Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]2)[N:4]=[CH:3]1.C(O)(C(F)(F)F)=O.[Br:28][C:29]1C(Cl)=[C:31]([N+:36]([O-:38])=[O:37])[C:32]([NH2:35])=[N:33][CH:34]=1>C(Cl)Cl>[Br:28][C:29]1[C:14]([N:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:5]3[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=3)[CH2:13][CH2:12]2)=[C:31]([N+:36]([O-:38])=[O:37])[C:32]([NH2:35])=[N:33][CH:34]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: Cn1cnc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cnc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)c1
Reaction time: 1 h
Yield: 51.1 %

Procedure:
tert-Butyl 4-((1-methyl-1H-imidazol-4-yl)methyl)piperazine-1-carboxylate (0.130 g, 0.46 mmol, 1.1 eq) was dissolved in DCM (1.45 mL) and the mixture cooled in a ice-water bath before the dropwise addition of TFA (1.45 mL). Stirring was continued at this temperature for 1 h. The solvents were removed in vacuo, the resulting crude material was azeotroped with toluene and dried. The resulting 1-((1-methyl-1H-imidazol-4-yl)methyl)piperazine (supposedly 0.083 g, 0.46 mmol, 1 eq) was suspended in iPrOH (1.4 mL) and DIPEA (0.35 mL). To this solution, 5-bromo-4-chloro-3-nitropyridin-2-amine (0.100 g, 0.42 mmol, 1 eq) was added and the mixture heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.085 g, 47%); 1H-NMR (500 MHz, DMSO-d6): δ 2.50-2.58 (br s, 4H, piperazine N(CH2)2), 3.03 (m, 4H, piperazine N(CH2)2), 3.39 (s, 2H, NCH2), 3.60 (s, 3H, imidazole Me), 6.95 (s) and 6.97 (s), (3H, NH2 and 6-H), 7.46 (s, 1H), 8.14 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): Rt=1.25 min—396/398 [(M+H+), Br isotopic pattern, 100%].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1.FC(F)(F)C(O)=[O:36].[OH-].[Na+].O>C(Cl)Cl>[CH3:25][C:23]1[CH:24]=[C:19]([O:18][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH2:14][CH:15]([OH:36])[CH2:17][OH:16])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[N:21][C:22]=1[CH3:26]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1OCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1OCC(O)CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
3-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-5,6-dimethyl-[2,2′]bipyridine (compound 341) (95 mg) was dissolved in methylene chloride (2 ml) to prepare a solution which was then brought to 0° C. Trifluoroacetic acid (1 ml) was added to the solution, the mixture was stirred at 0° C. for 30 min, and the mixture was then stirred at room temperature for 5 hr. The reaction solution was brought to 0° C., was stirred, and was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added thereto, the mixture was extracted with chloroform, and the chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (63 mg, yield 64%).
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[CH3:15])[CH:8]=[CH:7][CH:6]=1)(=O)C.[Cl-].[Al+3].[Cl-].[Cl-].O.Cl.[C:22](OCC)(=[O:24])[CH3:23]>>[OH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[CH3:15])[CH:8]=[CH:7][C:6]=1[C:22](=[O:24])[CH3:23]
Reactant: CC(=O)Oc1cccc2cccc(C)c12
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(=O)c1ccc2cccc(C)c2c1O

Procedure:
13 g of 8-methyl-1-naphthyl acetate and 13.8 g of aluminum chloride were reacted at 140° C. for 4 hours. Water, concentrated hydrochloric acid and ethyl acetate were added to the reaction mixture to dissolve all solid matters, followed by extraction with ethyl acetate. The organic phase was washed with a saturated saline solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (7% ethyl acetate/hexane) to obtain 5.5 g of the captioned compound as a yellow oily substance.
