH2:17][CH3:18])=[O:11]
Reactant: CCO
Reactant: O=C(O)c1cc(F)cc(Br)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1cc(F)cc(Br)c1
Temperature: 25 °C

Procedure:
Sulphuric acid (0.5 mL) was added to a stirring solution of 3-bromo-5-fluorobenzoic acid (473 mgs, 2.16 mmol) in ethanol (10 mL) and refluxed for 17 hours. The reaction mixture was cooled to room temperature and diluted with diethyl ether and water. The ether layer was washed with 5% sodium hydrogen carbonate solution, dried over magnesium sulphate and evaporated to dryness to give the title compound as a brown oil. (506 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:23])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:22])([C:14]([NH:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:15])[CH2:6][CH2:5]2.[O:24]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:24][C:7]([CH3:22])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:23])[C:14]([NH:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)CNC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Agent: [Ce+4]
Agent: [NH4+]
Product: COC(=O)CNC(=O)C(C)(O)CCC1=C(C)C(=O)C(C)=C(C)C1=O
Yield: 81 %

Procedure:
Oxidation as described in protocol B, using 110 mg (0.344 mmol) of methyl 2-(6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamido)acetate and 415 mg CAN (0.757 mmol) yielded 94.0 mg of methyl 2-(2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamido)acetate as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[O:6][CH2:7][C:8]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9].[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)#[N:24].C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH3:22][O:21][C:17]1[CH:16]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:18]=1[O:19][CH3:20])[O:6][CH2:7][C:8]([N:10]1[CH2:11][CH2:12][N:13]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([C:23]#[N:24])=[CH:26][CH:27]=2)[CH2:14][CH2:15]1)=[O:9]
Reactant: COc1cc(OCC(=O)N2CCNCC2)cc(OC)c1OC
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(OCC(=O)N2CCN(Cc3ccc(C#N)cc3)CC2)cc(OC)c1OC
Yield: 70.5 %

Procedure:
To a solution of 1-((3,4,5-trimethoxyphenoxy)methyl)carbonylpiperazine (0.22 g, 0.70 mmol) in 1% acetic acid in methanol (6 mL) was added 4-cyanobenzaldehyde (0.33 g, 2.5 mmol) and sodium cyanoborohydride (0.093 g, 1.4 mmol). The resultant mixture was stirred at ambient temperature for 1.5 hours and the mixture was then concentrated of volatiles in vacuo. Residue was taken up in ethyl acetate and washed with saturated aqueous NaHCO3 solution, water, and then brine. The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo to afford a yellow oil. Purification by flash column chromatography on silica gel afforded 0.21 g of 1-((3,4,5-trimethoxyphenoxy)methyl)carbonyl-4-(4-cyanobenzyl)piperazine, a compound of formula (Ib), as a clear oil: NMR (CDCl3) 7.6 (d, 2), 7.4 (d, 2), 6.2 (s, 2), 4.6 (s, 2), 3.8 (s, 6), 3.75 (s, 3), 3.6 (m, 4), 3.5 (s, 2), 2.2 (m, 4) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]([CH3:12])([CH3:11])[CH2:5][CH2:6][C:7]([O:9]C)=[O:8].[OH-].[K+]>CO>[CH3:1][O:2][C:3](=[O:13])[C:4]([CH3:11])([CH3:12])[CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: COC(=O)CCC(C)(C)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C(C)(C)CCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.4 %

Procedure:
To a solution of 2,2-dimethyl-pentanedioic acid dimethyl ester (2.40 g, 12.8 mmol) in MeOH (15 ml) is added potassium hydroxide (0.788 g, 14.0 mmol). The mixture is stirred at room temperature for 16 hours and refluxed for 2 hours. The mixture is cooled to room temperature and concentrated under reduced pressure. To the obtained residue, 1M aqueous HCl (14 ml) is added and the solution is extracted with ether. The organic layer is washed with H2O, dried over Na2SO4, and concentrated under reduced pressure to give 2,2-dimethyl-pentanedioic acid 1-methyl ester (1.97 g, 88%); 1H NMR (400 MHz, chloroform-d) ppm 1.20 (s, 6H), 1.87-1.91 (m, 2H), 2.32-2.36 (m, 2H), 3.67 (s, 3H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])=[N+]=[N-]>CO.[Pd]>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[N:7]=[C:6]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:5]([CH2:4][NH2:1])=[CH:14]2
Reactant: [N-]=[N+]=NCc1cc2cccc(Cl)c2nc1N1CCCCC1
Agent: [Pd]
Solvent: CO
Product: NCc1cc2cccc(Cl)c2nc1N1CCCCC1

