Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([O:13][CH:10]1[CH2:9][CH2:8][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(CN2CCC(O)CC2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(CN2CCC(OC(=O)c3ccccc3)CC2)cc1
Yield: 63.6 %

Procedure:
0.31 g (0.0015 mol) of 1-(4-methyl-benzyl)-piperidin-4-ol and 0.52 ml (0.00375 mol) of triethylamine were dissolved in 15 ml of toluene, treated with 0.25 ml (0.00215 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:4). 0.295 g (64%) of 1-(4-methyl-benzyl)-piperidin-4-yl benzoate was obtained as a yellow oil.
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:42])[C:11]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:41]=[CH:40][C:23]([C:24]([NH:26][C@H:27]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:25])=[CH:22][CH:21]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]>[Pd].FC(F)(F)C(O)=O.C(Cl)Cl>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:42])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][C:20]3[CH:41]=[CH:40][C:23]([C:24]([NH:26][C@H:27]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:25])=[CH:22][CH:21]=3)[CH2:15][NH:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1)C(=O)OCC
Agent: [Pd]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)cc1)C(=O)OCC
Reaction time: 24.5 h
Yield: 100.3 %

Procedure:
A mixture of 0.59 g of diethyl N-[4-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-ylethynyl)benzoyl]-L-glutamate and 1.5 g of 59% palladium on charcoal in 30 ml of trifluoroacetic acid is hydrogenated at 53 psi at room temperature for 24.5 hours. The reaction mixture is diluted with methylene chloride and filtered through Celite. The solvent is removed under reduced pressure. The residue is redissolved in methylene chloride and extracted with a saturated sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the residue chromatographed on silica gel using a 4% methanol:methylene chloride mixture as the eluent. Evaporation of the eluate yields 0.60 g (100%) of diethyl N-(4-[2-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl)-L-glutamate as a white solid: m.p. >250° C.; NMR (CDCl3, 300 MHz) delta 1.22 (t, 3H, J=7.20 Hz), 1.29 (s, 9H), 1.30 (t, 3H, J=7.20 Hz), 1.61-3.35 (m, 13 H), 4.11 (q, 2H, J=7.20 Hz), 4.23 (q, 2H, J=7.20 Hz), 4.77-4.84 (m, 1H), 5.15 (brs, 1H), 7.17 (d, 1H, J=7.50 Hz), 7.23 (d, 2H, J=8.10 Hz), 8.56 (brs, 1H); IR (KBr) 3400, 3280, 2980, 1735, 1630, 1570, 1460, 1390, 1350, 1310, 1200, 1155, 1025, 930, and 800 cm-1.
Reaction SMILES: C[CH:2]1[CH:7]([CH2:8][OH:9])[CH2:6][CH:5]=[CH:4][CH2:3]1.[CH3:10]S(C)=O.[H-].[Na+].[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O>[CH3:10][CH:4]1[CH:3]=[CH:2][CH:7]([CH2:8][O:9][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:6][CH2:5]1
Reactant: CS(C)=O
Reactant: CC1CC=CCC1CO
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCCCCCOCC1C=CC(C)CC1
Reaction time: 1 h

Procedure:
A 500 mL round bottom flask equipped with a mechanical stirrer was charged with 18.9g (0.15 mol) 6-methyl-3-cyclohexenemethanol, and 130 mL of DMSO. Sodium hydride (4.22 g, 95% in purity; 0.167 mol) was slowly added to above mixture in ice bath over 25 min. After the above mixture was reacted at room temperature for 2 hrs. Hexyl bromide (27.3 g, 0.165 mol) was slowly added to the above mixture over 25 min. The reaction was carried at room temperature for 1 hr, then 70° C overnight. The reaction mixture was added to water (150 mL), and then extracted with chloroform (3×150 mL), washed with water (2×150 mL), dried with sodium sulfate. The solvent was evaporated and the residue distilled to give pure product.
Reaction SMILES: [OH:1][C:2](=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[C:3](O)=[O:4].[C:16](=O)([O-])[O-].[Cs+].[Cs+].S([O:27][CH3:28])(OC)(=O)=O.O>CN(C=O)C.C(OCC)(=O)C>[CH3:16][O:1][C:2](=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[C:3]([O:27][CH3:28])=[O:4]
Reactant: COS(=O)(=O)OC
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C(O)=Cc1ccc([N+](=O)[O-])cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.1 %

