Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.O=S(Cl)Cl.O.[NH2:15][NH2:16]>CO>[Br:1][C:2]1[N:3]=[C:4]([C:7]([NH:15][NH2:16])=[O:9])[S:5][CH:6]=1
Reactant: O=C(O)c1nc(Br)cs1
Reactant: NN
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: O
Product: NNC(=O)c1nc(Br)cs1

Procedure:
To a solution of the 4-bromothiazole-2-carboxylic acid (2.0 g, 9.8 mmol) in MeOH (10 mL) was added SOCl2 (710 μL, 9.8 mmol) and the reaction was refluxed for 3 hours. The reaction was concentrated, the residue was suspended in EtOH (10 mL), hydrazine hydrate (2.4 mL, 49 mmol) was added and the reaction was heated to reflux for 90 minutes. The reaction was concentrated, suspended in CH3CN, filtered, and the solids were washed with CH3CN, Et2O, and dried to afford of 4-bromothiazole-2-carbohydrazide as a yellow solid. M+1=222.1
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:18](=O)[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[NH:11]1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:18]1[N:10]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[N:11]=[C:12]2[C:17]=1[CH2:16][CH2:15][CH2:14][CH2:13]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-n2[nH]c3c(c2=O)CCCC3)c(F)c1
Product: COc1ccc(-n2nc3c(c2Cl)CCCC3)c(F)c1
Yield: 10.8 %

Procedure:
The 4.32 g residue from Step B was mixed at ambient temperature with 5.37 g (0.035 mole) of phosphorus oxychloride until complete dissolution occurred. At this point the reaction mixture was heated at reflux under nitrogen for one hour. The phosphorus oxychloride was evaporated from the reaction mixture under reduced pressure, leaving a residue weighing 1.50 g. This residue, together with a similar residue weighing 0.30 g from an earlier experiment, was then was placed on a silica gel column and eluted with hexane/ethyl acetate (4:1). After the product-containing fractions were combined and the solvents evaporated under reduced pressure, 0.50 g of 3-chloro-2-(2-fluoro-4-methoxyphenyl)-4,5,6,7-tetrahydroindazole was isolated. The NMR was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2O.P(Cl)(Cl)([Cl:19])=O.C(=O)(O)[O-].[Na+]>[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[Cl:19]
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Product: CCC(=O)c1cnc2ccc(Br)cc2c1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
1-(6-Bromo-4-hydroxyquinolin-3-yl)propan-1-one (21 g, 67.7 mmol) was added to phosphoryl chloride (80 mL). The resultant suspension was then heated to 85° C. and stirred for 1.5 h. The reaction mixture was cooled to room temperature and poured carefully into a mixture of saturated sodium bicarbonate (250 mL) and 2N aqueous sodium hydroxide (250 mL). The solution was then extracted with ethyl acetate, the combined organics were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the desired product (16 g, 96%) as a tan solid: APCI MS m/z 298 [C12H9BrClNO+H]+.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.O[C@@H:21]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1>>[F:19][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=2)[C:8]([O:10][C@@H:21]2[CH2:25][CH2:24][NH:23][CH2:22]2)=[O:9])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: O=C(O)[C@](O)(c1ccc(Br)cc1)[C@@H]1CCC(F)(F)C1
Product: O=C(O[C@@H]1CCNC1)[C@](O)(c1ccc(Br)cc1)[C@@H]1CCC(F)(F)C1

Procedure:
Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)acetic acid and t-butyl(3R)-3-hydroxypyrrolidine-1-carboxylate, the title compound was prepared by a method similar to Steps 2 and 3 of Referential Example 12.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([C:18]#[CH:19])[C:15]([CH3:20])=[N:14]1.[Br:21]N1C(=O)CCC1=O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:21][C:19]#[C:18][C:16]1[C:15]([CH3:20])=[N:14][N:13]([C:3]2[C:4]([Cl:12])=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])[CH:17]=1
Reactant: C#Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C#CBr
Reaction time: 1 h

Procedure:
To a stirred solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)4-ethynyl-3-methylpyrazole (0.53 g) in acetone (5 ml) was added N-bromosuccinimide (0.295 g) and silver nitrate (0.028 g). Stirring was continued at room temperature for 1 hour. The reaction mixture was evaporated and the residue taken up in ether and washed with water. The organic layer was separated, dried and evaporated. The residue was purified by column chromatography on silica gel (10 g) eluted with hexane and then dichioromethane: hexane (1:1). Combination and evaporation of appropriate fractions, followed by crystailisation from hexane, gave the title compound as a very pale yellow solid m.p. 86-89° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](Cl)[C:5]2[C:6]([CH:10]=1)=[N:7][O:8][N:9]=2.[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][NH:13]1.C(N(CC)CC)C>CN1C(=O)CCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:12]2)[C:5]2[C:6]([CH:10]=1)=[N:7][O:8][N:9]=2
Reactant: Clc1cc(Br)cc2nonc12
Reactant: c1ccc2c(c1)CNC2
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Brc1cc(N2Cc3ccccc3C2)c2nonc2c1
Temperature: 85 °C
Yield: 41.1 %