Procedure:
3-(Azidomethyl)-8-chloro-2-(piperidin-1-yl)quinoline (30 mg, 0.1 mmol) was dissolved in MeOH (1 mL) and treated with 10% Pd—C (5 wt %) and the mixture was then stirred under H2 balloon over night. The mixture was filtered through a Celite™ pad followed by removal of solvents to give (8-chloro-2-(piperidin-1-yl)-quinolin-3-yl)methanamine as a colorless oil. N-((8-chloro-2-(piperidin-1-yl)-quinolin-3-yl)methyl)-9H-purin-6-amine was prepared according to Procedure H. 1H NMR (400 MHz, CDCl3) δ ppm 8.29 (s, 1H), 7.79 (m, 3H), 7.45 (m, 2H), 5.43 (2H, s), 3.90 (m, 4H), 2.23 (m, 4H), 1.84 (m, 2H). Mass Spectrum (ESI) m/e=394 (M+1).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9][C:10]1[N:20]2[C:21]3[C:16]([CH2:17][CH2:18][CH2:19]2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=1.C(=O)([O-])[O-:23].[Na+].[Na+]>O>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9]([C:10]1[N:20]2[C:21]3[C:16]([CH2:17][CH2:18][CH2:19]2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=1)=[O:23]
Reactant: O=C([O-])[O-]
Reactant: c1ccc(CSc2nc3cccc4c3n2CCC4)nc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=S(Cc1ccccn1)c1nc2cccc3c2n1CCC3
Temperature: -50 °C
Reaction time: 16 h

Procedure:
A solution of 5,6-dihydro-2-(2-pyridylmethylthio)-4H-imidazo-[4,5,1-ij]quinoline hydrochloride (4.0 g) in water (10 ml) was basified with sodium carbonate solution and extracted into chloroform. The extracts were dried (MgSO)4 and evaporated and the residue was dissolved in methylene chloride (50 ml) and cooled to -50° C. 3-chloroperoxybenzoic acid (2 g) was added with stirring and the solution was allowed to warm to -20° C. when a further (0.5 g) of 3-chloroperoxybenzoic acid was added and the solution was kept at 6° C. for 16 hours. It was then washed (Na2CO3 solution and brine), dried (MgSO4) and evaporated to give an oil which was purified by chromatography on alumina with ethyl acetate as eluent and crystallised from di-isopropylether to give the title compound as a quarterhydrate(2.1 g) mp 100°-102° C. (Found: C, 63.9; H, 5.1; N,14.0. C16H15N3OS, 1/4H2O requires C, 63.7; H,5.2; N,13.9%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:22]I>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH3:22])[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: COc1ccc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 49.6 g of N-t-butoxycarbonyl-5-methoxy-2-nitroaniline [prepared as described in step (b) above] in 300 ml of dehydrated dimethylformamide was added, whilst ice-cooling, to a suspension of 12.0 g of sodium hydride (as a 55% w/w dispersion in mineral oil) in 300 ml of dehydrated dimethylformamide, and the resulting mixture was stirred at room temperature for 30 minutes, after which 17.2 ml of methyl iodide were added at room temperature. The reaction mixture was stirred for 1 hour, after which it was allowed to stand overnight at room temperature. It was then concentrated to about one-fifth of its original volume by evaporation under reduced pressure. The concentrate was mixed with ice-water and the resulting aqueous mixture was extracted with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. On distilling off the solvent, there were obtained 52.1 g of the title compound, melting at 122°-124° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[NH:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.O>S(=O)(=O)(O)O>[N+:1]([C:13]1[C:8]2[N:7]=[N:6][NH:5][C:9]=2[CH:10]=[CH:11][CH:12]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2[nH]nnc2c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cccc2[nH]nnc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a cooled solution (20° C.) of 1,060 milliliters of 20% fuming sulfuric acid and 265 milliliters of 90% nitric acid is added in a dropwise fashion a solution of 537 grams of benzotriazole in 1000 milliliters of concentrated sulfuric acid. The temperature is not allowed to exceed 50° C. At the end of the addition, the reaction mixture is allowed to stand at room temperature overnight. The reaction mixture is then poured over 9 liters of ice and water and a heavy yellow precipitate forms. The solid is collected by filtration, washed with water and dried. The solid, which is a mixture of the 4-nitro (90%) and the 5-nitro (10%) isomers, is then slurried with 7.5 liters of refluxing acetonitrile, the mixture cooled and 537 grams (73%) of pure 4-nitrobenzotriazole is collected by filtration, m.p. 228°-231° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][CH2:11][NH:12]C(=O)OCC1C=CC=CC=1)=[O:8])(=[O:3])[CH3:2].C1CCCCC1>[Pd].C(O)C>[C:1]([NH:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][CH2:11][NH2:12])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCC(=O)NCCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCCCC1
Product: CC(=O)NCCC(=O)NCCN
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
A mixture of 1.3 g of [2-[[3-(acetylamino)-1-oxopropyl]amino]ethyl]carbamic acid, phenylmethyl ester, 25 ml of cyclohexane and 180 mg of 10% palladium on carbon in 50 ml of ethanol was heated for 15 hours under argon and then stirred at room temperature for 12 hours. The mixture was filtered through a pad of celite and washed with methanol. The combined filtrate and wash was evaporated, giving 670 mg of the desired compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][CH2:42][F:43]>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:41][CH2:42][F:43])=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCF)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To 315 mg (0.68 mmol) of di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-(4-hydroxy-benzyl)-L-glutamate in 30 mL N,N-dimethylformamide were added 206 mg (1.5 mmol) of powdered potassium carbonate and 104 mg (0.81 mmol) of 1-bromo-2-fluoroethane and the resulting suspension was stirred for 5 h at 60° C. and overnight at room temperature. The reaction mixture was then filtered, the solvent evaporated and the residue was taken up in ethyl acetate and water. The organic phase was separated off, washed with water until neutral, dried over sodium sulfate and filtered, and the filtrate was concentrated in vacuo. Di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-[4-(2-fluoroethoxy)benzyl]-L-glutamate was obtained as crude product (110 mg, 32.6%) and deprotected without further purification: 3 mL of trifluoro acetic acid were added to the oily residue and the solution was stirred for 2 days at room temperature. The excess of trifluoro acetic acid was evaporated and the residue was taken up three times in tetrahydrofuran and than evaporated. The resulting oil was chromatographed on C-18 reversed phase silica gel using a water/acetonitrile gradient, the appropriate fractions were combined and concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[N+]#N.[OH2:12]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[OH:12]
Reactant: O
Reactant: N#[N+]c1cc(Cl)c(Cl)cc1Cl
Product: Oc1cc(Cl)c(Cl)cc1Cl

