Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:30])[C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.Cl>C1COCC1.CO.CCOC(C)=O>[CH:24]1([C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([S:12]([C:9]3[CH:10]=[CH:11][C:6]([C:5]([OH:30])=[O:4])=[CH:7][CH:8]=3)(=[O:14])=[O:13])[CH:16]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(C3CCCCC3)c3ccccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CCCCC3)c3ccccc32)cc1
Reaction time: 1.5 h
Yield: 86.4 %

Procedure:
Add 5N sodium hydroxide (1.17 ml, 3 eq) to a solution of 4-(3-Cyclohexyl-indole-1-sulfonyl)-benzoic acid methyl ester (775 mg, 1.95 mmol, 1 eq) dissolve in a mixture of 10 ml THF and 5 ml MeOH. Stir for 1.5 hours. Remove solvent on rotovap and add 1 N HCl. Dissolve the solid that crashes out of solution in EtOAc. Extract product into organics, separate organics, dry over MgSO4, and concentrate on rotovap to give 4-(3-Cyclohexyl-indole-1-sulfonyl)-benzoic acid (646 mg, 86% yield) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:7]2=[CH:8][S:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[H][H].[CH3:15][N:16]([CH3:20])[C:17](Cl)=[O:18]>O.CN(C)C=O>[CH3:15][N:16]([CH3:20])[C:17](=[O:18])[O:1][C:2]1[C:7]2=[CH:8][S:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2nscc12
Reactant: [H][H]
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)Oc1cccc2nscc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.5 g. 4-hydroxy-2,1-benzisothiazole and 20 ml. dimethylformamide was added 0.4 g. of a 57 percent oil dispersion of sodium hydride at room temperature. After evolution of hydrogen from the mixture was completed, 1.1 g. dimethylcarbamoyl chloride was added and the mixture was stirred 16 hours at room temperature. Water (50 ml.) was added to the mixture, which was then extracted with chloroform. The chloroform extract was washed once with water and dried over calcium sulfate. Calcium sulfate was removed by filtration, and chloroform and dimethylformamide were evaporated from the filtrate in vacuo to give an oily residue. This was washed with hexane to give oily 2,1-benzisothiazol-4-yl N,N-dimethylcarbamate. This structure was confirmed by nmr. The insecticidal activity of this material was determined exactly as described in Example 12, whereby 2,1-benzisothiazole-4-yl N,N-dimethylcarbamate (500 ppm. concentration) destroyed 100 percent of bean aphides, two of five two-spotted mites, and had no effect on southern armyworms and Mexican bean beetle larvae.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S([O-])(O[CH3:22])(=O)=O>CO>[CH3:22][N:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9]1
Reactant: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Reactant: COS(=O)(=O)[O-]
Solvent: CO
Product: Cn1nc(-c2ccccc2)cc1-c1ccccc1
Yield: 9099 %

Procedure:
As in Example 2, a melt of 10 g (0.0455 mol) of 3,5-diphenylpyrazole and 0.051 g (0.000455 mol) of methyl sulfate was introduced and reacted over the course of 3 hours with 197.75 g (6.18 mol) of gaseous (vaporized at 160° C.) methanol. 9.7 g (86.7%) of 1-methyl-3,5-diphenylpyrazole were obtained, boiling point 190° C./3 mbar, with a content of 95.2% (GC).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]#[N:6].[ClH:11].C([OH:14])C>>[ClH:11].[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5](=[NH:6])[OH:14]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: CCO
Agent: Cl
Product: N=C(O)c1ccc(F)c(F)c1

