Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[CH2:6]1)=[O:4].C(N(CC)CC)C.[CH:24]([C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)([CH3:26])[CH3:25].O>C1COCC1>[CH3:1][O:2][C:3]([N:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:33]([C:30]3[CH:31]=[CH:32][C:27]([CH:24]([CH3:26])[CH3:25])=[CH:28][CH:29]=3)(=[O:35])=[O:34])[CH:11]=2)[CH2:6]1)=[O:4]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)N1CCC(c2cccc(N)c2)C1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(c2cccc(NS(=O)(=O)c3ccc(C(C)C)cc3)c2)C1
Reaction time: 16 h
Yield: 109.4 %

Procedure:
To a solution of 3-(3-amino-phenyl)-pyrrolidine-1-carboxylic acid methyl ester (500 mg, 2.27 mmol) and triethylamine (500 mg, 4.94 mmol) in THF (20 ml) at 10° C. 4-isopropyl-benzenesulfonylchloride (500 mg, 2.27 mmol) was added. The mixture was allowed to come to room temperature and was stirred for 16 h. The mixture was poured into water and extracted three times with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over MgSO4 and evaporated under reduced pressure to give the product as a brown oil (1 g, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[N+:15]([O-])([OH:17])=[O:16].O>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(C)c1cccc(O)c1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C)c1ccc([N+](=O)[O-])c(O)c1

Procedure:
A solution of Ethyl 2-(3-hydroxyphenyl)propanoate (2.51 g, 12.9 mmol) in acetic acid (20 mL) was added nitric acid (1.45 g, 13.8 mmol) in acetic acid (2 mL) at room temperature. Then the colorless oil changed to the dark brown oil after 1˜2 minutes stirred. The reaction mixture was stirred for 15 minutes at room temperature then poured into iced water (100 mL), and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:6) as eluant.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][OH:11])[CH2:7][C:6]=2[CH:12]=1.[H-].[Na+].[CH3:15]I>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][O:11][CH3:15])[CH2:7][C:6]=2[CH:12]=1
Reactant: CI
Reactant: OCC1Cc2cc(F)ccc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC1Cc2cc(F)ccc2O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.5 %

Procedure:
To a solution of (5-fluoro-2,3-dihydrobenzofuran-2-yl)methanol (854) (1.0 g, 6.0 mmol) in dimethylformamide (130.0 mL) was added 60% NaH in mineral oil (0.480 g, 12.0 mmol) and MeI (1.12 mL, 18.0 mmol). The suspension was stirred at room temperature for 24 h and diluted with water (50 mL), and extracted with ethyl acetate (2×25 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (0-10% EtOAc in hexanes) to provide the desired 5-fluoro-2-(methoxymethyl)-2,3-dihydrobenzofuran (855) (0.650 g, 59.5%) as a colorless oil.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([CH:58]([CH3:60])[CH3:59])([CH:55]([CH3:57])[CH3:56])[CH:52]([CH3:54])[CH3:53])[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6](O)[CH2:5][C:4]1=[O:66])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([CH:55]([CH3:57])[CH3:56])([CH:52]([CH3:54])[CH3:53])[CH:58]([CH3:60])[CH3:59])[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]=[CH:5][C:4]1=[O:66])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C(C)C)(C(C)C)C(C)C)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C(C)C)(C(C)C)C(C)C)C(OC)C3)C(C)C=CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 58.2 %