Procedure:
To a solution of 6-bromo-4-chlorobenzo[c][1,2,5]oxadiazole (372 mg, 1.6 mmol) in NMP (3 mL) in a 4 dram vial was added isoindoline (238 mg, 2 mmol) and triethylamine (400 μL, 2.9 mmol). A cap was tightly fitted and the reaction was heated at 85° C. O/N. The reaction was worked up by diluting with EtOAc (60 mL) and washing with 1M HCl (3×20 mL) and brine (1×20 mL). The organic phase was dried with MgSO4 filtered and concentrated in vacuo. The crude material was purified by flash column chromatography (9:1 Hex/EtOAc) to give 208 mg (41% yield) of 6-bromo-4-(isoindolin-2-yl)benzo[c][1,2,5]oxadiazole. 1H NMR (300 MHz, CDCl3) δ=7.38 (m, 4H), 7.26 (s, 1H), 6.14 (s, 1H), 5.14 (s, 4H). To a solution of the afore mentioned material, (200 mg, 0.6 mmol) in DME (4 mL)/Na2CO3 (0.9 mL) was added 3-formyl-phenylboronic acid (134 mg, 0.9 mmol) and Pd(P(Ph)3)4 (35 mg). The flask was then fitted with a reflux condenser, purged with argon and heated to 115° C. O/N. The reaction was worked up by diluting with 1 M NaOH (40 mL) and extracting with EtOAc (3×20 mL). The organic phase was washed with brine, dried with MgSO4 and concentrated in vacuo. The crude material was fused to SiO2 (2 g) and purified by flash column chromatography (2:1 DCM/Hex) to give 190 mg (92% yield). 1H NMR (500 MHz, CDCl3) δ=10.18 (s, 1H), 8.24 (m, 1H), 7.99 (dm, J=8 Hz, 2H), 7.70 (t, J=7 Hz, 1H), 7.44 (m, 4H), 7.26 (s, 1H), 6.30 (s, 1H), 5.25 (s, 4H). To a stirring solution of the afore mentioned material, (190 mg, 0.55 mmol) and Rupert's reagent (150 mg, 1.1 mmol) in DCM (5 mL) at 0° C. was added TBAF (0.1 mL, 1 M THF, 0.1 mmol). After 30 min at low temperature the cold bath was removed and the reaction was allowed to come to RT. After 3 hours an excess of TBAF was added and the reaction was diluted with DCM. The organic phases were washed with saturated NH4Cl, brine, and then dried with MgSO4 and concentrated in vacuo. The crude material was passed through a plug of SiO2 (DCM) and then purified by flash column chromatography (2:1 DCM/Hex). 1H NMR (500 MHz, CDCl3) δ=7.84 (s, 1H), 7.77 (dt, J=7 Hz, 2 Hz, 1H), 7.60 (m, 2H), 7.43 (m, 4H), 7.23 (s, 1H), 6.25 (s, 1H), 5.31 (s, 4H), 5.2 (m, 1H), 2.68 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[C:6](/[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)\[CH3:7])[CH3:2].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[C:6](/[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)\[CH2:7][Br:17])[CH3:2]
Reactant: CCOC(=O)/C=C(\C)Oc1ccc(C)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1ccc(C)nc1
Yield: 43.7 %

Procedure:
To a stirred mixture of (E)-3-(6-methyl-pyridin-3-yloxy)-but-2-enoic acid ethyl ester (3.50 g, 0.016 mol) in carbon tetrachloride (25 mL) under a nitrogen atmosphere was added N-bromosuccinimide (4.23 g, 0.024 mol) and benzoyl peroxide (383 mg, 0.002 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(6-methyl-pyridin-3-yloxy)-but-2-enoic acid ethyl ester (2.10 g, 44%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[N:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27](B(O)O)=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[Br:15][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[C:4](=[CH:3][C:2]([C:27]4[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][C:28]=4[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:14][CH:13]=3)[N:5]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:6]=2[CH:7]=1
Reactant: Brc1ccc2c3ccc(Br)cc3n(-c3ccccc3)c2c1
Reactant: COc1ccc(B(O)O)c(-c2ccccc2)c1
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: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ccc3c4ccc(Br)cc4n(-c4ccccc4)c3c2)c(-c2ccccc2)c1
Temperature: 110 °C
Yield: 59 %