Procedure:
A mixture of 2-hydroxy-3-(4-nitrophenyl)acrylic acid (15 g, 71.7 mmol), cesium carbonate (56 g, 172.1 mmol) and dimethyl sulphate (14.2 ml, 150.6 mmol) in DMF (270 ml) was stirred at RT for 18 hr. Water (220 ml) and ethyl acetate (150 ml) were added and the layers separated. The aqueous layer was further extracted with ethyl acetate (4×100 ml) then the combined organics were washed with water (6×100 ml), brine (2×120 ml) and concentrated to half volume. Heptane was added (70 ml) and the mixture concentrated to 200 ml volume. The resulting precipitated solid was collected by filtration, washed with heptane (2×100 ml) and suction dried on the filter to afford methyl 2-methoxy-3-(4-nitrophenyl)acrylate as a tan solid (9.2 g, 54% yield) containing a trace of heptane.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1)([CH3:3])[CH3:2].CO.O>O1CCCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH2:12])=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(CC#N)c([N+](=O)[O-])c1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1ccc(CCN)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 40.8 %

Procedure:
To a stirred solution of 0.154 g of (4-isopropyl-2-nitrophenyl)acetonitrile in 2 mL of tetrahydrofuran was added 1.62 mL of 0.93 mol/L borane-tetrahydrofuran complex under ice-cooling, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was cooled under ice-cooling, and to the mixture were added 2 mL of methanol and 20 mL of water. After the mixture was extracted with ethyl acetate, the organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on aminopropylated silica gel (eluent: ethyl acetate) to give 64 mg of 2-(4-isopropyl-2-nitrophenyl)ethylamine.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:36]=[CH:35][C:12]([O:13][CH2:14][C:15]3([CH3:34])[CH2:24][C:23](=[O:25])[C:22]4[C:17](=[C:18]([CH3:33])[C:19]([CH3:32])=[C:20]([O:27][CH2:28][C:29]([OH:31])=[O:30])[C:21]=4[CH3:26])[O:16]3)=[CH:11][CH:10]=2)[S:3]1.O1CCO[CH2:39][CH2:38]1.Cl.C(=O)(O)[O-].[Na+]>O.C(O)C>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]3([CH3:34])[CH2:24][C:23](=[O:25])[C:22]4[C:17](=[C:18]([CH3:33])[C:19]([CH3:32])=[C:20]([O:27][CH2:28][C:29]([O:31][CH2:38][CH3:39])=[O:30])[C:21]=4[CH3:26])[O:16]3)=[CH:35][CH:36]=2)[S:3]1
Reactant: Cc1c(C)c2c(c(C)c1OCC(=O)O)C(=O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reactant: C1COCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)COc1c(C)c(C)c2c(c1C)C(=O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reaction time: 8 h

Procedure:
A mixture of 0.5 g of α-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8-tetramethyl-4-oxo-chroman-6-yloxy}acetic acid (obtained as described in Example 59), 0.5 ml of a 4N dioxane solution of hydrogen chloride and 5 ml of ethanol was allowed to stand overnight at room temperature. The reaction mixture was then poured into water and the solution was neutralized with sodium bicarbonate and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to preparative silica gel thin layer chromatography (developing solvent, benzene:ethyl acetate=7:3 by volume) to obtain the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9](Br)[CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH:13]=[N:14][N:15]([CH3:16])[C:3]=12.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CN(C)C=[O:56]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:16][N:15]1[C:3]2[C:2](=[O:56])[C:11]3[CH:10]=[C:9](/[CH:19]=[CH:18]/[C:17]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=[CH:7][C:6]=3[NH:5][C:4]=2[CH:13]=[N:14]1
Reactant: C=CC(=O)OCC
Reactant: Cn1ncc2nc3ccc(Br)cc3c(Cl)c21
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccc2[nH]c3cnn(C)c3c(=O)c2c1
Temperature: 120 °C
Reaction time: 7 h
Yield: 74 %