Procedure:
A solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-triisopropylsilyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (150 mg, 0.16 mmol) in MeCl2 (5.0 ml) containing triethylamine (92.2 mg, 0.91 mmol) and 4-dimethylaminopyridine (61 mg, 0.49 mmol) at 0° C., was treated with methanesulfonyl chloride (69.6 mg, 0.61 mmol). After stirring at RT for 2.5 hr, the reaction mixture was diluted with MeCl2 (10 ml) and water. The aqueous layer was separated and extracted with additional MeCl2. After drying over magnesium sulfate, the solvent was removed in vacuo. The residue was chromatographed over SiO2 (10 g). Elution with n-hexane/ethyl acetate (3:1) yielded 17-ethyl-1-hydroxy-12-[2'-(4"-triisopropylsilyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos- 14,18-diene-2,3,10,16-tetraone (86.6 mg, 58%). Mass Spec: C52H89NO11Si (930.36) FAB+Li:1090 (M+ +Li+MATRIX) 936 (M+Li).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=[C:3]([C:16]([O:18]C)=[O:17])[CH:2]=1.[OH-].[K+].O.C(O)C>O1CCOCC1>[CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=[C:3]([C:16]([OH:18])=[O:17])[CH:2]=1
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1NC2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc2c(c1)Sc1ccccc1NC2

Procedure:
Stir a mixture of 136 mg. (0.5 mmole) of the ester of Example 7, 65.9 mg. (1 mmole) of 85% aqueous potassium hydroxide, 0.65 ml. of water, 3.25 ml. of ethanol, and 0.325 ml. of dioxane under argon at room temperature for 12 hours. Evaporate the mixture to dryness. Dissolve the residue in water and acidify with acetic acid. Recover the precipitate by filtration and wash with water. Dry in vacuo over calcium chloride and recrystallize from acetonitrile to obtain the title product (sinters and darkens at 237° C., m.p. 243° C. dec.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:18])[C:14](=O)[CH2:15]Br)[CH3:11]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[N:1]=[C:2]2[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[CH:6][N:7]2[CH:15]=1)=[O:18])[CH3:11]
Reactant: Nc1ccc(C=O)cn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1cn2cc(C=O)ccc2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
An ethanol solution (8.0 ml) containing the compound (318 mg) obtained in Example 30-1 was added with 3-bromo-2-oxo-propionic acid ethyl ester (0.33 ml) and the whole was stirred at room temperature for 18 hours. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (230 mg) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15](C=O)=[CH:14][CH:13]=1.OOS([O-])=O.[K+].CC[O:28][C:29](C)=[O:30]>CN(C=O)C>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:29]([O:30][C:15]1[CH:14]=[CH:13][C:12]([OH:11])=[CH:19][CH:18]=1)=[O:28]
Reactant: CCOC(C)=O
Reactant: O=Cc1ccc(O)cc1
Agent: O=C(O)c1ccc(O)cc1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: O=COc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To prepare 4-hydroxy benzoic acid, 4-hydroxybenzaldehyde (100 mg) was dissolved in DMF (10 mL), and OXONE (0.503 g) was added and stirred at room temperature for 18 hours with the reaction having a final volume (11 mL). The reaction was monitored by TLC or GC analysis. EtOAc was added to extract the products and 1N HCl was used to dissolve the salts. The organic extract was washed with 1N HCl (30 mL×3) and brine (30 mL), dried over Na2SO4, and the solvent was removed under reduced pressure to obtain 4-hydroxy benzoic acid in 19% yield and 4-hydroxyphenol formate in 62% yield after purification by silica gel column chromatography. 4-Hydroxyphenyl Formate: 1H NMR (CDCl3, 300 MHz): δ8.27 (s, 1H), 6.98(d, 2H, J=9.0), 6.78 (d, 2H,J=8.9), 5.35 (bs, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[CH:19]=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.Cl([O-])=[O:24].[Na+]>C(#N)C>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[C:19]([OH:24])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)c(C=O)c1
Reactant: [O-][Cl+][O-]
Agent: OO
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 1.4 gm (5.2 mmol) of methyl 4-benzyloxy-3-formylbenzoate (prepared by benzylation of methyl 3-formyl-4-hydroxybenzoate) in 25 mL of acetonitrile is added an aqueous solution of NaH2PO4.2H2O (268 mg, 1.68 mmol in 3 mL of water) and 2.8 mL (5 equiv) of 30% hydrogen peroxide. To this mixture is added dropwise an aqueous solution of 79% sodium chlorite (830 mg, 7.25 mmol of NaClO2 in 7 mL of water). After 2 hr at room temperature at room temperature, the reaction mixture is concentrated to remove most of the acetonitrile. The residue is taken up in water and acidified with aqueous HCl. The aqueous acidic solution is extracted with ethyl acetate several times. The combined extracts are washed with brine and dried over Na2SO4. Rotoevaporation of solvent gives 1.5 gm (5.2 mmol) of methyl 4-benzyloxy-3-carboxybenzoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([OH:12])=[O:11]>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[CH3:9]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(F)cc1F
Agent: O=S(=O)(O)O
Product: Cc1c(F)cc(F)cc1[N+](=O)[O-]
Temperature: 45 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a stirred solution of 2,4-difluorotoluene (25.0 g, 195.3 mmol) in conc. H2SO4 (60 mL) was added fuming HNO3 (30 mL) drop wise at the rate that temperature was maintained between 40-50° C. over a period of 1.5 h. The reaction mixture was stirred at 40° C. for an additional 1 h. The reaction mixture was poured into ice-cold water (500 mL) and the solid precipitated was filtered and washed with water (2×50 mL). The solid residue was dissolved in EtOAc (200 mL), washed with aq. NaHCO3 (2×200 mL). The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to afford 1,5-difluoro-2-methyl-3-nitrobenzene (21.0 g, 62%) as a light brown liquid.
Reaction SMILES: [I-:1].[Zn+2:2].[I-].[CH3:4][C:5]1([CH3:12])[CH2:10][CH:9](O)[CH2:8][CH2:7][O:6]1>C1COCC1>[I-:1].[CH3:4][C:5]1([CH3:12])[CH2:10][CH:9]([Zn+:2])[CH2:8][CH2:7][O:6]1
Reactant: [Zn+2]
Reactant: CC1(C)CC(O)CCO1
Agent: [I-]
Solvent: C1CCOC1
Product: CC1(C)CC([Zn+])CCO1