Procedure:
In the fourth stage, the 2,4,5-trichlorobenzenediazonium strong mineral acid salt in solution in water is hydrolytically decomposed at a temperature from the reflux temperature to a temperature of 375° C. At the lower temperatures, the solution is refluxed in the presence of a cupric salt, the 2,4,5-trichlorophenol formed is steam distilled from the reaction and separately recovered. At higher temperatures of 130° C. to 375° C., preferably from 140° C. to 220° C., the aqueous solution is injected into a column packed with a suitable inert material and maintained at the desired temperature, either with or without additional super-heated steam. The 2,4,5-trichlorophenol steam distills from the top of the heated column and the concentrated aqueous strong mineral acid is recovered from the bottom of the column.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:6]([N+:21]([O-:23])=[O:22])[CH:5]=1.[Br:24][CH2:25][CH2:26]Br.O>CN(C=O)C>[Br:24][CH2:25][CH2:26][N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:7]1[CH:19]=[CH:20][C:4]([Cl:3])=[CH:5][C:6]=1[N+:21]([O-:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(CCBr)c2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
To a suspension of sodium hydride (60%, 0.20 g (5.00 mmol)) in DMF (7.0 ml), 4′-chloro-2′-nitro-p-toluenesulfonanilide (1.20 g (3.67 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, 1,2-dibromoethane (2.00 ml (23.2 mmol)) was added and the mixture was heated at 130° C. for one hour with stirring. The reaction mixture was cooled to room temperature, poured into water and extracted with diethyl ether. The extract was washed with 1% aqueous sodium hydroxide solution, a saturated sodium chloride solution successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to make the residue crystalline. Hexane was added to the crystals and the crystals were collected while washing to give 1.12 g (70%) of the title compound as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>O.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(Nc2cccc(F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(Nc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
Methyl 4-(3-fluorophenylamino)benzoate (0.110 g; 0.448 mmol) was added to a mixture of NaOH in water (1 mL; 2M) and dioxane (1 mL) and stirred vigorously at room temperature overnight. The resulting mixture was concentrated under reduced pressure and dissolved in water. The aqueous layer was acidified with a solution of hydrogen chloride 6M and the precipitated product was collected by filtration to yield 0.040 g (70%) of the title compound as a grey solid which was used without further purification.