Procedure:
A mixture of 4 g (10 mmol) of 2,7-dibromo-9-phenyl-9H-carbazole, 75 g (12 mmol) of 5-methoxybiphenyl-2-ylboronic acid, 0.12 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium, 15 ml of 2M Na2CO3, 20 ml of EtOH and 60 ml toluene was degassed and placed under nitrogen, and then heated at 110° C. for 8 h. After finishing the reaction, the mixture was allowed to cool to room temperature. The reaction mixture was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was evaporated in vacuum. The residue was purified by column chromatography on silica (hexane-dichloromethane) afforded a white solid (3 g, 5.9 mmol, 59%).
Reaction SMILES: IC1C=CC(C)=CC=1C(O)=O.OOS([O-])=O.[K+].[CH3:18][CH2:19][CH2:20][CH2:21][CH:22]([OH:27])[CH2:23][CH2:24][CH2:25][CH3:26]>[N+](C)([O-])=O>[CH3:18][CH2:19][CH2:20][CH2:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCC(O)CCCC
Agent: Cc1ccc(I)c(C(=O)O)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: C[N+](=O)[O-]
Product: CCCCC(=O)CCCC
Temperature: 70 °C
Reaction time: 12 h

Procedure:
1.57 mg (0.006 mmol) of 2-iodo-5-methylbenzoic acid prepared by Preparation Example 3, 1.11 g (1.8 mmol) of powdered Oxone (registered trademark) and 433 mg (3 mmol) of 5-nonanol were added to 3.75 ml of nitromethane, and the mixture was heated at 70° C. while being stirred for 12 hours. After being heated, the mixture was cooled to room temperature, and the insoluble substance was removed by means of filtering. Water was added in the filtrate, extraction was carried out using diethyl ether. The organic phase was dried by using sodium sulfate, and then 5-nonanone was obtained by means of vacuum-concentration. The yield of the obtained 5-nonanone was determined and the result is shown in Table 1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6](=O)[C:7]([OH:9])=[O:8])=[CH:2]1.[C:11]([O:15][C:16]([CH2:18][O:19][NH2:20])=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(Cl)(Cl)(Cl)Cl>[C:11]([O:15][C:16]([CH2:18][O:19][N:20]=[C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[C:7]([OH:9])=[O:8])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)CON
Reactant: O=C(O)C(=O)c1ccsc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)CON=C(C(=O)O)c1ccsc1

Procedure:
Thien-3-ylglyoxylic acid and t-butoxycarbonylmethoxyamine were reacted as described in Preparation 1 to give the title compound, m.p. 102.6°-104.4° (from carbon tetrachloride); λmax (pH6 phosphate buffer) 258 nm (ε 13,700).
Reaction SMILES: C(N)C1C=CC=CC=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1.[CH:18]1([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[C:29]([CH:34]=[CH:35][N:36]=3)[C:30](OC)=[O:31])[C:23]2=[O:37])[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[C:29]([CH:34]=[CH:35][N:36]=3)[C:30]([NH:15][CH2:14][C:13]3[CH:16]=[CH:17][C:10]([F:9])=[CH:11][CH:12]=3)=[O:31])[C:23]2=[O:37])[CH2:20][CH2:19]1
Reactant: COC(=O)c1ccnc(N2CCN(CC3CC3)C2=O)c1
Reactant: NCc1ccc(F)cc1
Solvent: NCc1ccccc1
Product: O=C(NCc1ccc(F)cc1)c1ccnc(N2CCN(CC3CC3)C2=O)c1
Yield: 77 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace benzylamine with 4-fluorobenzylamine to react with methyl 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)isonicotinate, 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-N-(4-fluorobenzyl)isonicotinamide was obtained as a colorless solid in 77% yield: mp 150-151° C.; 1H NMR (300 MHz, CDCl3) δ 8.53 (s, 1H), 8.34 (d, J=5.4 Hz, 1H), 7.39 (d, J=5.4 Hz, 1H), 7.30-7.24 (m, 2H), 7.01-6.91 (m, 3H), 4.55 (d, J=5.7 Hz, 2H), 4.06 (t, J=8.1 Hz, 2H), 3.59 (t, J=8.1 Hz, 2H), 3.13 (d, J=7.2 Hz, 2H), 99-0.85 (m, 1H), 0.59-0.51 (m, 2H), 0.24-0.19 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 165.7, 163.9, 160.6, 156.9, 153.1, 148.0, 133.6, 133.6, 129.8, 129.7, 115.9, 115.7, 115.4, 108.9, 48.6, 43.4, 41.6, 41.5, 9.0, 3.4; MS (ES+) m/z 369.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH2:18][CH2:19][N:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH:22]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.ClCCl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]2[CH2:22][CH2:21][N:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH:18]=2)=[N:3][CH:4]=1
Reactant: Clc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)NN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NN1CC=C(c2ccc(Cl)cn2)CC1
Temperature: 80 °C