Procedure:
In anhydrous ethanol, compound [L'], commercially available 3,4-difluorobenzonitrile is reacted with gaseous hydrogen chloride to yield compound [M'], 3,4-difluorobenzimidate hydrogen chloride. In ethanol, compound [M'] is reacted with gaseous ammonia to yield compound [N'], 3,4-difluorobenzamidine hydrogen chloride.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].O1[CH:17]=[CH:16][CH2:15][C:14](=[O:18])[NH:13]1.[CH2:19]1[CH2:23][O:22][CH2:21][CH2:20]1>>[CH2:16]([CH:15]1[O:22][C:21]2[C:2]([CH:3]=[CH:4][CH3:5])=[CH:1][CH:23]=[CH:19][C:20]=2[N:13]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[C:14]1=[O:18])[CH3:17]
Reactant: O=C1CC=CON1
Reactant: C1CCOC1
Reactant: O=C(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CC=Cc1cccc2c1OC(CC)C(=O)N2C(=O)c1ccccc1
Yield: 77 %

Procedure:
Procedure & NMR Data: 142 μL (2.5 eq, 1.23 mmol) of benzoyl chloride was added to a mixture of 78 mg of NaH (4 eq, 1.96 mmol) and 100 mg (0.49 mmol) of oxazinone P2 in THF (9.5 ml). 58 mg of P4 were obtained, yield 77%.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1.Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:49]=[CH:48][CH:47]=[C:41]2[C:42]([NH:44][C:45](=[O:46])[C:40]=12)=[O:43]>CS(C)=O>[C:7]([S:8][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:49]=[CH:48][CH:47]=[C:41]2[C:42]([NH:44][C:45](=[O:46])[C:40]=12)=[O:43])([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1NC(=O)c2c(CCCCCCBr)cccc21
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1NC(=O)c2c(CCCCCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cccc21

Procedure:
Triphenylmethanethiol (11.90 g, 43.08 mmol) was suspended in DMSO (40 mL). DBU (7.41 mL, 49.55 mmol) and 6-bromohexylphthalimide (13.32 g, 42.94 mmol) were added, and the mixture was allowed to react for approximately 15 min. The reaction mixture was partitioned between ethyl acetate (700 mL) and 0.1 M HCl (200 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL), and the combined organic fractions were washed with NaHCO3 sat. (80 mL) and brine (80 mL), dried over MgSO4, filtered and concentrated. The crude yellow oil was recrystallized from n-heptane/ethyl acetate. The intermediate 6-(S-Trityl-)mercaptohexylphthalimide was obtained as a white solid (13.3 g, 26.4 mmol, 62%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[CH:21][C:7]1=2)=[O:5].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)(C)C>[ClH:1].[N:22]1([CH2:2][CH2:3][C:4]([N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[NH:9][C:8]3[CH:18]=[CH:19][CH:20]=[CH:21][C:7]2=3)=[O:5])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C1Nc2ccccc2N(C(=O)CCCl)c2ccccc21
Reactant: C1CCNCC1
Solvent: CC(C)O
Product: Cl
Product: O=C1Nc2ccccc2N(C(=O)CCN2CCCCC2)c2ccccc21
Yield: 68.7 %

Procedure:
60.0 gm (0.2 mol) of 5-(3-chloro-propionyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 42.5 gm (0.5 mol) of piperidine were refluxed in 600 ml of isopropanol and worked up as described in Example 1. 53 gm of the hydrochloride (recrystallized from n-propanol), m.p. 250°-252° C., were obtained
Reaction SMILES: C1(S(O[CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)(=O)=O)C=CC=CC=1.[C:24]([O:32][CH2:33][CH3:34])(=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].CC[O-].[Na+].CCO>CCO>[CH2:29]([O:28][C:26](=[O:27])[CH:25]([CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:15][CH2:16]1)[C:24]([O:32][CH2:33][CH3:34])=[O:31])[CH3:30]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(OS(=O)(=O)c2ccccc2)CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 22 h