Procedure:
A mixture of 9-chloro-7-bromo-1-methyl-1H-pyrazolo[4,3-b]quinoline (EXAMPLE 19, step 2, 1 g, 3.4 mmol), ethyl acrylate (0.42 ml, 3.9 mmol), triethylamine (0.53 ml, 3.8 mmol), palladium acetate (76 mg, 0.34 mmol) and tri-o-tolylphosphine (0.62 g, 2.0 mmol) in N,N-dimethylformamide (80 ml) was stirred at 120° C. for 7 h. The mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated, diluted with ethyl acetate (50 ml) and washed with saturated aqueous sodium bicarbonate (50 ml). The water layer was extracted with ethyl acetate (50 ml×2) and the organic layers were combined. After dryness over sodium sulfate and evaporation, the residue was purified by column chromatography on silica gel eluting with ethyl acetate/hexane (1:3) to afford 0.79 g (74%) of the title compound as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:15]=[C:14]2[N:5]([C:6](=[O:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[N:4]=1.[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)(=O)C>N1C=CC=CC=1>[C:17]1([NH:23][C:24]([O:1][CH2:2][C:3]2[CH:15]=[C:14]3[N:5]([C:6](=[O:16])[NH:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=43)[N:4]=2)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1[nH]c2ccccc2c2cc(CO)nn12
Reactant: O=C=Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1)OCc1cc2c3ccccc3[nH]c(=O)n2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.0 g (0.0093 mole) of 2-(hydroxymethyl)pyrazolo[1,5-c]-quinazolin-5(6H)-one prepared as described in Example 6B and 1.55 ml (≅ 1.7 g or 0.014 mole) of 98% phenylisocyanate are refluxed in 20 ml of dry pyridine under N2 for 1 hour. The crude product is poured onto 200 ml of ice-water layered with ethyl acetate (50 ml) and stirred for 30 minutes. The precipitates that form are filtered off, air-dried and taken up in dioxane (150 ml). The solution is filtered while hot and the clear filtrate concentrated down to a volume of 100 ml and cooled. The precipitates are filtered off and dried in vacuo at 85°. Yield 2.45 g, 78.8% crude yield.
Reaction SMILES: C[O-].[Na+].[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6]([O:8]C)=O.[NH2:13][CH:14]=[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)[CH:16]=O>CO>[O:8]=[C:6]1[C:5]([C:4]([O:11][CH3:12])=[O:10])=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=2)=[CH:14][NH:13]1
Reactant: NC=C(C=O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c[nH]c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.5 g. of sodium methoxide in 85 ml. of methanol is added 2.25 g. of dimethyl malonate and 2.93 g. of 3-amino-2-[3-(trifluoromethyl)phenyl]-2-propenal. The mixture is stirred at room temperature for 16 hours with precipitation of a yellow solid. The mixture is heated at reflux temperature for 2 hours, cooled and filtered to obtain a white solid. The solid is washed with ether, suspended in water and acidified with hydrochloric acid to yield 1.75 g. of the product of the Example as a white solid, m.p. 195°-201° C.
Reaction SMILES: [Na].Br[C:3]1[O:4][C:5]2[CH:16]=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:14]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:13][C:6]=2[C:7](=[O:12])[C:8]=1[NH:9][CH:10]=[O:11].[OH2:29].[CH3:30]O>>[CH:10]([NH:9][C:8]1[C:7](=[O:12])[C:6]2[CH:13]=[C:14]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][C:5]=2[O:4][C:3]=1[O:29][CH3:30])=[O:11]
Reactant: CS(=O)(=O)Nc1cc2oc(Br)c(NC=O)c(=O)c2cc1Oc1ccccc1
Reactant: CO
Reactant: O
Agent: [Na]
Product: COc1oc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c(=O)c1NC=O
Reaction time: 2 h
Yield: 71 %

Procedure:
510 mg of metallic sodium was dissolved in 60 ml of methanol. The solution was ice-cooled. Thereto was added 4.25 g of 2-bromo-3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one. The mixture was stirred for 2 hours at 0°-5° C. 600 ml of water was added thereto. The resulting mixture was washed with 200 ml of ethyl acetate, adjusted to pH 4 with 4N hydrochloric acid, and extracted with two 300-ml portions of ethyl acetate. The extracts (the organic layers) were combined, washed with a saturated aqueous sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting crystal was recrystallized from acetonitrile to obtain 2.87 g (yield: 71%) of 3-formylamino-2-methoxy-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 188° C. (decomposed).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([OH:22])[C:2]1[CH:3]=[C:4]([CH3:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COc1ccc(C)cc1Br
Product: COc1ccc(C)cc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 90.8 %

