Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]#[N:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[C:13]([N:21]=[C:22]=[O:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:11]([C:3]1[C:2]([NH:1][C:22]([NH:21][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:23])=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1)#[N:12]
Reactant: N#Cc1cc2c(cc1N)OCO2
Reactant: O=C=NC(=O)c1ccccc1
Product: N#Cc1cc2c(cc1NC(=O)NC(=O)c1ccccc1)OCO2

Procedure:
Prepared as in Example 53a from 6-aminobenzo[d][1,3]dioxole-5-carbonitrile and benzoyl isocyanate as a yellow solid (157 mg, 82%). 1H NMR (400 MHz, DMSO-d6) δ 6.19 (s, 2H), 7.42 (s, 1H), 7.54 (t, J=8 Hz, 2H), 7.66 (t, J=7.6 Hz, 1H), 7.74 (s, 1H), 8.03 (d, J=9.2 Hz, 2H), 11.32 (d, J=12.8 Hz, 2H). MS 309 (MH+).
Reaction SMILES: CO[C:3]([CH:5]1[CH2:10][C:9]([C:26]#[N:27])([C:11]2[C:19]3[C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[O:16][C:15]=3[C:14]([O:24][CH3:25])=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6]1=O)=[O:4].Cl.[C:30]([NH2:33])(=[NH:32])[CH3:31].C[O-].[Na+]>CO>[CH3:25][O:24][C:14]1[C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[C:19]=2[C:11]([C:9]2([C:26]#[N:27])[CH2:8][CH2:7][C:6]3[N:32]=[C:30]([CH3:31])[NH:33][C:3](=[O:4])[C:5]=3[CH2:10]2)=[CH:12][CH:13]=1
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC)c3oc4ccccc4c23)CCC1=O
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C2(C#N)CCc3nc(C)[nH]c(=O)c3C2)c2c1oc1ccccc12
Temperature: 65 °C
Reaction time: 18 h

Procedure:
To a mixture of the compound obtained in example 1 (200 mg, 0.53 mol), acetamidine HCl (124.5 mg, 1.32 mmol) and sodium methoxide (98.3 mg, 1.85 mmol) in 7 ml of methanol was stirred at 60-70° C. for 18 hrs under nitrogen atmosphere. Once the reaction is complete, the reaction mass was evaporated under vacuum and the residue was diluted with ethyl acetate and water. The organic layer was washed with water followed by brine, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography to get 200 mg (40% yields) of the solid product. MP-more than 300° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:21][N:5]2[C:6](=[O:20])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)[CH2:8][C@@H:4]2[CH2:3]1.[C:22]1([CH2:28][S:29](Cl)(=[O:31])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(CC)CC>ClCCl>[O:20]=[C:6]1[N:5]2[CH2:21][C@H:2]([NH:1][S:29]([CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:31])=[O:30])[CH2:3][C@H:4]2[CH2:8][N:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:17])[F:18])=[CH:11][CH:10]=1
Reactant: N[C@@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@@H](NS(=O)(=O)Cc3ccccc3)CN12
Reaction time: 12 h
Yield: 66.5 %

Procedure:
(6R,7aS)-6-Amino-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (example 1, step h) (100 mg, 0.33 mmol), phenylmethanesulfonyl chloride (125 mg, 0.66 mmol) and Et3N (0.1 g, 0.99 mmol) were added to dichloromethane (3 mL), and the mixture was stirred for 12 hours. The mixture was directly purified by prep-TLC (DCM/MeOH=30:1) to yield 100 mg (67%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.58-7.55 (m, 2H), 7.43-7.40 (m, 5H), 7.20-7.17 (m, 2H), 4.40-4.37 (m, 1H), 4.29 (s, 2H), 4.05-3.97 (m, 4H), 3.68-3.62 (m, 1H), 2.85-2.81 (m, 1H), 2.11-2.07 (m, 1H), 1.78-1.72 (m, 1H); LC-MS: 456.1 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH:13](I)([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:13]([O:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5])([CH3:15])[CH3:14]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc([N+](=O)[O-])cc1C=O
Temperature: 95 °C
Yield: 89.2 %