Procedure:
A mixture of 1-tert-butoxycarbonylpiperidin-4-ol, triethylamine, benzenesulfonyl chloride, and methylene chloride was stirred at ambient temperature for 2 days to yield 1-tert-butoxycarbonylpiperidin-4-yl benzenesulfonate. A mixture of 1-tert-butoxycarbonylpiperidin-4-yl benzenesulfonate obtained, diethyl malonate, 20% NaOEt-EtOH, and EtOH was heated under reflux with stirring for 22 hours to yield diethyl[1-(tert-butoxycarbonyl)piperidin-4-yl]malonate. A mixture of diethyl [1-(tert-butoxycarbonyl)piperidin-4-yl]malonate obtained, lithium borohydride, toluene, and THF was stirred at 60° C. for 18 hours to yield 2-(1-tert-butoxycarbonylpiperidin-4-yl)propane-1,3-diol, which was stirred together with 4M HCl-dioxane solution in MeOH at ambient temperature for 1 hour to yield 2-piperidin-4-ylpropane-1,3-diol hydrochloride.
Reaction SMILES: C([Li])(C)(C)C.BrC1C(C)=CC(C)=CC=1C.[CH3:16][O:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2=[O:35]>CCCCC.C1COCC1>[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2([OH:35])[C:23]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[O:17][CH3:16]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COc1cccnc1
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1cnccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A 1.7 M solution of tert-butyllithium in pentane (57.8 mL) was added to THF (200 ml) at −78° C. 2-Bromomesitylene (3.6 mL) was added dropwise, keeping the temperature below −60° C., and the mixture stirred at −78° C. for 1 h. 3-Methoxypyridine (3.6 mL) was added dropwise at −78° C. and then the mixture was allowed to warm to −5° C. over 2 h. The reaction mixture was re-cooled to −78° C. and a slurry of 5-chloroisatin (3.26 g) in THF (100 mL) was added portionwise keeping the temperature below −60° C. The reaction mixture was stirred at −78° C. for 1 h. The cooling bath was removed and the reaction mixture was stirred for 30 min. The reaction mixture was quenched with 10% aqueous ammonium chloride solution and extracted several times with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate and evaporated to low volume. Upon standing, 0.73 g of a pale yellow solid separated which was filtered off, washed with ethyl acetate and dried in vacuo.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:18])=[C:5]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[N:9]2)[N:6]=1.[F:19][C:20]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C(O)C>[F:19][C:20]1[C:25]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:23]=[CH:22][C:21]=1[C:2]1[S:3][C:4]([CH3:18])=[C:5]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[N:9]2)[N:6]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1F
Reactant: CCOC(=O)c1cnn(Cc2nc(Br)sc2C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3F)sc2C)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
