Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:5]=1[CH2:6]P(=O)(OCC)OCC.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].COCCOC>O>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31](=[CH:6][C:5]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:4]=2[Br:3])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1cc(OC)ccc1Br)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(Br)c(C=C2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 1.5 h
Yield: 79 %

Procedure:
Sodium hydride (60% in paraffin, 14.4 g, 0.360 mol) was added in small portions to a mixture of the crude product (147 g) of diethyl 2-bromo-5-methoxybenzylphosphonate, N-tert-butoxycarbonyl-4-piperidone (65.1 g, 0.327 mol) and 1,2-dimethoxyethane (200 mL) at room temperature, and the resulting mixture was stirred as it was for 1.5 hours. Water (1200 mL) was added to the reaction mixture, followed by extraction with ether (500 mL×3). The combined organic layer was washed with water (200 mL) and a saturated aqueous sodium chloride solution (200 mL). The combined organic layer washed was dried over anhydrous magnesium sulfate and then concentrated to dryness, and the residue was washed with hexane to obtain 98.2 g (0.257 mol, 79%) of N-tert-butoxycarbonyl-4-(2-bromo-5-methoxybenzal)piperidine.
Reaction SMILES: [C:1]([CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[N:23]=[C:22]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH:21][N:20]=1>C(O)(=O)C>[CH2:25]([S:24][C:22]1[N:23]=[C:19]2[N:18]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:20]2[N:21]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Product: c1ccc(CSc2nc3nc(-c4ccccc4)cc(-c4ccccc4)n3n2)cc1
Temperature: 25 °C
Yield: 34.3 %

Procedure:
A solution of 8.40 g (37.5 mmol) of dibenzoylmethane and 7.73 g (37.5 mmol) of 3-amino-5-benzylthio-1,2,4-triazole in 50 ml of glacial acetic acid was heated at reflux for 24 hours. Upon cooling to room temperature the solid which separated was collected by filtration and dried. The product was chromatographed on silica gel (HPLC) eluting with EtOAc-hexane (3:7, v/v) to afford 5.08 g (34%) of the desired product as a colorless solid, m.p. 122.5°-123.5° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])=[CH:27][CH:28]=4)[O:23][CH2:22][C:21]=3[C:38]3[CH:43]=[CH:42][C:41]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])=[CH:40][C:39]=3O)([OH:19])[CH3:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[C:34]([Si:31]([CH3:32])([CH3:33])[O:30][C:26]1[CH:27]=[CH:28][C:29]2[C:20]3[C:17]([C:14]4[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]5)=[CH:12][CH:13]=4)([CH3:18])[O:19][C:39]4[CH:40]=[C:41]([O:44][Si:45]([C:48]([CH3:50])([CH3:51])[CH3:49])([CH3:47])[CH3:46])[CH:42]=[CH:43][C:38]=4[C:21]=3[CH2:22][O:23][C:24]=2[CH:25]=1)([CH3:35])([CH3:36])[CH3:37]