Procedure:
To commercially available 2-hydroxy-5-nitrobenzaldehyde (500 mg, 3.0 mmol) in DMF (10 mL) in a sealable tube was added isopropyl iodide (1.02 g, 6.0 mmol) and potassium carbonate (1.7 g, 12 mmol). The tube was sealed and heated to 95° C. overnight. After cooling to rt, the reaction was diluted with ethyl acetate. The layers were separated, and the organic layer was washed with brine, then concentrated and purified via silica gel chromatography (10-20% ethyl acetate/hexane) to provide 8A (560 mg, 89%). 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (d, J=6.15 Hz, 6H) 4.69-4.96 (m, 1H) 7.10 (d, J=9.23 Hz, 1H) 8.40 (dd, J=9.23, 3.08 Hz, 1H) 8.70 (d, J=3.08 Hz, 1H) 10.46 (s, 1H).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([NH2:12])=[C:8]([NH2:13])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:14]([C:16]1[C:17]([CH3:39])=[CH:18][C:19]([CH3:38])=[C:20]([CH:37]=1)[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].CN(C=O)C>O>[CH3:38][C:19]1[CH:18]=[C:17]([CH3:39])[C:16]([C:14]2[NH:12][C:9]3[CH:10]=[N:11][C:6]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:7][C:8]=3[N:13]=2)=[CH:37][C:20]=1[C:21]([N:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:22]
Reactant: Nc1cnc(N2CCCC2)cc1N
Reactant: Cc1cc(C)c(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1C=O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(-c2nc3cc(N4CCCC4)ncc3[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 100 °C
Yield: 13.3 %

Procedure:
To a 100 mL round bottom flask was added 6-(pyrrolidin-1-yl)pyridine-3,4-diamine (compound 20.2, 641 mg, 3.60 mmol, 1.0 equiv), 4-(1-(5-formyl-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile (compound 16.4, 1.25 g, 3.60 mmol, 1.0 equiv), sodium metabisulfite (890 mg, 4.68 mmol, 1.3 equiv) and DMF (36 mL). The mixture was heated at 100° C. under air for 22 hours then allowed to cool to room temperature. Water (80 mL) was added slowly to the stirred solution until no further product precipitated. The solids were filtered and washed with water (2×15 mL) and dried to a brown solid (1.42 g). Additional product precipitated from the filtrate upon standing which was filtered and washed with water (2×10 mL) to obtain an off white solid (241 mg). The above reaction was repeated a second time in the exact manner and quantities as described to yield additional product (1.26 g of brown solid upon initial precipitation, plus 288 mg of off white solid from additional precipitation). The aqueous filtrates from the two reactions were combined and aqueous NaHCO3 was added to adjust the pH to 7. The aqueous was extracted with DCM/2% MeOH (300 mL), dried (Na2SO4), filtered and evaporated to obtain a brown solid (547 mg). All products obtained were combined and purified by silica gel chromatography (DCM/MeOH) to obtain the title compound as a yellow solid (2.37 g, 65% based on the theoretical yield for the two reactions). m/z (ES+) 505.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.41 (br s, 1H), 8.52 (s, 1H), 7.77 (d, J=8.2 Hz, 2H), 7.66 & 7.56 (2 br singlets, amide rotamers, ArH, 1H), 7.49 (s, J=8.2 Hz, 2H), 7.29 (s, 1H), 6.31 (br s, 1H), 4.79-4.67 (m, 1H), 3.54-3.34 (m, 5H), 3.17 (app t, J=11.8, 1H), 2.99-2.82 (m, 2H), 2.63 (s, 3H), 2.33 & 2.24 (2 singlets, amide rotamers, ArCH3, 3H), 2.03-1.87 (m, 5H), 1.82-1.38 (m, 3H). Elemental analysis (C31H32N6O.1.3H2O, 528.04), found (calcd), C, 70.66 (70.51); H, 6.54 (6.60); N, 15.78 (15.92).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][C:8]1([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:17][O:16][C:14]([C:8]1([CH2:7][C:6]([OH:18])=[O:5])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)=[O:15]
Reactant: COC(=O)C1(CC(=O)OC(C)(C)C)CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1(CC(=O)O)CCOCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 104.5 %