Procedure:
A solution of 2-bromo-5-chloropyridine (131 mg) in DMF (degassed with nitrogen; 4.5 ml) was added to a mixture of tert-butyl 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-carbamate (Eastwood, Paul R., Tetrahedron Lett, 41, 19, 2000, 3705-3708; 200 mg), potassium carbonate (0.265 g) and Pd(dppf)Cl2 (50 mg). The mixture was heated at 80° C. for 8 hours. After cooling, the mixture was diluted with dichloromethane and washed with sodium carbonate solution and water. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, mobile phase: heptane/ethyl acetate (2%)/dichloromethane (5%), later heptane/ethyl acetate (5%)/dichloromethane (5%).
Reaction SMILES: Cl[CH:2]([O:4][CH2:5][CH3:6])[CH3:3].[CH2:7]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([O-:30])=[O:29])=[CH:26][CH:25]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Na+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:7]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:30][CH:2]([O:4][CH2:5][CH3:6])[CH3:3])=[O:29])=[CH:31][CH:32]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCOC(C)Cl
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC(C)OCC)cc1
Reaction time: 3 h

Procedure:
A mixture of 22.0 g. of ethyl 1-chloroethyl ether, 77.0 g. of sodium 4-(hexadecylamino)benzoate and 250 ml. of hexamethylphosphoramide is stirred at 20° C. for 24 hours. After slow addition of water to the crystallization point and standing for 3 hours, the acetal ester is collected on a filter.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][Br:9])[C:3](Br)=[O:4].[C:10]([O:13][CH:14]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[CH2:15][NH:16][C:17]([C:19]1[C:24]([I:25])=[C:23]([NH2:26])[C:22]([I:27])=[C:21]([C:28]([NH:30][CH2:31][CH:32]([O:38][C:39](=[O:41])[CH3:40])[CH2:33][O:34][C:35](=[O:37])[CH3:36])=[O:29])[C:20]=1[I:42])=[O:18])(=[O:12])[CH3:11]>CN(C)C(=O)C>[C:10]([O:13][CH:14]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[CH2:15][NH:16][C:17]([C:19]1[C:24]([I:25])=[C:23]([NH:26][C:3](=[O:4])[CH:2]([Br:1])[CH2:6][CH2:7][CH2:8][Br:9])[C:22]([I:27])=[C:21]([C:28]([NH:30][CH2:31][CH:32]([O:38][C:39](=[O:41])[CH3:40])[CH2:33][O:34][C:35](=[O:37])[CH3:36])=[O:29])[C:20]=1[I:42])=[O:18])(=[O:12])[CH3:11]
Reactant: O=C(Br)C(Br)CCCBr
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(=O)OCC(CNC(=O)c1c(I)c(NC(=O)C(Br)CCCBr)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Reaction time: 1 h
Yield: 95.5 %