Reactant: CC(O)(C1=C(c2ccc(O[Si](C)(C)C(C)(C)C)cc2O)COc2cc(O[Si](C)(C)C(C)(C)C)ccc21)c1ccc(OCCN2CCCCCC2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(c2ccc(OCCN3CCCCCC3)cc2)Oc2cc(O[Si](C)(C)C(C)(C)C)ccc2C2=C1c1ccc(O[Si](C)(C)C(C)(C)C)cc1OC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-[4-{1-[4-(2-azepan-1-yl-ethoxy)-phenyl]-1-hydroxy-ethyl}-7-(tert-butyl-dimehyl-silyloxy)-2H-chromen-3-yl]-5-(tert-butyl-dimethyl-silyloxy)-phenol, prepared as in STEP A above, was dissolved in toluene (8 mL) and treated with diluted HCl (0.4 mL of concentrated HCl:H2O=1:2 v/v). The reaction mixture was vigorously stirred at room temperature for 1.5 h, then diluted with water and ethyl acetate. The resulting layers were separated and organic layer washed successively with saturated NaHCO3, brine and dried over MgSO4. The desiccant was filtered off, and the filtrate concentrated. Flash chromatography with ethyl acetate:hexane:CH3OH (containing 1% NH4OH)=49:49:2 as the eluent yielded the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:53]=[C:54]([CH:60]=[CH:61][CH:62]=1)[O:55][CH2:56][CH2:57]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][CH2:57][CH2:56][O:55][C:54]2[CH:60]=[CH:61][CH:62]=[C:52]([F:51])[CH:53]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: OCCCOc1cccc(F)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCCCOc4cccc(F)c4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 62.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2,3-di-methylaniline (68 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (94 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(3-fluorophenoxy)-1-propanol (53 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (68 mg, yield 56%).
Reaction SMILES: [O:1]=[C:2]([CH3:13])[CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O.CCN(C(C)C)C(C)C.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]2[C:41]3[C:36](=[C:37]([CH3:54])[CH:38]=[C:39]([S:42]([C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][NH:52][CH3:53])[CH:46]=4)(=[O:44])=[O:43])[CH:40]=3)[N:35]=[CH:34][C:33]=2[C:55]([NH2:57])=[O:56])[CH:28]=[CH:29][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]2[C:41]3[C:36](=[C:37]([CH3:54])[CH:38]=[C:39]([S:42]([C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][N:52]([C:7]([C:6]5[CH:10]=[CH:11][CH:12]=[C:4]([CH2:3][C:2](=[O:1])[CH3:13])[CH:5]=5)=[O:9])[CH3:53])[CH:46]=4)(=[O:43])=[O:44])[CH:40]=3)[N:35]=[CH:34][C:33]=2[C:55]([NH2:57])=[O:56])[CH:28]=[CH:29][CH:30]=1
Reactant: CNCc1cccc(S(=O)(=O)c2cc(C)c3ncc(C(N)=O)c(Nc4cccc(OC)c4)c3c2)c1
Reactant: CC(=O)Cc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(CN(C)C(=O)c5cccc(CC(C)=O)c5)c4)cc23)c1
Reaction time: 0.08 h
Yield: 88 %