Procedure:
The title compound was prepared in an analogous, manner to tetrahydro-2H-pyran-4-yl)zinc(II) iodide except that 2,2-dimethyltetrahydro-2H-pyran-4-ol (Combi Blocks) was used instead of tetrahydro-2H-pyran-4-ol in Step 1 to afford a 0.24M solution of (2,2-dimethyltetrahydro-2H-pyran-4-yl)zinc(II) iodide in THF.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Br:11]Br>S(=O)(=O)(O)O.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[Br:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])=[CH:10]2
Reactant: Cc1cc2ccccc2[nH]1
Reactant: BrBr
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: Cc1cc2cc(Br)ccc2[nH]1
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
To a solution of 2-methyl-1H-indole (5.0 g, 38.12 mmol) in sulfuric acid (80 ml) was added Ag2SO4 (12.5 g, 40.06 mmol) with ice cooling, and the solution was stirred for 30 min. Then Br2 (6.4 g, 40.05 mmol) was added to the solution dropwise over 30 min. After the solution was stirred for 4 h at room temperature, the reaction was quenched by the addition of water/ice (300 ml). The reaction mixture was extracted with dichloromethane (3×200 ml) and the organic layers combined, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 5-bromo-2-methyl-1H-indole as a light brown solid (4.7 g, 59%).
Reaction SMILES: [BH4-].[Na+].[CH:3](=[N:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)[CH2:4][CH3:5].C(O)(=O)C.[H][H]>CN1C(=O)CCC1.CCCCCCC.O>[CH2:3]([NH:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)[CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCC=Nn1ccc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCCCCCC
Product: CCCNn1ccc2ccccc21
Temperature: 30 °C