Under a nitrogen atmosphere, to a mixed solution of the compound (230 mg, 0.71 mmol) obtained in Example 80e and 2-fluoro-3-(trifluoromethyl)phenylboronic acid (190 mg, 0.92 mmol) in 1,2-dimethoxyethane/ethanol (v/v=3/1, 4 mL) were added 2N aqueous sodium carbonate solution (0.71 mL, 1.4 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (60 mg, 0.071 mmol), and the mixture was stirred at 90° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=75/25) to give the title compound (200 mg, 68%) as colorless crystals.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[C:15](/[C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)\[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:7]=1)C.[OH-].[Na+].O>C1COCC1.C(O)C>[Br:28][C:25]1[CH:24]=[CH:23][C:22](/[C:15](/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:14]/[CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:29])=[O:3])=[CH:7][CH:8]=2)=[CH:27][CH:26]=1
Reactant: CCOC(=O)Cc1ccc(OC/C=C(\c2ccccc2)c2ccc(Br)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(OC/C=C(\c2ccccc2)c2ccc(Br)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a solution of (E)-{4-[3-(4-bromo-phenyl)-3-phenyl-allyloxy]-phenyl}-acetic acid ethyl ester (example 11) (700 mg, 1.6 mmol) in THF (5 m) and ethanol (5 ml) was added 1N, NaOH (5.0 ml) and the reaction mixture was stirred for 1 h at 60° C. for 1 h and at room temperature over night. The reaction mixture was added water and the organic solvent evaporated. 1 N HCl was added to pH ˜1-2 and the product extracted with dichloromethane/isopropanol (19:1). The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The residue was suspended in toluene/petroleum ether (1:1) and 490 mg (70%) of the title compound was isolated by filtration.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:11][C:12](=[O:14])[CH:13]=2)=[O:10])=[CH:4][CH:3]=1.[F-].[Cs+].[C:17]([Si](C)(C)C)([F:20])([F:19])[F:18]>C(#N)C.C(OCC)C>[F:18][C:17]([F:20])([F:19])[C:9](=[O:10])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[CH:13][C:12]([OH:11])=[O:14]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C1C=C(c2ccc(F)cc2)C(=O)O1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: CCOCC
Product: O=C(O)C=C(C(=O)C(F)(F)F)c1ccc(F)cc1
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a stirred solution of 4-fluorophenylmaleic anhydride (1.42 g, 7.39 mmol) (prepared by procedures similar to those described in Dean, W. D.; Bum, D. M. J. Org. Chem. 1993, 58, 7916-7917), in acetonitrile (15 ml) at 0° C. (ice/water/sodium chloride bath—temperature of the bath −10° C.), was added CsF (1.1 g, 7.39 mmol), followed by the drop-wise addition of CF3SiMe3 (1 ml, 7.39 mmol), under nitrogen. The reaction mixture was stirred for 1 h, and then diluted with diethyl ether and extracted with 2M sodium hydroxide (200 ml). The organic layer was removed and the aqueous layer acidified to pH=1 by the addition of conc. hydrochloric acid. The mixture was extracted with dichloromethane and the organic layer removed, dried (Na2SO4), and the solvent evaporated in vacuo to yield D5 (1.4 g, 72%) as a mixture of isomers. C11H6F4O3 requires 262 Found 261 (M-H−).
Reaction SMILES: O[C:2]1[C:14]2[C:6](=[C:7]3[C:12]([N:13]=2)=[CH:11][N:10]([CH3:15])[CH:9]=[CH:8]3)[CH:5]=[CH:4][CH:3]=1.[C:16]([O-:19])([O-])=O.[K+].[K+].[CH2:22](I)C>CN(C=O)C>[CH2:16]([O:19][C:3]1[CH:4]=[CH:5][C:6]2[C:14]([CH:2]=1)=[N:13][C:12]1[C:7]=2[CH:8]=[CH:9][N:10]([CH3:15])[CH:11]=1)[CH3:22]
Reactant: CCI
Reactant: O=C([O-])[O-]
Reactant: Cn1ccc2c3cccc(O)c3nc-2c1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc2c3ccn(C)cc-3nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.5 %