Procedure:
To a solution of methyl 4-(2-tert-butoxy-2-oxoethyl)tetrahydro-2H-pyran-4-carboxylate (1.1 g, 4.26 mmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (5.0 mL) and the resulting solution was stirred at rt for 5 h. The mixture was concentrated under reduced pressure to afford [4-(methoxycarbonyl)tetrahydro-2H-pyran-4-yl]acetic acid (900 mg, 94%), which was used in the next step without further purification. LC-MS ret. time 0.93 min, m/z 202.9 (MH+); 1H NMR (300 MHz, DMSO-d6), 1.60-1.70 (m, 2H), 2.10-2.15 (m, 2H), 2.68 (s, 2H), 3.62-3.71 (m, 2H), 3.72 (s, 3H), 3.79-3.86 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([Cl:18])[CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:3]1.[OH-:19].[Na+:20]>O.O1CCOCC1>[NH2:3][C:4]1[C:5]([Cl:18])=[CH:6][CH:7]=[C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]=1[CH2:10][C:2]([O-:19])=[O:1].[Na+:20]
Reactant: O=C1Cc2c(Oc3ccccc3)ccc(Cl)c2N1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1c(Cl)ccc(Oc2ccccc2)c1CC(=O)[O-]
Yield: 37.1 %

Procedure:
A mixture of 2-oxo-4-phenoxy-7-chloroindoline (4.2 g) and sodium hydroxide (1.3 g) in water (40 ml) and dioxane (10 ml) was refluxed for 24 hrs. After cooling, the reaction mixture was filtered, and the filtrate was evaporated in vacuo. The residue was dissolved in ethanol under heating, and the solution was filtered. The filtrate was allowed to stand under ice-cooling, and the precipitating crystals were collected by filtration, washed with ethanol and dried to give sodium 2-(2-amino-3-chloro-6-phenoxyphenyl)acetate (1.8 g). The same product (2.3 g) was obtained from the mother liquid. Total yield 4.1 g. mp>240° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([S:8](Cl)(=[O:10])=[O:9])[C:4]([CH3:12])=[N:3]1.[C:13]1([CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:29][C:30]4[S:31][C:32]([CH2:35][NH2:36])=[CH:33][N:34]=4)[CH:25]=3)[O:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>O1CCCC1>[C:13]1([CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:29][C:30]4[S:31][C:32]([CH2:35][NH:36][S:8]([C:5]5[C:4]([CH3:12])=[N:3][N:2]([CH3:1])[C:6]=5[CH3:7])(=[O:10])=[O:9])=[CH:33][N:34]=4)[CH:25]=3)[O:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1cnc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)s1
Reactant: Cc1nn(C)c(C)c1S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(C)c1S(=O)(=O)NCc1cnc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)s1
Temperature: 40 °C