Procedure:
Prepare a solution of 0.83 kg (21.9 mol) sodium borohydride in 16.6 kg NMP. Add 31.9 kg N-(propylidene)-1H-indol-1-amine as a 19.7% solution in n-heptane (36.5 mol) and additional 7.7 kg n-Heptane. Prepare a solution of 1.32 kg (21.9 mol) glacial acetic acid in 2.8 kg n-heptane. Add the acetic acid solution over a period of about 30 min at 30° C. to the sodium borohydride solution using a pump. Immediately hydrogen evolution will occur. Rinse the pump with 2 kg n-heptane. Stir the reaction mixture at 30° C. until completion of the reaction (˜1 h). The reaction mixture is then worked-up by adding 20 L water. No or only minimal foaming is observed during the addition of water. Stir the mixture over night and separate the phases. Add 0.9 kg HCl (30%) and 3.4 kg water to the n-heptane phase, check whether the pH is below 1. Add additional amounts of HCl if necessary to adjust the pH around 1. Heat this mixture to 75° C. internal temperature for ˜2 h. Cool the mixture to 25° C. in order to control the residual hydrogen that is evolved. If no more residual hydrogen is evolved, add additional 20.3 kg water, and adjust pH to a level >7 with NaOH (33%). Separate the phases and wash the n-heptane phase with 20.3 kg water. Evaporate the n-heptane phase to dryness. This results in 5.84 kg N-propyl-1H-indol-1-amine (82.6%) as a brown liquid.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[Br:18][C:19]1[C:20]([CH:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[OH:27])=[C:21]([Cl:25])[S:22][C:23]=1[Cl:24].[O:35]1[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36]1>C(Cl)Cl.C(Cl)(Cl)Cl>[Br:18][C:19]1[C:20]([CH:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[O:27][CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40][O:35]2)=[C:21]([Cl:25])[S:22][C:23]=1[Cl:24]
Reactant: C1=COCCC1
Reactant: OC(c1cccc(Cl)c1)c1c(Cl)sc(Cl)c1Br
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Clc1cccc(C(OC2CCCCO2)c2c(Cl)sc(Cl)c2Br)c1
Reaction time: 3.5 h

Procedure:
Pyridinium p-toluenesulfonate (74.0 mg, 0.293 mmol) was added to (4-bromo-2,5-dichloro-3-thienyl)(3-chlorophenyl)methanol from Example 8, Step 1 (1.09 g, 2.93 mmol) and 3,4-dihydro-2H-pyran (2.67 mL, 29.3 mmol) in CH2Cl2 (12 mL). After 3.5 h, the reaction mixture was diluted with CHCl3 and washed with 5% aq. NaHCO3, water and brine, dried (Na2SO4) and concentrated. The crude product was purified by Combi Flash chromatography system (30-50% CHCl3/hexane in 20 min.) to afford the desired product as a colorless gum.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:27]=[CH:26][C:6]2[NH:7][C:8]([C:10]3[CH:11]=[C:12]([N:17]4[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=O)[CH2:19][CH2:18]4)[CH:13]=[CH:14][C:15]=3[F:16])=[N:9][C:5]=2[CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:52][NH:53][CH:54]1[CH2:58][N:57]([CH3:59])[CH2:56][CH2:55]1>>[CH3:52][N:53]([CH:54]1[CH2:55][CH2:56][N:57]([CH3:59])[CH2:58]1)[C:23]([CH:20]1[CH2:21][CH2:22][N:17]([C:12]2[CH:13]=[CH:14][C:15]([F:16])=[C:10]([C:8]3[NH:7][C:6]4[CH:26]=[CH:27][C:3]([Cl:2])=[CH:4][C:5]=4[N:9]=3)[CH:11]=2)[CH2:18][CH2:19]1)=[O:25]
Reactant: CNC1CCN(C)C1
Reactant: O=C(O)C1CCN(c2ccc(F)c(-c3nc4cc(Cl)ccc4[nH]3)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: CN1CCC(N(C)C(=O)C2CCN(c3ccc(F)c(-c4nc5cc(Cl)ccc5[nH]4)c3)CC2)C1
Temperature: 35 °C
Yield: 25.5 %