Procedure:
A solution of the product from example 23 (60 mg, 0.30 mmol) in DMF (3 ml) was treated with K2CO3 (100 mg) and ethyl iodide (0,029 ml, 0.36 mmol). After stirring at RT for 18 h, the reaction was partitioned in EtOAc and water. The organic layer was dried (brine; MgSO4) and then concentrated. The residue was chromatographed (1:1 hexane-acetone) on silica gel to give 20 mg of 7-ethoxy-2-methyl-β-carboline.
Reaction SMILES: Cl[C:2](OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].CCN(C(C)C)C(C)C.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][C@H:25]1[CH2:31][OH:32].[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>C(Cl)Cl>[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[N:41]1[CH2:42][CH2:43][N:44]([C:2]([O:32][CH2:31][C@@H:25]2[CH2:26][N:27]([CH3:30])[CH2:28][CH2:29][N:24]2[CH3:23])=[O:3])[CH2:45][CH2:46]1
Reactant: Fc1ccc(N2CCNCC2)c(F)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN1CCN(C)[C@H](CO)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(C)[C@H](COC(=O)N2CCN(c3ccc(F)cc3F)CC2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 39.3 %

Procedure:
4-Nitrophenyl chloroformate (5.17 g, 25.7 mmol) was dissolved in DCM (200 mL) at room temperature and the reaction mixture was cooled to 0° C. and DIPEA (6.94 g, 9.38 mL, 53.9 mmol) and 1,4-dimethyl-(S)-2-hydroxymethyl piperazine (Intermediate 3; 3.70 g, 25.7 mmol) were added. The reaction mixture was stirred at room temperature for 2 h and then split into three equal volumes. To one portion was added 1-(2,4-difluoro-phenyl)-piperazine (1.68 g, 8.5 mmol) and stirred for 48 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc (500 mL) and 1.0M aq NaOH solution (200 mL). The organic layer was washed with 1.0M aq NaOH solution (5×125 mL), brine (100 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was dissolved in DCM (100 mL) and isocyanate resin (3 g) was added, the reaction mixture was shaken for 14 h, filtered and the solvents were removed in vacuo. The residue was purified by reverse phase column chromatography (LiChroprep RP-18, 40-63 μm, 460×26 mm (100 g), 30 mL/min, gradient 0% to 30% (over 75 min) to 100% (over 13 min) MeOH in water with 1% formic acid). The residue was de-salted using K2CO3 in DCM to give [(2S)-1,4-dimethylpiperazin-2-yl]methyl 4-(2,4-difluorophenyl)piperazine-1-carboxylate (1.23 g, 39.4%) as a light yellow gum.
Reaction SMILES: [N+:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][N:5]=1)([O-])=O.Cl[CH2:13][P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17].C(O[Na])(C)(C)C.Cl>CS(C)=O>[CH2:16]([O:15][P:14]([CH2:13][C:7]1[CH:6]=[N:5][C:4]([NH2:1])=[C:9]([O:10][CH3:11])[CH:8]=1)(=[O:21])[O:18][CH2:19][CH3:20])[CH3:17]
Reactant: CCOP(=O)(CCl)OCC
Reactant: COc1cccnc1[N+](=O)[O-]
Agent: CC(C)(C)O[Na]
Agent: Cl
Solvent: CS(C)=O
Product: CCOP(=O)(Cc1cnc(N)c(OC)c1)OCC
Reaction time: 0.5 h
Yield: 19.2 %

Procedure:
A solution of 2-nitro-3-methoxypyridine (300 mg, 1.95 mmol) and diethyl chloromethylphosphonate (363 mg, 1.95 mmol) in DMSO (4 mL) was added dropwise to vigorously stirred solution of t-BuONa (0.561 g, 5.84 mmol) in DMSO (4 mL) at room temperature. The reaction mixture turned to deep orange immediately. Stirring was continued for 30 min, then the mixture was poured into 1 M HCl (aq) (10 mL). The product was extracted into ether (3×30 mL), dried over MgSO4, concentrated, and purified by silica gel chromatography (3% MeOH in DCM) to afford 102.6 mg of diethyl[(6-amino-5-methoxypyridin-3-yl)methyl]phosphonate (yield: 17%). 1H NMR (CD3OD, 400 MHz): δ=1.30 (t, J=6.8 Hz, 6H), 3.45 (d, J=22.4 Hz, 2H), 4.00 (s, 3H), 4.09-4.17 (m, 4H), 7.79 (t, J=2.4 Hz, 1H), 7.97 (t, J=2.4 Hz, 1H). MS (ES+): m/z 305.07 [MH+]. HPLC: tR=1.17 min (UPLC TOF, polar—3 min).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[CH:5]=[O:6].[OH-].[K+].Cl.Cl[CH2:15][C:16]1[NH:17][CH:18]=[CH:19][N:20]=1>CS(C)=O.C(Cl)Cl.O>[NH:17]1[CH:18]=[CH:19][N:20]=[C:16]1[CH2:15][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[CH:5]=[O:6]
Reactant: O=Cc1ccc(I)c(O)c1
Reactant: ClCc1ncc[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: O=Cc1ccc(I)c(OCc2ncc[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
To a flask, were added 3-hydroxy-4-iodobenzaldehyde (200 mg, 0.806 mmol), KOH (43.0 mg, 0.766 mmol) and DMSO (2 ml). The mixture was stirred at rt for 2 h. 2-(chloromethyl)-1H-imidazole hydrochloride (105.4 mg, 0.689 mmol) in 1 ml of DMSO was added to this mixture and stirred overnight. The mixture was diluted with DCM and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated to afford crude product, which was purified on silica gel (MeOH/DCM=8/92) to afford desire product (97.4 mg, 0.297 mmol, 36.8% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[C:20](=O)[C:21](C)([CH3:36])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([Br:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])C>C(#N)C>[Br-:35].[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][N+:13]([CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH:21]([CH3:20])[CH3:36])=[CH:12][C:11]=2[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(C)(C)CCCCCC(Br)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)n1ccc2cnccc21
Solvent: CC#N
Product: CC(C)CCCCCC(c1ccccc1Cl)[n+]1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Product: [Br-]
Temperature: 45 °C
Reaction time: 52 h
Yield: 68.5 %