Procedure:
With 4.36 g of 3-bromo-4-methoxy toluene and 2.81 g of 5-chloroisatin as starting materials, 4.27 g of the title compound (light brown solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:22][C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:24]=1[NH2:25].C(Cl)Cl.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][C:24]1[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:23]=1[CH3:22])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cccc(C)c1N
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1c(C)cccc1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
A mixture of 3-butyryl-4-chloro-8-(2-methylthioethoxy)quinoline (0.8 g, 2.5 mmol) and 2,6-dimethylaniline (0.45 g, 3.7 mmol) in toluene (12 ml) was heated to 90° C. and stirred 3.0 h. After cooling to room temperature, methylene chloride and water were added. The mixture was neutralized with a saturated solution of sodium bicarbonate. The organic layer was dried over sodium sulfate and evaporated. Chromatography (SiO2 ; EtOAc) gave 0.7 g (68%) of the title compound.
Reaction SMILES: [Cl-:1].[NH3+:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[NH+:11][CH:12]=[CH:13][CH:14]=1)=O.[Cl-].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=O)[CH:17]=1.Cl>Cl.C(O)C>[ClH:1].[ClH:1].[ClH:1].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[C:6](=[CH:7][C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)[CH2:5][CH2:4][CH2:3][N:2]=2)[CH:17]=1
Reactant: O=Cc1cccnc1
Reactant: [Cl-]
Reactant: [NH3+]CCCCC(=O)c1ccc[nH+]c1
Agent: Cl
Solvent: CCO
Product: C(=C1CCCN=C1c1cccnc1)c1cccnc1
Temperature: 85 °C
Yield: 54.4 %

Procedure:
3-(5-Ammoniopentanoyl)pyridinium chloride (152 mg, 0.60 mmol) was suspended into ethanol (10 mL) in a reaction vessel and treated with concentrated hydrochloric acid (5 drops). Pyridine-3-carboxaldehyde (84 mg, 0.78 mmol) was added and the reaction vessel was sealed. The reaction was heated to 85° C. for 48 hours, then cooled to room temperature. The reaction mixture was concentrated under reduced pressure and treated with saturated NaHCO3(aq), then extracted three times with EtOAc. The EtOAc extracts were washed with brine, combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The recovered material was then eluted through a 20 gram column of silica gel with a 98:2:0.2 and 96:4:0.4 CH2Cl2:MeOH:NH4OH step gradient (500 mL each step). The recovered material was dissolved into MeOH and treated with 3 eq. of 6 N HCl(aq). This solution was concentrated under reduced pressure and the recovered material dissolved into hot isopropanol. This solution was allowed to cool to room temperature, then diluted with ether which produced a precipitate. The precipitate was recovered by vacuum filtration, washed with fresh isopropanol, then dried under vacuum giving 39 mg (18%) of a brown solid. LC-MS: RT=2.14 min, [M+H]+=250.1.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.[CH3:21][O:22][C:23](=[O:33])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26](Br)[C:25]=1[CH2:31][Br:32]>C(Cl)(Cl)(Cl)Cl>[CH3:21][O:22][C:23](=[O:33])[C:24]1[CH:29]=[C:28]([Br:1])[CH:27]=[CH:26][C:25]=1[CH2:31][Br:32]
Reactant: COC(=O)c1cccc(Br)c1CBr
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)ccc1CBr
Temperature: 25 °C

Procedure:
The mixture of 3- and 5-bromo-2-methylbenzoic acid methyl ester (35.79 g; 156 mmol) is dissolved in carbon tetrachloride (200 mL). To the solution is added N-bromosuccinimide (29.5 g; 166 mmol), followed by AIBN (54 mg) and the mixture was heated at reflux temperature for 20 hours. Then the mixture was cooled to room temperature and the succinimide was filtered from solution and rinsed with carbon tetrachloride. The solvent was evaporated to yield a mixture of the title compound and 3-bromo-2-bromomethylbenzoic acid methyl ester (48.1 g; crude mass).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[I:23][CH2:24]I>O.CCOCC.CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:24][I:23])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: ICI
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: O=S(=O)(CI)c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A stirred mixture of 4-bromo-benzenesulfonyl chloride (5.12 g, 20 mmol), sodium sulfite (4.69 g, 37.3 mmol) and sodium bicarbonate (3.07 g, 36.6 mmol) in water (20 mL) is heated at 100° C. for 1 h. The crude sodium sulfinate solution is allowed to cool for 30 min and then treated with diiodomethane (25 mL) and tetra-N-butyl ammonium bromide (0.65 g, 2.0 mmol). The resulting mixture is heated at 75° C. overnight. The organic layer was separated. The aqueous solution was extracted with CH2Cl2 (×2). The combined organics were washed with water and brine, and dried over anhydrous MgSO4. The filtration through Celite-silica gel pad and concentration in vacuo gave light yellow liquid residue. Et2O/hexane (1:1) was added to the residue and the mixture was stirred to make homogenous and sit at 0 C for 20 min. The product was crushed out of the solution, filtered and washed with Et2O/hexanes. 1H NMR (300 MHz, CDCl3) 7.83 (d, 2H), 7.75 (d, 2H), 4.48 (s, 2H).
Reaction SMILES: Br[CH2:2][C:3]([CH2:14][CH2:15][CH2:16][O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:5]([NH:11][CH:12]=[O:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[P:24]([O:33]C(C)C)([O:29][CH:30]([CH3:32])[CH3:31])[O:25][CH:26]([CH3:28])[CH3:27]>>[CH2:22]([O:21][C:19]([CH2:18][O:17][CH2:16][CH2:15][CH2:14][C:3]([CH2:2][P:24]([O:29][CH:30]([CH3:32])[CH3:31])([O:25][CH:26]([CH3:28])[CH3:27])=[O:33])=[CH:4][CH:5]([NH:11][CH:12]=[O:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:20])[CH3:23]
Reactant: CCOC(=O)COCCCC(=CC(NC=O)C(=O)OCC)CBr
Reactant: CC(C)OP(OC(C)C)OC(C)C
Product: CCOC(=O)COCCCC(=CC(NC=O)C(=O)OCC)CP(=O)(OC(C)C)OC(C)C
Reaction time: 18 h