Procedure:
3-(2-Oxopropyl)benzoic acid (33 mg, 0.185 mmol) and DIEA (0.097 mL, 0.555 mmol) were added to a stirring solution of Intermediate 136 (100 mg, 0.204 mmol) in DMF (2 mL) at rt. The reaction mixture was stirred for 5 min and HATU (78 mg, 0.204 mmol) was added. The resulting solution was stirred for 3 h then poured into H2O (50 mL). The precipitate was filtered, washed with H2O (30 mL), and dried to give the title compound (106 mg) as a yellow solid. ES/MS calcd for C36H35N4O6S+ 651.2. Found m/z=651.4 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][N:10]([CH3:19])[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:7][CH:8]=1)#[N:2].[NH2:20][OH:21]>C(O)C>[OH:21][N:20]=[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][N:10]([CH3:19])[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])=[N:7][CH:8]=1)[NH2:2]
Reactant: NO
Reactant: CN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)cn1
Solvent: CCO
Product: CN(CC(=O)OC(C)(C)C)Cc1ccc(C(N)=NO)cn1
Yield: 76.4 %

Procedure:
A solution of tert-butyl 2-(((5-cyanopyridin-2-yl)methyl)(methyl)amino)acetate (2.17 g; 8.31 mmol) and 50% aqueous hydroxylamine (2.50 mL; 40.8 mmol) in ethanol (40 mL) was heated at 60° C. for 2 hours. The solvent was evaporated in vacuo. The residue was partitioned between DCM and water. The organic phase was poured through a hydrophobic frit and evaporated in vacuo. The residue was triturated with ether to afford the title product as an off-white solid (1.87 g, 77%). 1H NMR (DMSO-d6, 400 MHz) δ 9.81 (1 H, s), 8.79 (1 H, d, J=2 Hz), 8.03 (1 H, dd, J=8.2, 2.2 Hz), 7.48 (1 H, d, J=8.2 Hz), 5.97 (2 H, br s), 3.80 (2 H, s), 2.32 (3 H, s), 1.46 (9 H, s).
Reaction SMILES: S(Cl)(C)(=O)=O.C([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])C.[CH2:13]1[CH2:17]OC[CH2:14]1.Cl[CH2:19]Cl>C(Cl)(Cl)Cl>[CH:11]([N:8]([CH:13]([CH3:17])[CH3:14])[CH2:9][CH3:10])([CH3:12])[CH3:19]
Reactant: CCN(CC)CC
Reactant: ClCCl
Reactant: C1CCOC1
Agent: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCN(C(C)C)C(C)C

Procedure:
The compound of formula (XIV) is reacted with a chlorinating agent, such as thionyl chloride, phosphorus oxychloride, and the like, optionally with a base, such as pyridine, and the like, in an organic solvent, such as toluene, benzene, chloroform, methylene chloride, and the like, in a temperature range of 0° C. to 80° C., preferably in the range of 25° C. to 60° C., to yield the corresponding compound of formula (XV). Alternatively, compound of formula (XV) is reacted with a chlorinating agent, such as mesyl chloride, and the like, with a base, such as triethylamine, diisopropylethylamine, and the like, in an organic solvent, such as THF, dichloromethane, chloroform, and the like, in a temperature range of 0° C. to 60° C., preferably in the range of 25° C. to 40° C., to yield the corresponding compound of formula (XV).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].S([O-])(O)(=O)=O.[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.[OH-].[Na+]>ClCCl>[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:14][CH2:13][CH2:12][CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(CCCCO)cc1
Reactant: BrCCCCCCBr
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CCCCOCCCCCCBr)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 20.1 %

Procedure:
A stirred mixture of 4-(4-nitrophenyl)butan-1-ol (2.0 g, 10 mmol), tetra-n-butylammomium hydrogen sulfate (0.17 g, 0.5 mmol), and 1,6-dibromohexane (3.2 mL, 20 mmol) in dichloromethane (10 mL) was treated with aqueous sodium hydroxide solution (10 M, 1 mL). The reaction mixture was stirred for 6 days at room temperature. The organic and aqueous phases were separated. The aqueous phase was extracted thrice with dichloromethane. The combined organics were washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified via automated flash silica gel chromatography, using a 40 g Silicycle SiliSep flash column (hexanes/ethyl acetate). Concentration of the desired fractions under reduced pressure provided the title compound as pale straw-colored oil (0.72 g, 20%). ES/MS calcd. for C16H25BrNO3+ 358.1. Found m/z=358.2 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18]O)[CH:13]=2)=[C:8]([CH3:20])[CH:7]=1>>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][Cl:3])[CH:13]=2)=[C:8]([CH3:20])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(Cl)ccc1-c1cccc(CO)c1
Product: Cc1cc(Cl)ccc1-c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride was added to (4′-chloro-2′-methylbiphenyl-3-yl)methanol under cooing with ice-methanol, followed by stirring at room temperature for 1 hour to obtain 4-chloro-3′-(chloromethyl)-2-methylbiphenyl.
Reaction SMILES: CS[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.O[O:12][S:13]([O-:15])=O.[K+].[CH3:17]O>O>[CH3:17][S:13]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1)(=[O:15])=[O:12]
Reactant: O=S([O-])OO
Reactant: CO
Reactant: CSc1ccc(CO)cc1
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 58 %