Procedure:
A mixture of pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.81 g, 3.73 mmol), 8-bromo-8-(2-chlorophenyl)-2,2-dimethyloctanoic acid ethyl ester (1.44 g, 3.73 mmol), and acetonitrile (25 mL) were stirred at 45° C. for 52 hours. The solvent was evaporated under reduced pressure and residue was washed with diethyl ether (3×20 mL) to afford 1-tert-butoxycarbonyl-5-[1-(2-chlorophenyl)-7-methyloctyl]-1H-pyrrolo[3,2-c]pyridin-5-ium bromide (1.37 g, 60.6% yield) as a yellow oil. 1H NMR (Field: 300 MHz, Solvent: CD3OD/TMS) δ (ppm): 10.52 (s, 1H), 8.84 (d, 1H, J=7.2 Hz), 8.23 (d, 1H, J=7.8 Hz), 7.91 (t, 1H, J=3.6 Hz), 7.54-7.31 (m, 4H), 7.39 (s, 1H), 6.95 (s, 1H), 6.42 (t, 1H, J=7.2 Hz), 4.09 (q, 2H, J=7.2 Hz), 2.67 (m, 1H), 1.70 (s, 9H), 1.42-1.19 (m, 8H), 1.21 (t, 3H, J=6.9 Hz), 1.10 (s, 6H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 178.00, 147.44, 140.17, 136.60, 133.19, 131.97, 131.45, 130.42, 130.03, 128.64, 113.10, 108.61, 88.15, 71.55, 60.34, 42.23, 40.54, 34.54, 29.69, 28.13, 26.42, 25.28, 24.92, 14.46. HRMS (HR, DIP-CI): Calculated for C30H40ClN2O2 (M+H)+: not found (decomposed on analysis).
Reaction SMILES: ClCCl.C(=O)(O)[O-].[Na+].[NH:9]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]1.Cl[C:16]([O:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:17]>O>[OH:14][C@H:11]1[CH2:12][CH2:13][N:9]([C:16]([O:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:17])[CH2:10]1
Reactant: CC(C)(C)COC(=O)Cl
Reactant: O[C@H]1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)COC(=O)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of dichloromethane (5 mL) and water (5 mL) was added sodium bicarbonate (0.96 g, 11 mmol), followed by (3S)-pyrrolidin-3-ol (1.00 g, 11.5 mmol). Neopentyl chloroformate (1.71 mL, 11.5 mmol) was then added dropwise, and the resulting suspension was stirred at room temperature for 1.5 hours. Chromatography over silica gel, eluting with hexanes/ethyl acetate, afforded the title compound. 1H NMR (500 MHz, CDCl3) δ 4.50 (br s, 1H), 3.81-3.77 (m, 2H), 3.59-3.41 (m, 4H), 2.07-1.96 (m, 2H), 1.75-1.72 (m, 1H), 0.97 (s, 9H).