Procedure:
6.4 g (15 mmol) of ethyl 4-bromomethyl-7-ethoxycarbonylmethoxy-2-formylamino-hept-3-enoate and 14.8 ml (60 mmol) of triisopropyl phosphite (90%) are heated to 80° C. and stirred for 18 hours under a pressure of 100 mbar. Excess triisopropyl phosphite is removed by distillation and the residue is chromatographed over silica gel with hexane/ethyl acetate (1:2:5%) to give ethyl 7-ethoxycarbonylmethoxy-2-formylamino-4-diisopropylphosphonomethyl-hept-3-enoate as a brown oil.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]([O:15][CH3:16])=[O:14])[CH:5]=1.C(OCC)C.[ClH:39].O1CCOCC1>>[NH2:1][C@@H:2]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]([O:15][CH3:16])=[O:14])[CH:5]=1.[ClH:39]
Reactant: COC(=O)n1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)n1cc(C[C@@H](N)C(=O)OCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of Boc-DTrp-OBzl (12.19 g) in dichloromethane (60 ml) were added methyl chloroformate (4.8 ml), pulverized sodium hydroxide (4.1 g) and TBAHS (9.2 g), and the mixture was stirred at room temperature for 4 h. The reaction mixture was washed with water, dried over MgSO4 and evaporated in vacuo. The residue was crystallized from dichloromethane and hexane to give Boc-DTrp(COOMe)-OBzl (12.57 g). Boc-DTrp(COOMe)-OBzl (4.52 g) was dissolved in 4N-hydrogen chloride/1,4-dioxane (50 ml) and the mixture was stirred at room temperature for 45 min. Ethyl ether (50 ml) was added to the mixture to complete the precipitation. The precipitate was collected by filtration and dried in vacuo to give H-DTrp(COOMe)-OBzl.HCl (3.71 g). To a suspension of H-DTrp(COOMe)-OBzl.HCl (1.94 g) in dichloromethane (50 ml) were added NMM (0.55 ml), 2,6-dimethylpiperidinocarbonyl-γMeLeu-OH (1.42 g), HOBT.H2O (0.84 g) and EDCI.HCl (1.05 g) under ice cooling. The mixture was stirred at the same temperature for 2 h and at room temperature over night. The reaction mixture was washed with sat. aq NaHCO3 (50 ml), 10% aq. citric acid (50 ml) and brine (50 ml) successively, dried over MgSO4 and evaporated. The residue was purified by MPLC (Merck, LiChroprep Si 60) with hexane/ethyl acetate=2/1 for elution to give 2,6-dimethylpiperidinocarbonyl-γMeLeu-DTrp(COOMe)-OBzl (1.17 g). A solution of 2,6-dimethylpiperidinocarbonyl-γMeLeu-DTrp(COOMe)-OBzl (1.10 g) in methanol (30 ml) was hydrogenated over 10% Pd/C (50 mg) at an atmospheric pressure of hydrogen for 1.5 h. After removal of the catalyst by filtration, the filtrate was evaporated in vacuo to give the product (0.93 g).