Procedure:
4-(Methylthio)benzyl alcohol (50 mmol, 7.71 g) was dissolved in methanol (150 ml) and cooled to 0° C. Oxone® (110 mmol, 67.6 g) in water (250 ml) was added. The stirred mixture was warmed to room temperature after 5 minutes. After 40 minutes, the mixture was diluted with water (250 ml), and extracted with methylene chloride (300 ml, then 2×100 ml). The combined organic layers were dried (MgSO4), filtered through silica, and concentrated to afford the title compound (5.48 g, 58%) as a waxy solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14](=O)[CH2:15][C:16](=O)[C:17]([F:20])([F:19])[F:18])[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[NH2:23][C:24]1[C:28]([Br:29])=[CH:27][NH:26][N:25]=1>>[Br:29][C:28]1[CH:27]=[N:26][N:25]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:14]([C:6]3[CH:7]=[CH:8][C:9]([C:10]([F:13])([F:12])[F:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)=[N:23][C:24]=12
Reactant: Nc1n[nH]cc1Br
Reactant: CCOc1cc(C(=O)CC(=O)C(F)(F)F)ccc1C(F)(F)F
Product: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(Br)c3n2)ccc1C(F)(F)F
Yield: 92.8 %

Procedure:
Prepared from 1-(3-ethoxy-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (example C.3 step 1) (8.00 g, 24 mmol) and commercially available 3-amino-4-bromopyrazole (4.03 g, 24 mmol) as described in example C.1 step 2a to give the 3-bromo-5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (10.12 g, 91%) as a yellow solid. MS (ISP) 454.0 [(M+H)+] and 456.0 [(M+2+H)+].
Reaction SMILES: [CH2:1]([NH:5][CH3:6])[CH2:2][CH2:3][CH3:4].[Br:7][CH2:8][C:9](Br)=[O:10]>CCOCC.O>[Br:7][CH2:8][C:9]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH3:6])=[O:10]
Reactant: O=C(Br)CBr
Reactant: CCCCNC
Solvent: CCOCC
Solvent: O
Product: CCCCN(C)C(=O)CBr
Reaction time: 0.5 h