Reaction SMILES: CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.[CH2:59]([C:62]1[C:71]([O:72][CH3:73])=[CH:70][CH:69]=[C:68]2[C:63]=1[CH2:64][CH2:65][C:66]([CH3:76])([CH3:75])[C:67]2=[O:74])[CH:60]=[CH2:61].C(O)(C)(C)C.S([O-])([O-])=O.[Na+].[Na+].[OH2:88]>>[OH:88][CH:60]([CH2:61][OH:22])[CH2:59][C:62]1[C:71]([O:72][CH3:73])=[CH:70][CH:69]=[C:68]2[C:63]=1[CH2:64][CH2:65][C:66]([CH3:76])([CH3:75])[C:67]2=[O:74]
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: O
Reactant: C=CCc1c(OC)ccc2c1CCC(C)(C)C2=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: COc1ccc2c(c1CC(O)CO)CCC(C)(C)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.47 g of AD-mix-β was added to a mixture consisting of 1.09 g of 5-allyl-6-methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one, 17 ml of tert-butanol, and 17 ml of water. The obtained mixture was stirred at room temperature overnight. Thereafter, 5.37 g of sodium sulfite was added to the reaction solution, and the obtained mixture was stirred for 35 minutes, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the reaction solution was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol), so as to obtain 1.25 g of the subject compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:33])[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: O=C1NC(=S)NC12CC(c1ccccc1)Oc1ccc(Br)cc12
Yield: 66.8 %

Procedure:
A suspension of 6-bromo-2-phenylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (1.12 g, 3 mmol) and Lawesson's Reagent (1.21 g, 3 mmol) in dry 1,4-dioxane (25 mL) was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (780 mg, 67%). 1H-NMR (CDCl3): 2.26 (dd, 1H), 2.43 (dd, 1H), 5.76 (dd, 1H), 6.84 (m, 2H), 7.32-7.36 (m, 6H), 8.22 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C([N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32])(=O)C>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[N:7][C:2]([N:27]4[CH2:31][CH2:30][NH:29][C:28]4=[O:32])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)nn3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCNC4=O)nn3)CC2)c(C)c1
Yield: 12.2 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 230 and 1-acetylimidazolidin-2-one (87 mg) and by the reaction and treatment in the same manner as in Example 638, the title compound (21 mg) was obtained.
Reaction SMILES: [C:1]1([C:7]2OC(S)=[N:9][N:8]=2)C=CC=CC=1.[C:13]([OH:21])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-:22].[Na+].Cl>O>[O:22]1[CH:1]=[C:7]([C:19]2[C:14]([C:13]([OH:21])=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:8]=[N:9]1
Reactant: Sc1nnc(-c2ccccc2)o1
Reactant: [OH-]
Reactant: O=C(O)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccccc1-c1conn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of phenyl-1,3,4-oxadiazole-2-thiol and a benzoic acid in water was added NaOH. After stirring at RT for 16 h, the reaction mixtures pH was adjusted to 2 upon addition of aqueous solution of HCl (10%). The precipitate was collected by filtration. The solid was dissolved in acetone and purified by MPLC (30-70% ethyl acetate in hexanes) to afford the corresponding oxadiazol-benzoic acid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:24]2[C:25]3=[C:26]4[C:21](=[CH:22][CH:23]=2)[CH:20]=[CH:19][CH:18]=[C:17]4[CH:16]=[CH:15][C:14]3=[CH:13][CH:12]=1.[Br:27]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:27][C:18]1[C:17]2[C:26]3=[C:25]4[C:14](=[CH:15][CH:16]=2)[CH:13]=[CH:12][C:11]([C:2]2[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=2)=[C:24]4[CH:23]=[CH:22][C:21]3=[CH:20][CH:19]=1
Reactant: c1ccc2cc(-c3ccc4ccc5cccc6ccc3c4c56)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2ccc3c(-c4ccc5ccccc5c4)ccc4ccc1c2c43