Procedure:
Method J—Step a To a mixture of 1-[3-(5-Chloro-1H-benzoimidazol-2-yl)-4-fluoro-phenyl]-piperidine-4-carboxylic acid hydrochloride (obtained as described in general method 10, step b) (0.01 g, 0.25 mmol) in dcm (2 mL), HATU (0.10 g, 0.26 mmol), TEA (0.07 mL, 0.55 mmol) and N,N′-dimethyl-3-aminopyrrolidine (0.04 g, 0.31 mmol) were added. The reaction mixture was heated at 35° C. overnight, cooled to room temperature and washed with ammonium chloride solution (2 mL), saturated Na2CO3 solution (2 mL) and water (2 mL). The organic layer was then filtrated on an NH2 cartridge and further purified by flash chromatography (eluent: EtOAc:NH3 2N in MeOH/9:1) to obtain 0.03 g of the title compound (30%).
Reaction SMILES: [Na].C(OC(=O)[CH2:6][CH2:7][N:8]([CH3:17])[C:9](=[O:16])[CH2:10][C:11]([O:13]CC)=O)C.CN1CCC(=O)C(C(OCC)=O)C1=O>C(O)C.CCOCC>[CH3:17][N:8]1[CH2:7][CH2:6][C:11](=[O:13])[CH2:10][C:9]1=[O:16]
Reactant: CCOC(=O)CCN(C)C(=O)CC(=O)OCC
Agent: CCOC(=O)C1C(=O)CCN(C)C1=O
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CN1CCC(=O)CC1=O
Temperature: 80 °C

Procedure:
Into a 50-mL round bottomed flask was added ethanol (4 mL) under argon, followed by sodium (0.121 g, 5.25 mmol). The mixture was stirred at room temperature for 15 min, during which a solution of ethyl 3-((3-ethoxy-3-oxopropyl)(methyl)amino)-3-oxopropanoate (1.17 g, 4.77 mmol) in ethanol (5 mL) was added. The resulting clear, colorless mixture was heated at 80° C. for 1 h, during which LC-MS indicated completion of reaction and a clean conversion to the desired ethyl 1-methyl-2,4-dioxopiperidine-3-carboxylate intermediate. Upon cooling to room temperature, the reaction was diluted with Et2O, resulting in the formation of a white precipitate (desired product). The white precipitate was collected via filtration, taken up in 5% aqueous HCl solution (8 mL), and refluxed for 1 h. The cooled mixture was extracted with CH2Cl2 (5×) and the combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (20% EtOAc/Hexanes to 100% EtOAc) afforded 1-methylpiperidine-2,4-dione as a viscous milky oil. [M+1]=128.1.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:13][N:14]([CH3:18])[C:15](=[S:17])[S-:16].C[NH2+]C>C(=S)=S>[CH3:13][N:14]([CH3:18])[C:15](=[S:16])[S:17][CH:6]([CH2:7][N+:8]([O-:10])=[O:9])[C:5]1[CH:11]=[CH:12][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])C=Cc1ccc(Br)cc1
Reactant: CN(C)C(=S)[S-]
Agent: C[NH2+]C
Solvent: S=C=S
Product: CN(C)C(=S)SC(C[N+](=O)[O-])c1ccc(Br)cc1