Procedure:
26 g of butylmethylamine in solution in 120 ml of ether were added to a solution, cooled down to -20° C., of 11.9 ml of bromoacetyl bromide in 180 ml of ether. The temperature was returned to 0° C. and the mixture was stirred for 30 minutes, diluted with water and extracted with ether. The extracts were evaporated to dryness under reduced pressure. The 27.4 g of residue were distilled under reduced pressure (0.05 mbar) at 79° C. to 83° C. to obtain 19.36 g of the desired product.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])=[CH:9][N:8]=1.CN([CH:23]=[O:24])C.[Cl-].[NH4+]>C1(C)C=CC=CC=1.O.C1COCC1>[CH2:15]([O:14][CH:13]([O:17][CH2:18][CH3:19])[C:10]1[CH:11]=[CH:12][C:7]([CH:23]=[O:24])=[N:8][CH:9]=1)[CH3:16]
Reactant: CN(C)C=O
Reactant: CCOC(OCC)c1ccc(Br)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(OCC)c1ccc(C=O)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
To toluene (3 mL) were added dropwise at −78° C. n-butyllithium (2.6 mol/L solution in n-hexane, 0.94 mL, 2.43 mmol) and a solution of 2-bromo-5-(diethoxymethyl)pyridine (575 mg, 2.21 mmol) obtained in Step 1 of Reference Example 42 in toluene (2 mL), and the mixture was stirred at −78° C. for 30 minutes. THF (2 mL) was added to the resulting suspension and the mixture was stirred at −78° C. for 30 minutes. DMF (0.51 mL, 6.63 mmol) was added and the mixture was stirred for 30 minutes allowing the temperature to rise slowly to room temperature. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give 5-(diethoxymethyl)picolinaldehyde (149 mg, 32% yield).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:42])([F:41])[C:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])[CH2:17][CH2:18][CH2:19][N:20]([CH2:27][C:28](O)=[O:29])[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[O:11].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:70][CH2:71][CH:72]1[CH2:76][O:75][CH:74]([O:77][CH2:78][CH2:79][CH2:80][C:81]([N:83]([CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][CH2:107][CH2:108][CH2:109][CH2:110][CH3:111])[CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH3:97])=[O:82])[O:73]1>ClCCl>[F:8][C:9]([F:41])([F:42])[C:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:40])[C:36]([F:37])([F:38])[F:39])[CH2:17][CH2:18][CH2:19][N:20]([C:21](=[O:26])[C:22]([F:24])([F:25])[F:23])[CH2:27][C:28]([NH:70][CH2:71][CH:72]1[CH2:76][O:75][CH:74]([O:77][CH2:78][CH2:79][CH2:80][C:81]([N:83]([CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][CH2:107][CH2:108][CH2:109][CH2:110][CH3:111])[CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH3:97])=[O:82])[O:73]1)=[O:29])=[O:11]
Reactant: O=C(O)CN(CCCN(CCCNC(=O)C(F)(F)F)CCCNC(=O)C(F)(F)F)C(=O)C(F)(F)F
Reactant: CCCCCCCCCCCCCCN(CCCCCCCCCCCCCC)C(=O)CCCOC1OCC(CN)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCN(CCCCCCCCCCCCCC)C(=O)CCCOC1OCC(CNC(=O)CN(CCCN(CCCNC(=O)C(F)(F)F)CCCNC(=O)C(F)(F)F)C(=O)C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.9 ml of triethylamine (13.8 mmol), 2 g of [(3-{bis[3-(2,2,2-trifluoroacetylamino)propyl]amino}-propyl)trifluoroacetylamino]acetic acid (trifluoroacetate salt, 3.04 mmol) and 1.8 g of BOP (4.14 mmol) were successively added to 1.65 g of 4-(4-aminomethyl-[1,3]dioxolan-2-yloxy)-N,N-ditetradecylbutyramide (2.76 mmol) dissolved in 30 ml of dichloromethane. The solution was stirred for 1 hour at room temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([NH2:11])[C:4]=1[NH2:12].CO[C:15]1C(OC)=C[C:18]2[NH:19][C:20](CCCNC)=N[C:17]=2[CH:16]=1>>[CH3:10][O:9][C:6]1[C:5]2[N:11]=[C:15]([CH2:16][CH2:17][CH2:18][NH:19][CH3:20])[NH:12][C:4]=2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: COc1ccc(OC)c(N)c1N
Reactant: CNCCCc1nc2cc(OC)c(OC)cc2[nH]1
Product: CNCCCc1nc2c(OC)ccc(OC)c2[nH]1

Procedure:
Prepared from 3,6-dimethoxy-benzene-1,2-diamine in analogy to the methods described for [3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].O[CH2:13][CH:14]([CH2:16]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.OS(O)(=O)=O.O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]2[C:8]=1[CH:13]=[CH:14][CH:16]=[N:7]2
Reactant: OCC(O)CO
Reactant: Cc1ccc([N+](=O)[O-])c(N)c1
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c2ncccc12
Temperature: 105 °C
Yield: 76.8 %

Procedure:
5-methyl-2-nitroaniline (1.0 g, 6.57 mmol), glycerol (1.88 g, 20.4 mmol), 3-nitrobenzenesulfonic acid sodium salt (1.92 g, 8.54 mmol) were added to H2SO4/H2O (6 ml, 7:5) solution and heated at 105° C. for 48 h. After completion of the reaction (monitored by LCMS), the mixture was cooled to 45° C. and poured slowly onto ice water (50 ml) and the mixture was extracted with DCM. The combined organic phases were dried (Na2SO4) and concentrated in vacuo to give the title compound (950 mg, 77%) which was used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.N1C=CC=CC=1.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([Cl:28])(=[O:27])=[O:26])[CH:20]=1.Cl>ClC(Cl)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:29]([C:19]2[CH:20]=[C:21]([S:25]([Cl:28])(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=2)(=[O:31])=[O:30])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: O=S(=O)(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccc(F)cc1C(F)(F)F
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: O=S(=O)(Cl)c1cccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
8.78 g (30 mmol) of 4-fluoro-2-(trifluoromethyl)-aniline is dissolved in 88 ml of dichloroethane with exclusion of moisture, 5.55 g (70 mmol) of pyridine is added and the solution is cooled to 0° C. With this temperature being maintained, a solution of 9.9 g (36 mmol) of 1,3-benzenedisulfonic acid dichloride in 50 ml of dichloroethane is instilled, it is stirred for 30 more minutes at 0° C. and for 5 hours more at room temperature. The suspension is shaken out three times with 2N hydrochloric acid and twice with water, the organic phase is dried on sodium sulfate, filtered, concentrated by evaporation and the residue is chromatographed on silica gel 60 (Merck) with ethyl acetate/hexane 1:1. The fractions of the corresponding polarity, concentrated by evaporation, yield 9.7 g (23.22 mmol)=77.4% of the theoretical yield is obtained of a partially crystalline product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].[Cl:13][CH2:14][CH2:15][CH:16](OS(C)(=O)=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][CH2:14][Cl:13])[CH:9]=[CH:10][C:3]=12.[Cl:1][C:2]1[C:3]2=[C:4]3[N+:5]([CH2:14][CH2:15][CH:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:8]3[CH:9]=[CH:10]2)=[CH:6][CH:7]=1
Reactant: Clc1ccnc2[nH]ccc12
Reactant: CS(=O)(=O)OC(CCCl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ClCCC(c1ccccc1)n1ccc2c(Cl)ccnc21
Product: Clc1cc[n+]2c3c1ccn3C(c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a RT solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (200 mg, 1.31 mmol) in DMF (5 mL) was added NaH (60% in mineral oil, 57.7 mg, 1.44 mmol) followed by methanesulfonic acid 3-chloro-1-phenyl-propyl ester (326 mg, 1.31 mmol). The reaction mixture was stirred at RT overnight, poured into ice-water, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to yield 4-Chloro-1-(3-chloro-1-phenyl-propyl)-1H-pyrrolo[2,3-b]pyridine as a mixture with the cyclization product 8-Chloro-3-phenyl-4,5-dihydro-3H-2a-aza-5a-azonia-acenaphthylene. The mixture was used in the next step without purification.
Reaction SMILES: [CH2:1]([P:5]([CH2:8][CH:9]([C:22]([O:24]CC1C=CC=CC=1)=[O:23])[CH2:10][CH2:11][C:12]([O:14]CC1C=CC=CC=1)=[O:13])(=[O:7])[OH:6])[CH2:2][CH2:3][CH3:4]>O>[CH2:1]([P:5]([CH2:8][CH:9]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:22]([OH:24])=[O:23])([OH:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCP(=O)(O)CC(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Solvent: O
Product: CCCCP(=O)(O)CC(CCC(=O)O)C(=O)O
Yield: 43.3 %

Procedure:
Butyl[2,4-di(benzyloxycarbonyl)butyl]phosphinic acid (2.9 g, 6.5 mmol) in 30 mL of water containing 0.32 g 10% Pd/C was hydrogenated on a Parr hydrogenator at 40 psi for 4.5 hours. The mixture was filtered through a pad of Celite and evaporated under high vacuum to give 2-[(butylhydroxyphosphinyl)methyl]pentanedioic acid (4, R=n-butyl) (0.75 g, 43%) as a clear and colorless viscous oil. 1H NMR (D2O): 2.4 ppm (m, 1H), 2.1 ppm (t, 2H), 1.9 ppm (m, 1H), 1.6 ppm (m, 3H), 1.4 ppm (m, 2H), 1.1 ppm (m, 4H), 0.6 ppm (t, 3H) Elemental Analysis Calculated C10H19O6P. 0.5 H2O: C 43.64, H 7.32: Found C 43.25, H 7.12