Temperature: 50 °C
Reaction time: 7.5 h
Yield: 21.5 %

Procedure:
Next, a mixed solution of 7.5 g of 1-(2-naphthyl)pyrene, 4.1 g of N-bromosuccinimide and 115 ml of dimethylformamide was heated with stirring under a nitrogen gas flow at 50° C. for 7.5 hours. After cooling the solution to room temperature, 100 ml of water was injected, followed by stirring at room temperature for 0.5 hours. The precipitated solid was collected by filtration, washed twice with 100 ml of water and then washed twice with 100 ml of methanol. The solid was washed three times with 50 ml of 1,2-dimethoxyethane and then vacuum-dried to obtain 2.0 g of 1-bromo-6-(2-naphthyl)pyrene.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:38]=[CH:37][C:8]([CH2:9][NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([C:28]([NH:30][CH2:31][C:32](O)=[O:33])=[O:29])=[CH:26][CH:25]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[CH2:39]([S:42]([NH2:45])(=[O:44])=[O:43])[CH:40]=[CH2:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:4][C:5]1[CH:38]=[CH:37][C:8]([CH2:9][NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C:19]([F:20])([F:21])[F:22])[N:14]=[C:13]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([C:28]([NH:30][CH2:31][C:32]([NH:45][S:42]([CH2:39][CH:40]=[CH2:41])(=[O:44])=[O:43])=[O:33])=[O:29])=[CH:26][CH:25]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCS(N)(=O)=O
Reactant: C=CCOc1ccc(CNc2nc(Nc3ccc(C(=O)NCC(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCOc1ccc(CNc2nc(Nc3ccc(C(=O)NCC(=O)NS(=O)(=O)CC=C)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
To a solution of 2-(4-(4-(4-(allyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)acetic acid (50 mg, 0.09 mmol) in DMF (2 mL) was added prop-2-ene-1-sulfonamide (17 mg, 0.14 mmol), HATU (71 mg, 0.19 mol) and iPr2NEt (66 uL, 0.38 mmol). The mixture was stirred at r.t. for 16 hours before all the solvents were removed under vacuum. All solvents were removed under vacuum and the residue was purified by silica gel column (MeOH/DCM=5% to 10%) to give 4-(4-(4-(allyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-N-(2-(allylsulfonamido)-2-oxoethyl)benzamide (53 mg, 89%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>N1C=CC=CC=1>[C:10]1([S:16]([O:1][CH2:2][C:3]([CH2:8][O:9][S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])([CH2:6][O:7][S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])[CH2:4][O:5][S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: OCC(CO)(CO)CO
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(OCC(COS(=O)(=O)c1ccccc1)(COS(=O)(=O)c1ccccc1)COS(=O)(=O)c1ccccc1)c1ccccc1
Temperature: 3 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
2.27 g (16.7 mmol) of pentaerythritol and 32.6 g of pyridine were placed in a 100 ml reaction vessel and 17.7 g (100 mmol) of benzenesulfonyl chloride was dropped over 0.7 hour while stirring at a temperature of 2 to 4° C. in a nitrogen atmosphere. After dropping, the temperature was raised to 15° C. and reaction was conducted for 4 hours. In a separate 300 ml reaction vessel, the reaction solution was dropped in an 11.3% by weight aqueous solution of hydrochloric acid while stirring at a temperature of 10 to 23° C. After dropping, the water phase was separated. The crystal precipitated by dissolving the oily matter by heating in 48 g of a mixed solution of acetone:methanol (weight ratio 3:1) and then concentrating was separated by filtration, washed and dried under reduced pressure to obtain 9.08 g of 2,2-bis(benzenesulfonyloxymethyl)-1,3-propanediol dibenzenesulfonate (yield: 78.0% [based on pentaerythritol]).