Procedure:
As in Example 17, reaction of p-bromo-β-nitrostyrene with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide gave p-bromo-α-(nitromethyl)benzyl dimethyldithiocarbamate melting at 79° C.-81° C. when recrystallized without heating from acetone-ethanol solution.
Reaction SMILES: [I:1][C:2]1[C:10]([I:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:13]([O:32][CH2:33][CH2:34][CH2:35][OH:36])(=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N(CC)CC)C>C(Cl)Cl>[I:1][C:2]1[C:10]([I:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([O:36][CH2:35][CH2:34][CH2:33][O:32][C:13](=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:5]
Reactant: O=C(Cl)c1cc(I)cc(I)c1I
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCOC(=O)c1cc(I)cc(I)c1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,3,5-Triiodobenzoyl chloride (1.54 g, 3.08 mmol) was added to a mixture of 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (1 g, 2.97 mmol) and triethylamine (1 ml) in methylene chloride (80 ml) and the resulting mixture stirred overnight at room temperature under nitrogen. The mixture was concentrated and purified by flash chromatography (ethyl acetate/hexane) to yield 1-(2,3,5-triiodobenzoyloxy)-3-(z,z,z-octadeca-6,9,12-trienoyloxy) propane.
Reaction SMILES: [CH:1]1([CH2:4][C@H:5]([NH:26]C(=O)OC(C)(C)C)[CH2:6][O:7][C:8]2[C:9]([CH3:25])=[CH:10][C:11]3[C:20]4[C:15](=[C:16]([CH3:21])[N:17]=[CH:18][CH:19]=4)[C:14](=[O:22])[N:13]([CH3:23])[C:12]=3[CH:24]=2)[CH2:3][CH2:2]1.Cl>CO>[NH2:26][C@@H:5]([CH2:4][CH:1]1[CH2:3][CH2:2]1)[CH2:6][O:7][C:8]1[C:9]([CH3:25])=[CH:10][C:11]2[C:20]3[C:15](=[C:16]([CH3:21])[N:17]=[CH:18][CH:19]=3)[C:14](=[O:22])[N:13]([CH3:23])[C:12]=2[CH:24]=1
Reactant: Cc1cc2c3ccnc(C)c3c(=O)n(C)c2cc1OC[C@H](CC1CC1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: Cc1cc2c3ccnc(C)c3c(=O)n(C)c2cc1OC[C@@H](N)CC1CC1
Reaction time: 1 h
Yield: 30.8 %

Procedure:
An ambient temperature solution of (S)-tert-butyl (1-cyclopropyl-3-((4,6,9-trimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)propan-2-yl)carbamate (41 mg, 0.091 mmol) in methanol (0.5 mL) was treated with HCl (4M in 1,4-dioxane) (0.454 mL, 1.816 mmol) and stirred for 1 h. The resulting mixture was concentrated under reduced pressure to yellow solid. The crude material was purified by reverse phase high performance liquid chromatography (Phenomenex Luna C18 30×100 mm 10 micron; water/methanol/TFA gradient elution). Product containing fractions were neutralized with saturated aqueous sodium bicarbonate and concentrated under reduced pressure. The resulting residue was partitioned between water and ethyl acetate and the layers were separated. The aqueous was extracted twice more with ethyl acetate and the pooled organics were dried over magnesium sulfate, filtered, and concentrated to afford (S)-8-(2-amino-3-cyclopropylpropoxy)-4,6,9-trimethylbenzo[c][2,7]naphthyridin-5(6H)-one (10.7 mg, 0.028 mmol, 93% yield) as a colorless solid. LC/MS, (ESI) m/z 352.2 [(M+H)+, calcd for C21H26N3O2 352.2]; HPLC retention time (method C): tR=13.71 min; HPLC retention time (method D): tR=14.29 min; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.63 (d, J=5.5 Hz, 1H), 7.98 (s, 1H), 7.84 (d, J=5.8 Hz, 1H), 6.74 (s, 1H), 4.15 (dd, J=8.8, 4.0 Hz, 1H), 4.00 (dd, J=8.7, 6.9 Hz, 1H), 3.76 (s, 3H), 3.50-3.37 (m, 1H), 3.17 (s, 3H), 2.37 (s, 3H), 1.61-1.44 (m, 2H), 1.02-0.74 (m, 1H), 0.68-0.45 (m, 2H), 0.30-0.06 (m, 2H).