Procedure:
2,5-Dibromopentanoyl bromide (11 g, 34 mmol ) was added dropwise to a stirred solution of N,N'-bis[2,3bis(acetyloxy)propyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide (23.0 g, 26.3 mmol) in N,N-dimethylacetamide (240 ml) at 0°. After the addition, the reaction mixture was stirred at 0° for 1 hour, and then at room temperature for 20 hours. The solvent was removed in vacuo at 45° and the resulting solid was dissolved in ethyl acetate (400 ml). The organic layer was washed with saturated aqueous sodium bicarbonate (1×70 ml), water (1×70 ml) and saturated sodium chloride (1×70 ml). After drying over magnesium sulfate, the solvent was removed in vacuo to obtain a yellow residue (28 g). Purification by column chromatography over silica gel furnished pure N,N'-bis[2,3-bis(acetyloxy)propyl]-5-[(2,5-dibromo-1-oxopentyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide as an off-white crystalline compound (20.2 g, yield 69%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH:14]3[CH2:16][CH:11]2[C:12](=O)[CH2:13]3)=[CH:6][CH:5]=1)([O-:3])=[O:2].[O-]S([O-])(=O)=O.[Na+].[Na+].[C@@H:25]1([NH2:32])[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[NH2:31].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH:14]3[CH2:16][CH:11]2[C@@H:12]([NH:31][C@@H:26]2[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]2[NH2:32])[CH2:13]3)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CC2CC1N(c1ccc([N+](=O)[O-])cc1)C2
Reactant: N[C@@H]1CCCC[C@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: N[C@@H]1CCCC[C@H]1N[C@H]1CC2CC1N(c1ccc([N+](=O)[O-])cc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a round bottom flask was added 2-(4-nitrophenyl)-2-azabicyclo[2.2.1]heptan-6-one (120 mg, 0.517 mmol), CH2Cl2 (3 mL) and Na2SO4 (5 gms). The reaction was purged with argon. Then (1R,2R)-cyclohexane-1,2-diamine (118 mg, 1.033 mmol) and acetic acid (0.592 mL, 10.33 mmol) were added to the reaction. The reaction was stirred at rt for 1 hr. Then sodium triacetoxyborohydride (548 mg, 2.58 mmol) was added to the reaction and the reaction was stirred at rt overnight. The reaction was diluted with CH2Cl2 (50 ml) and filtered. The filtrate was washed with NaOH (0.5N, 30 ml), water (30 ml) and saturated aqueous NaCl (30 ml). The organic layer was dried with MgSO4, filtered and concentrated. The residue was purified by RP prep-HPLC. Two isomers were separated from RP prep-HPLC. The fractions with desired product, which eluted later than the undesired isomer, were concentrated to give (1R,2R)—N1-((6S)-2-(4-nitrophenyl)-2-azabicyclo[2.2.1]heptan-6-yl)cyclohexane-1,2-diamine (80 mg, 0.242 mmol, 46% yield) as a yellow solid. Anal. Calcd. for C18H26N4O2 m/z 330.4, found: 331.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]([CH3:14])[C:12]([C:15]2[N:20]=[C:19]3[N:21]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:22]([N:24]=CN(C)C)=[N:23][C:18]3=[CH:17][CH:16]=2)=[C:11]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:10]=1.C(O)(=O)C.Cl.[OH-].[Na+]>O.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]([CH3:14])[C:12]([C:15]2[N:20]=[C:19]3[N:21]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:22]([NH2:24])=[N:23][C:18]3=[CH:17][CH:16]=2)=[C:11]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:10]=1
Reactant: CC(C)Cn1c(N=CN(C)C)nc2ccc(-c3c(-c4ccccc4)nc(-c4c(F)cccc4F)n3C)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)Cn1c(N)nc2ccc(-c3c(-c4ccccc4)nc(-c4c(F)cccc4F)n3C)nc21
Temperature: 25 °C
Yield: 0.1 %

Procedure:
Heat N′-{5-[2-(2,6-difluorophenyl)-3-methyl-5-phenyl-3H-imidazol-4-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-yl}-N,N-dimethylformamidine (0.02 g, 0.04 mol) in 1:1 glacial acetic acid:concentrated HCl (0.6 mL) at 100° C. for 30 min. Cool to RT. Add CH2Cl2 and water, neutralize with 5N NaOH to about pH=7 with rapid stirring. Extract the aqueous phase 3× with CH2Cl2, combine organic layers, wash with saturated aqueous NaCl and dry over Na2SO4. Filter and concentrate to give the title compound (0.02 g).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:3]=1[NH2:4].C[Al](C)C.[NH:19](/[C:23](/[CH3:29])=[CH:24]\[C:25](OC)=[O:26])[C:20]([CH3:22])=O>C(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:3]=1[N:4]1[C:25](=[O:26])[CH:24]=[C:23]([CH3:29])[N:19]=[C:20]1[CH3:22]
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: Nc1cc(N2CCOCC2)ccc1F
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2cc(N3CCOCC3)ccc2F)c(C)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68.5 %

Procedure:
To a solution of 2-fluoro-5-morpholinoaniline (0.35 g, 1.78 mmol) in CH2Cl2 (20 mL) was added trimethylaluminum (3.3 mL, 6.6 mmol, 2 M in toluene) dropwise. The reaction mixture was stirred at rt for 20 min, followed by the addition of a solution of methyl 3-acetaminocrotonate (0.30 g, 1.78 mmol) in anhydrous CH2Cl2 (10 mL). The reaction mixture was stirred at rt overnight, then quenched with saturated NH4Cl aqueous solution (80 mL) and extracted with CH2Cl2 (100 mL×3). The combined organic phases were washed with brine (150 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:2) to give the title compound as a yellow solid (0.37 g, 69%). The compound was characterized by the following spectroscopic data: