Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[S:12]([OH:15])(=O)=[O:13].P(Cl)(Cl)(Cl)(Cl)[Cl:17].Cl>>[Br:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[S:12]([Cl:17])(=[O:15])=[O:13]
Reactant: O=S(=O)(O)c1c(F)c(F)c(F)c(F)c1Br
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl
Product: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1Br
Reaction time: 0.33 h
Yield: 88.1 %

Procedure:
1Bromo-2,3,4,5-tetrafluorobenzene (5.0 g, 21.8 mmol) was mixed at ambient temperature with 20% fuming sulfuric acid (20 ml). The mixture was heated at 40° C. for 3 h and at 110° C. for 2 h. The reaction mixture was allowed to cool to ambient temperature and poured onto 12 g of crushed ice. The mixture was acidified dropwise with concentrated HCl (2 ml) until a solid, consisting mostly of 2-bromo-3,4,5,6-tetrafluorophenylsulfonic acid was formed. The solid was filtered, washed with 12N HCl, and dried under high vacuum to afford 5.3 g of 2-bromo-3,4,5,6-tetrafluorophenylsulfonic acid as a white hygroscopic solid that was used without further purification. To the sulfonic acid (3.0 g, 9.7 mmol) was then added phosphorous pentachloride (8.0 g, 38.4 mmol) in small portions, at ambient temperature (Caution: exothermic reaction with significant evolution of HCl). The reaction was allowed to stir for 20 minutes after the final addition of phosphorous pentachloride. The reaction mixture was then poured onto crushed ice and the white solid that formed was filtered and dried to afford 2.8 g of the title compound, which was used without further purification. MS (EI): 328 (30, M+), 293 (70), 229 (30), 148 (100).
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:19]=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[Li]CCCC.[CH:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[C:33]1([CH:32]([C:4]2[CH:3]=[CH:2][CH:10]=[C:9]3[C:5]=2[C:6]([CH:19]=[CH:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:7][N:8]3[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])[OH:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(I)cc21
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2c(C(O)c3ccccc3)cccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of 6-iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole, prepared in Example 14, step (i), (143 mg, 0.3 mmol) in THF (1 mL) cooled to −78° C. under an atmosphere of argon was added n-BuLi (0.2 mL, 0.315 mmol) dropwise. The resulting mixture was stirred at −78° C. for 30 min, then a solution of benzaldehyde (0.035 mL, 0.33 mmol) in THF (0.5 mL) was added rapidly via a cannula. After 0.5 h the reaction was quenched with saturated NH4Cl (aq) and diluted with EtOAc (10 mL) and H2O (3 mL). The phases were separated and the aqueous was extracted 2×10 mL EtOAc. The pooled EtOAc was washed with brine (5 mL), dried with Na2SO4, decanted and concentrated under reduced pressure. The crude mixture was purified by silica gel chromatography (eluting with hexane:EtOAc 4:1) to give phenyl-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-yl}-methanol (68 mg, 50% yield). Rf sm=0.72; Rf p=0.39 (7:3 hexane:EtOAc); FTIR (thin film) 3368, 2952, 2893, 1621, 1478, 1449, 1374, 1307, 1249, 1216, 1078, 960, 859, 835 cm−1. MS (ESI) [M+H]/z Calc'd 457, found 457.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([NH:10][CH2:11][CH3:12])[CH:3]=1>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][CH2:11][CH3:12])[C:5]([CH:8]=[O:9])=[CH:6][N:7]=1
Reactant: CCNc1cc(Cl)ncc1CO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCNc1cc(Cl)ncc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To a solution of (6-chloro-4-(ethylamino)pyridin-3-yl)methanol (2.5 g, 13.4 mmol) in DCM (30 mL) was added MnO2 (5.8 g, 67 mmol) and the reaction mixture was stirred at RT overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 6-chloro-4-(ethylamino)nicotinaldehyde (2.2 g, 89% yield). 1H NMR (400 MHz, CDCl3): δ 9.82 (s, 1H), 8.51 (br s, 1H), 8.27 (s, 1H), 6.56 (s, 1H), 3.28 (m, 2H), 1.31 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 185.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]12[C:16](=[O:17])[CH:6]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][C:9]=31)[NH:5][CH2:4][CH2:3]2.N>Br>[CH3:1][C:2]12[C:16](=[O:17])[CH:6]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=31)[NH:5][CH2:4][CH2:3]2
Reactant: COc1ccc2c(c1)C1(C)CCNC(C2)C1=O
Agent: Br
Agent: N
Product: CC12CCNC(Cc3ccc(O)cc31)C2=O

Procedure:
A mixture of 1,2,3,4,5,6-hexahydro-6-methyl-8-methoxy-11-oxo-2,6-methano-3-benzazocine (2.18 g.) and hydrobromic acid (48%, 20 ml.) was stirred under reflux (for 30 min.), basified with dilute ammonia and extracted with chloroform. Desiccation and concentration of the chloroform extracts afforded a tan solid (1.1 g.), recrystallization of which from acetone afforded 1,2,3,4,-5,6-hexahydro-6-methyl-8-hydroxy-11-oxo-2,6-methano-3-benzazocine (III: R=CH3, X"=HO, Y+Z=O; 0.4 g.), a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].I[CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6])[CH3:12]
Reactant: CCI
Reactant: OCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cccc(CO)c1
Yield: 95.1 %

Procedure:
To a mixture of 3-hydroxybenzyl alcohol (3.56 g) and acetone (100 ml) were added iodoethane (6.7 g) and potassium carbonate (7.9 g), and the resulting mixture was heated at reflux for 61 hours. The reaction mixture was concentrated, ethyl acetate was added to the residue and the resulting mixture was washed successively with water and an aqueous saturated solution of sodium chloride, and was then dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 3-ethoxybenzyl alcohol (4.15 g) as an oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:9])([F:8])[CH:5]([OH:7])[CH3:6].F[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1>CN(C=O)C.O>[F:3][C:4]([F:9])([F:8])[CH:5]([O:7][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH3:6]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Oc1ccc(C#N)cc1)C(F)(F)F
Temperature: 50 °C
Reaction time: 20 h
Yield: 77.6 %

Procedure:
Sodium hydride (297 mg, 12.4 mmol) was suspended in DMF (3 ml) at 0° C. 1,1,1-trifluoropropan-2-ol (500 μl, 5.52 mmol) was added slowly and the reaction was stirred for 15 minutes at 0° C. before addition of 4-fluorobenzonitrile (500 mg, 4.13 mmol). The mixture was allowed to reach room temperature and was then stirred at 50° C. for 20 hours. The reaction was cooled, diluted with water (75 ml) and extracted with EtOAc (4*20 ml). Combined organics were washed with water (20 ml), dried over MgSO4 and evaporated. The product was purified by flash chromatography using pet.ether/EtOAc (8:1) as eluent to give 690 mg (78%) of the title compound as a clear liquid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[C:29](OC(=O)C)(=[O:31])[CH3:30]>[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:29](=[O:31])[CH3:30])=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Product: CC(=O)Nc1ccc(O[C@@H]2SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Yield: 51 %

Procedure:
30 mg of 10% palladium-on-charcoal are added to a solution of 150 mg (0.36.10-3 mol) of 4-nitrophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside in acetic anhydride, under a nitrogen atmosphere, and the reaction mixture obtained is then kept under hydrogen pressure (3.5.105Pa) at 50° C. for 15 hours. After filtration, the mixture is evaporated to dryness under reduced pressure and the residue obtained is purified by chromatography using a methylene chloride/methanol mixture (98/2 v/v) as the eluent to give 80 mg (yield: 51%) of the expected product.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][N:10]1C(=O)CCC1>[C-]#N.[Zn+2].[C-]#N.O>[Cl:8][C:7]1[C:2]([C:9]#[N:10])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCCC1=O
Reactant: Clc1cccnc1Cl
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1ncccc1Cl
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 29.6 g of 2,3-dichloropyridine, 46.97 g of zinc cyanide, 11.56 g of tetratris(triphenylphosphine)palladium(0) and 150 mL of NMP was stirred at 100° C. for 2 hours. Water was added to the reaction mixture cooled to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 9.08 g of 3-chloropyridine-2-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=4)=[CH:15][C:8]=23)=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl>CCO.Cl>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([C:16]4[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=4)=[CH:15][C:8]=23)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc3c(Oc4ccc(Cl)cc4)cncc3s2)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2cc3c(Oc4ccc(Cl)cc4)cncc3s2)cc1
Reaction time: 22 h
Yield: 66.7 %

Procedure:
To a suspension of Example 272A (0.13 g, 0.34 mmol) in EtOH (3.5 mL), a solution of tin(II) chloride dihydrate (0.31 g, 1.36 mmol) in conc. HCl (0.68 mL) was slowly added. The reaction was stirred for 22 hours and partitioned between dichloromethane (75 mL) and 1 N NaOH (75 mL). The organic layer was washed with 1 N NaOH (1×50 mL), brine (1×50 mL), partially dried (Na2SO4), and concentrated to a colored solid (0.13 g). The desired product was crystallized from acetonitrile to yield colored crystals (0.08 g, 68%).
Reaction SMILES: [C:1]1([N:7]2[CH:16]=[C:15]3[C:9]([CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1(=O)[CH2:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.C(O)(=O)C>[CH:17]1([N:12]2[CH2:13][CH2:14][C:15]3=[CH:16][N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]3[CH2:10][CH2:11]2)[CH2:20][CH2:19][CH2:18]1
Reactant: c1ccc(-n2cc3c(n2)CCNCC3)cc1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(-n2cc3c(n2)CCN(C2CCC2)CC3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-phenyl-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (may be prepared as described in Description 46) (39 mg, 0.18 mmol) in dichloromethane (4 ml) was added 3 drops of acetic acid, cyclobutanone (28 μl, 0.36 mmol) and sodium triacetoxyborohydride (77 mg, 0.36 mmol). The resulting mixture was allowed to stir at room temperature for 1 hour. The resulting reaction mixture was acidified with 2M hydrochloric acid and applied to an pre equilibrated ion exchange cartridge (SCX), washed with methanol and then a 2M ammonia in methanol solution. The basic fractions were then evaporated in vacuo to afford the title product (E45); MS (ES+) m/e 268 [M+H]+ as a 95:5 mixture of the title compound and 7-cyclobutyl-2-phenyl-2,4,5,6,7,8-hexahydropyrazolo[3,4-c]azepine.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].O[CH:12]=[C:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=O>C(O)C>[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=2[CH:12]=[N:10]1
Reactant: O=C1CCCCC1=CO
Reactant: NNc1ccccc1Br
Agent: Cl
Solvent: CCO
Product: Brc1ccccc1-n1ncc2c1CCCC2

Procedure:
2-Bromophenylhydrazine hydrochloride (1.00 g, 4.47 mmol) was added to a solution of 2-(hydroxymethylene)cyclohexanone (0.564 g, 4.47 mmol) in ethanol (20 mL) and the resulting solution was refluxed 3 h before being concentrated. The crude material was taken up in DCM and washed with saturated ammonium chloride, 1N NaOH, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give 1-(2-bromophenyl)-4,5,6,7-tetrahydro-1H-indazole.
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:14]([O:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cccc([N+](=O)[O-])c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 2-hydroxy-3-nitrobenzoic acid (36.6 g) in N,N-dimethylformamide (500 mL) were added benzyl bromide (50.0 mL) and potassium carbonate (66.3 g), and the mixture was stirred overnight at 60° C. The reaction mixture was poured into water and the resulting mixture was extracted with a mixture of ethyl acetate and n-hexane (1:1). The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in a mixture of tetrahydrofuran (100 mL) and methanol (200 mL), and the resulting mixture was stirred for 30 minutes at 50° C. The reaction mixture was concentrated and the residue was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from isopropanol (50 mL)/n-hexane (200 mL) to give the title compound (31.99 g) having the following physical data.
Reaction SMILES: [N+]([C:4]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])([O-])=O.[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC(C)([O-])C.[K+]>CN(C)C=O>[CH2:15]([S:22][C:4]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: SCc1ccccc1
Reactant: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C)c1SCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 76.7 %

Procedure:
In a 5 1 pot was charged 483 g of methyl 2-nitro-3-methylbenzoate, 319 g benzyl mercaptan and 100 mL dimethyl formamide. Upon cooling to 0° C., a solution of 321 g potassium tert-butoxide in 1500 mL dimethyl formamide was added dropwise over 2.5 hours at 0°-5° C. The reaction mixture was stirred at 0° C. for 1.5 hours and then at room temperature overnight. The reaction was quenched by addition of 1 1 water and worked up by extraction with 2 1 methylene chloride. Upon washing with water (3×1 1), the methylene chloride layer was dried over MgSO4, filtered and rotovapped to give 517 g of crude methyl 2-benzylthio-3-methylbenzoate (77% yield) as a liquid.
Reaction SMILES: C[O:2][P:3]([CH2:19][CH:20]([C:25](=[O:36])[NH:26][C@H:27]([C:32](=[O:35])[NH:33][CH3:34])[CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:21][CH:22]([CH3:24])[CH3:23])([CH2:5][N:6]1[C:10](=[O:11])[CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]1=[O:18])=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:23][CH:22]([CH3:24])[CH2:21][CH:20]([C:25](=[O:36])[NH:26][C@H:27]([C:32](=[O:35])[NH:33][CH3:34])[CH2:28][CH:29]([CH3:30])[CH3:31])[CH2:19][P:3]([CH2:5][N:6]1[C:10](=[O:11])[CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]1=[O:18])(=[O:2])[OH:4]
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN1C(=O)C=C(c2ccccc2)C1=O)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(O)CN1C(=O)C=C(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
0.1 g of [(RS) -4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl][(2-phenylmaleimido)methyl]phosphinic acid methyl ester was dissolved in 1 ml of dichloromethane and 2 ml of trifluoroacetic acid were added. The mixture was stirred at room temperature for 2 hours and the solvent was then removed by evaporation. The residue was taken up in 30 ml of acetone/ dichloromethane (1:1) and the solution was evaporated to give 95 mg of [(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl) butyl]carbamoyl]pentyl][(2-phenylmaleimido)methyl]phosphinic acid in the form of a tan colored foam.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=O)(=[O:3])[CH3:2].[O-]CC.[K+].I[CH2:14][CH2:15][CH2:16][Si:17]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>C(O)C>[C:1]([NH:4][CH2:5][C:6]([CH2:14][CH2:15][CH2:16][Si:17]([O:18][CH2:19][CH3:20])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)NCC(=O)O
Reactant: CCO[Si](CCCI)(OCC)OCC
Agent: CC[O-]
Agent: [K+]
Solvent: CCO
Product: CCO[Si](CCCC(=O)CNC(C)=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25 %

Procedure:
A 5 L, 4-neck flask equipped with a heating mantle, a mechanical stirrer, a pot thermometer, an addition funnel, and a short Vigreux column with a distillation head connected to a nitrogen bubbler was charged with 2500 g of ethanol and 146.4 g of N-acetylglycine. This mixture was stirred at room temperature for 15 minutes. 110.5 g of potassium ethoxide were added while maintaining the pot temperature below 50° C. The mixture was heated to a pot temperature of 80° and 362.7 g of 3-iodopropyltriethoxysilane was added. Ethanol was removed by distillation until the pot temperature rose to 90° C. to 95° C. The reaction was followed by GC and heating continued for ˜100 hours until less than 10% of the 3-iodopropyltriethoxysilane remained. The flask and the contents were allowed to cool to room temperature and then filtered to give a clear to slightly hazy solution with 25-30% solids. A sample of solution was stripped of solvent at 120° C. and 1 mm vacuum to remove all solvents and unreacted starting materials. The product was purified by wiped film distillation at 190° C. at 0.5 mm. IR and NMR results were consistent with the target structure.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][CH2:17][C:18](N)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:21].[OH2:22]>CC(C)=O>[ClH:21].[ClH:21].[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][CH2:17][C:18]([OH:19])=[O:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)COCCN1CCN(Cc2ccccc2)CC1
Reactant: O
Agent: Cl
Solvent: CC(C)=O
Product: O=C(O)COCCN1CCN(Cc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
III.1.A. 13.9 g (0.05 mol) of 2-(4-benzyl-1-piperazinyl)ethoxyacetamide are dissolved in 15 ml of water in a 100 ml three-necked round-bottomed flask fitted with a water-cooled condenser and a mechanical stirrer. 31 ml (0.375 mol) of aqueous 37% hydrochloric acid solution are added. The mixture is heated at 60° C. for 1 hour. The water is removed on a rotary evaporator under reduced pressure at 60° C. The white solid obtained is taken up in 75 ml of acetone and is stirred for 1 hour at room temperature. The mixture is filtered and 19.7 g of 2-(4-benzyl-1-piperazinyl)ethoxyacetic acid dihydrochloride are obtained in the form of white crystals.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(OC(C)C)(=O)C.[F:18][C:19]([F:26])([F:25])[C:20](OCC)=[O:21]>CCCCCCC>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[NH:1][C:20](=[O:21])[C:19]([F:26])([F:25])[F:18]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NC1Cc2ccccc2C1
Solvent: CCCCCCC
Solvent: CC(=O)OC(C)C
Product: O=C(NC1Cc2ccccc2C1)C(F)(F)F
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
A 1 L, 3-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, cooling bath, and nitrogen inlet-outlet, was charged with 2-aminoindan, (104 g, 0.781 mole) and isopropyl acetate (200 mL) at 20-25° C. The solution was cooled to 0-5° C. Ethyl trifluoroacetate (133 g, 0.936 mol) was added over 40 minutes while maintaining the internal temperature at 0-10° C. (in a 0-5° C. bath). The thick slurry was stirred at 0-10° C. for 2 hours. The reaction mixture is warmed to 20-25° C. over 30 minutes and heptane (60 mL) was added. The slurry was stirred for 30 minutes and the solids were collected by filtration over a polypropylene filter paper in a Büchner funnel with suction. The filter cake was washed with 0.003% (w/v) Stadis-450 (4.5 mg Lot # 200 Dolder)/heptane (3×50 mL) or until the filtrate was colorless. The solids were dried at 60-65° C. under vacuum (10-30 torr) with nitrogen bleeding to obtain 149.2 g (83.4% yield) of N-(2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide as a beige white solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCCN1CCOCC1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCCN2CCOCC2)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (65 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and 4-(2-chloroethyl)morpholine (136 mg, 0.73 mmol) in order. The mixture was stirred at room temperature for 8 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (8% methanol/chloroform) to give the subject compound (34 mg, yield 18%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1.[C:15](#[N:18])[CH:16]=[CH2:17]>COCCOC>[C:15]([CH2:16][CH2:17][N:2]([CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)[CH3:1])#[N:18]
Reactant: CNCCCc1c[nH]c2ccccc12
Reactant: C=CC#N
Solvent: COCCOC
Product: CN(CCC#N)CCCc1c[nH]c2ccccc12
Reaction time: 2 h

Procedure:
A mixture of 37.6 g N-methyl-3-(3-indolyl)-propylamine and 21, 2 g acrylonitrile in 65 ml anhydrous 1,2-dimethoxyethane are warmed with stirring at 60°0 for 21/2 hours. N-(2-cyanoethyl-N-methyl-3-(3-indolyl)propylamine (M.pt 48°-49° after crystallization from isopropyl ether) is obtained after working up.