Reaction SMILES: [CH:1]#[C:2][CH2:3][NH:4][C@H:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6]1.[C:14]([OH:26])(=[O:25])[CH2:15][C:16]([CH2:21][C:22]([OH:24])=[O:23])([C:18]([OH:20])=[O:19])[OH:17]>>[CH:1]#[C:2][CH2:3][NH:4][C@H:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6]1.[C:14]([O-:26])(=[O:25])[CH2:15][C:16]([CH2:21][C:22]([O-:24])=[O:23])([C:18]([O-:20])=[O:19])[OH:17]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: C#CCN[C@@H]1CCc2ccccc21
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
The experiments conducted in this example are listed below in Table 2. In each of the experiments, rasagiline free base, excipient, and citric acid were combined and mixed in the corresponding solvent. A solid dispersion was prepared from the mixture by rotary evaporation of the solvent at conditions listed in Table 2 below.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1)[CH2:3][OH:4].[CH3:11][I:12]>CO>[I-:12].[CH3:11][N+:9]1[CH:8]=[CH:7][N:6]=[C:5]([CH:2]([OH:1])[CH2:3][OH:4])[CH:10]=1
Reactant: OCC(O)c1cnccn1
Reactant: CI
Solvent: CO
Product: C[n+]1ccnc(C(O)CO)c1
Product: [I-]

Procedure:
2.8 g of 2-(1,2-dihydroxyethyl) pyrazine (2100) was dissolved in 20 ml of methanol, 10 ml of methyl iodide added and the solution refluxed for 3 days. The solvent was then removed, the residue taken up in 100 ml of water and washed with chloroform. The aqueous solution was concentrated and purified by gel permeation chromatography (Biogel P-2/water). Freeze-drying yielded 3.7 g product (2200) which was recrystallized from ethyl acetate/ethanol, m.p. 105°-6°. UV H2O Max: 227 (4.13), 281 (3.83).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=NC1CCCCC1)=NC1CCCCC1.N1(O)C2C=CC=CC=2N=N1.[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48](O)[CH2:47]2>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:10]([O:12][C@@H:48]1[CH:49]2[CH2:52][CH2:53][N:46]([CH2:51][CH2:50]2)[CH2:47]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COc1ccc(C(NC(=O)OC(C)(C)C)C(=O)O[C@H]2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.7 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-(4-methoxyphenyl)acetic acid (I43) (1.39 g, 4.94 mmol) in dry THF (60 ml), were added N,N′-methanediylidenedicyclohexanamine (1.22 g, 5.94 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (802 mg, 5.94 mmol), and (R)-quinuclidin-3-ol (755 mg, 5.94 mmol). The reaction was stirred at RT for 15 hours, and the solvent was evaporated. The residue was taken up with DCM, the insoluble solid was filtered off, and the organic solution was washed twice with aq. Na2CO3 and then brine, dried over Na2SO4 and evaporated. The crude was purified by flash chromatography (DCM/MeOH=95/5 to 93/7) to obtain (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-(4-methoxyphenyl)acetate (630 mg; 33% yield).
Reaction SMILES: [C:1]1(=O)[CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+].[CH3:11][C:12]1([CH3:20])[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[O:13]1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[C:1]1(=[C:15]2[C:16](=[O:18])[O:17][C:12]([CH3:20])([CH3:11])[O:13][C:14]2=[O:19])[CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C1CCC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC1(C)OC(=O)C(=C2CCC2)C(=O)O1
Temperature: 50 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
Cyclobutanone (0.50 g, 7.1 mmol) (Aldrich, Cat. #C96001) was added to a mixture of ammonium acetate (1.1 g, 14 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (1.0 g, 7.1 mmol) (Acros Organics, Cat. #19845) in toluene (10 mL), followed by acetic acid (1.0 mL). The reaction mixture was stirred at 50° C. for 4 h. After cooled to r.t., the mixture was diluted with water, and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-30%) to afford the desired product (0.68, 48%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:2]1.C([Li])CCC.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1>C1COCC1.C([O-])(O)=O.[Na+].CCOC(C)=O>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]([C:2]2[S:1][CH:5]=[CH:4][C:3]=2[CH2:6][CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[OH:24])=[CH:21][CH:20]=1
Reactant: c1cc(CCN2CCCC2)cs1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1ccc(F)cc1)c1sccc1CCN1CCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 21.1 %

Procedure:
A solution of 1-(2-(thiophen-3-yl)ethyl)pyrrolidine (1.0 g, 5.5 mmol) in THF (11.0 mL) was cooled to −78° C. in a dry-ice acetone bath before dropwise addition of n-butyllithium solution (2.5 M in hexanes, 2.4 mL, 6.0 mmol). The reaction mixture was stirred at −78° C. for 1 h and then neat p-fluorobenzaldehyde (0.65 mL, 6.1 mmol) was added dropwise via syringe. The mixture was allowed to warm to room temperature over 16 h and subsequently diluted with saturated aqueous NaHCO3 and EtOAc. The organic layer was separated, washed with brine, and dried over Na2SO4. The residue remaining after solvent removal in vacuo was purified by flash chromatography to afford the desired alkylation product as a white solid (353 mg, 1.16 mmol, 21% yield). MS (M+H)+ 306.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40].CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][C:2]1([CH3:9])[O:6][C@@H:5]([CH2:7][O:8][N:30]2[C:31](=[O:40])[C:32]3=[CH:39][CH:38]=[CH:37][CH:36]=[C:33]3[C:34]2=[O:35])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@H](CO)O1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](CON2C(=O)c3ccccc3C2=O)O1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-2,2-dimethyl-1,3-dioxolane-4-methanol (27 g, 0.2 mol), triphenylphosphine (53.5 g, 0.2 mol) and N-hydroxyphthalimide (33.3 g, 0.2 mol) in dry tetrahydrofuran (500 ml) cooled to 0° C. was added diethylazodicarboxylate (38.5 g, 0.22 mol). After stirring for 18 hours at 20° C. the originally dark red solution turned pale yellow and was then evaporated to dryness under reduced pressure. The residue was loaded onto a silica column in chloroform and eluted with hexane-acetone (3:1), yielding (R)-N-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)phthalimide as white plates (31.2 g, 55%), m.p. 100°-2° C. [α]D20 =+15.6° (C 0.98 in methanol); 1R: υmax (nujol) 1790, 1770, 1720, 1600 cm-1 ; 1H NMR: δH (CDCl3), 1.35 (3H, s, CH3), 1.41 (3H, s, CH3), 3.97 (1H, q, J=5.5, 8.8 Hz, CH2ON/CH2OC), 4.17 (2H, m, 1H of CH2ON+1H of CH2OC), 4.32 (1H, q, J=5.5, 10.0 Hz, CH2ON/CH2OC), 4.50 (1H, m, CH), 7.74-7.87 (4H, m, aromatic); m/z 262 (M+-CH3, 50%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH:15]([CH3:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18].C(N(CC)CC)C>CN(C=O)C>[CH3:20][O:19][C:17](=[O:18])[CH2:16][CH:15]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=2)[CH2:6][CH2:5]1)[CH3:21]
Reactant: COC(=O)CC(C)Br
Reactant: Oc1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CC(C)N1CCN(c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To a mixture of 4-piperazin-1-yl-phenol (2 g, 11.2 mmol) and methyl 3-bromo-butyrate (2.03 g, 11.2 mmol) in DMF (5 mL) was added triethylamine (4.5 mL, 11.53 mmol) dropwise and the reaction mixture was stirred at ambient temperature overnight. The mixture was poured onto water and extracted with ethyl acetate (50 ml×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and evaporated under vacuum to dryness. The residue was purified by silica gel flash chromatography (1% methanol in CH2Cl2) to furnish the title compound (1.85 g, 59.3%); MS; m/z 279 (M+H).
Reaction SMILES: [C:1]1([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][NH:13][C:8]=1[CH:7]=[CH:6]2.[H-].[Na+].[CH2:18](Br)[CH:19]1[O:23][CH2:22][CH2:21][CH2:20]1.Cl>CC(C)=O.CN(C)C=O>[O:23]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:18][N:13]1[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[C:1]([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=3)[C:9]=2[CH:11]=[CH:12]1
Reactant: BrCC1CCCO1
Reactant: Nc1nc(N)c2c(ccc3[nH]ccc32)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: Nc1nc(N)c2c(ccc3c2ccn3CC2CCCO2)n1
Reaction time: 24 h

Procedure:
In a manner similar to that of Example 2, 3.98 g. of 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in ca. 260 ml. dry dimethylformamide are reacted with 1.06 g. ca. 50% sodium hydride-mineral oil dispersion and then with 3.63 g. tetrahydrofurfuryl bromide. After stirring the mixture at ca. 25° for 24 hours, 0.21 g. ca. 50% sodium hydride-mineral oil dispersion are added. Stirring is continued for one-hour, 0.73 g. tetrahydrofurfuryl bromide is added, and, after stirring for 6 hours, the reaction mixture is kept at ca. 25° for ca. 70 hours. Processing of the reaction mixture in the manner described in Example 2 (Method A) yields a brown gum which is dissolved in 40 ml. N hydrochloric acid. Dilution of the aqueous acidic solution with 40 ml. acetone gives crystals that are collected and twice recrystallized from methanol-acetone to yield 1.20 g. title compound as a monohydrochloride salt bearing one-third molecule of water per molecule of diamine salt, m.p. 310°-311° (dec.).