Procedure:
33 mg of 1,3,5-trimethyl-1H-pyrazole-4-sulfonic acid chloride (0.16 mmol, 1.2 eq) were weighted into a reaction tube and dissolved in dry tetrahydrofuran (1 ml). 44 mg of [2-(2-phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]amine (0.13 mmol) in dry tetrahydrofuran (3 ml) and 30 mg triethylamine (0.3 mmol, 2.3 eq) were added, the tube was flushed with argon, closed with a screw cap, and shaken over night at 40° C. 0.008 ml of tris-(2-aminoethyl)amine in 0.5 ml tetrahydrofuran were added, the mixture was shaken for 2 h at room temperature and then evaporated. The residue was dissolved in 2 ml of a mixture of dimethylformamide/trifluoroacetic acid (19:1), filtered, and submitted to preparative reversed phase HPLC purification (water/acetonitrile gradient (+0.1% trifluoroacetic acid)). 1,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid [2-(2-phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide was obtained as a white solid (42 mg, 63%).
Reaction SMILES: [C:1](=[O:26])([O:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](I)[CH:20]=2)[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(B(O)O)C=CC=CC=1>>[C:1](=[O:26])([O:2][C:3]([CH3:6])([CH3:5])[CH3:4])[O:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:11]=[C:10]([C:19]2[CH:20]=[C:21]([C:38]3[CH:39]=[CH:40][C:35]([O:34][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:36][CH:37]=3)[CH:22]=[CH:23][CH:24]=2)[CH:9]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2cccc(I)c2)nn1-c1ccccn1
Agent: OB(O)c1ccccc1
Product: CC(C)(C)OC(=O)Oc1cc(-c2cccc(-c3ccc(OCc4ccccc4)cc3)c2)nn1-c1ccccn1
Yield: 99 %

Procedure:
The title compound was prepared in the same manner as in Example C-1, except that an equimolar amount of each of 3-(3-iodophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl tert-butyl carbonate (23) prepared in Example B-4 and 4-benzyloxyphenylboronic acid (manufactured by Aldrich) was used in place of Compound 21 prepared in Example B-2 and phenylboronic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[C:3]=1[CH:12]=[CH2:13].[CH3:14][CH:15]([NH2:18])[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(O)C>[F:1][C:2]1[C:3]([CH:12]=[CH2:13])=[C:4]([NH:18][CH:15]([CH3:14])[CH:16]=[CH2:17])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C=Cc1c(F)ccc([N+](=O)[O-])c1F
Reactant: C=CC(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Product: C=Cc1c(F)ccc([N+](=O)[O-])c1NC(C)C=C
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 1,3-difluoro-4-nitro-2-vinylbenzene (150 mg, 0.81 mmol) in DMF (3 mL) was added a mixture of 1-methylallylamine in ethanol (0.4 mL). Potassium carbonate (0.224 g, 1.62 mmol) was added and the mixture stirred at RT for 1 h. A further portion of 1-methylallylamine in ethanol (0.3 mL) was added and stirring was continued for 1 h, and then the reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 2-6% EtOAc in cyclohexane) affording the title compound as a yellow oil (134 mg, 70%). 1H NMR (CDCl3, 300 MHz): 8.06 (1H, dd J=9.4, 5.7 Hz), 7.23 (1H, bs), 6.62 (1H, t, J=9.3 Hz), 6.48 (1H, dd, J=18.0, 11.6 Hz), 5.81-5.62 (2H, m), 5.64 (1H, dt, J=11.6, 1.3 Hz), 5.12-5.00 (2H, m), 4.38-4.25 (1H, m), 1.27 (3H, d, J=6.6 Hz)
Reaction SMILES: [Cr](O)(O)(=O)=O.[CH3:6][C:7]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19])([CH3:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH2:23]>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:14][C:7]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]([OH:23])=[O:19])([CH3:6])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O
Reactant: CCCCCCC(C)(C)c1cccc(C=O)c1
Agent: O=[Cr](=O)(O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCCCCCC(C)(C)c1cccc(C(=O)O)c1
Reaction time: 0.03 h
Yield: 99 %

Procedure:
Chromic acid (105.4 mg, 1.05 mmol, 1.2 eq) was dissolved in acetic acid (2 ml), and a solution of 3-(1,1-dimethylheptyl)benzaldehyde (205 mg, 0.878 mmol) in acetic acid (2 ml) was added to the solution under ice-cooling, which was followed by stirring for 2 minutes. The mixture was further stirred at room temperature for 30 minutes. Conc. sulfuric acid (2 drops) was added, and the mixture was stirred for 3 hours. To this reaction mixture, water (10 ml) was added, and the mixture was extracted twice with ethyl acetate (10 ml). The organic layers were combined, washed with saturated brine (20 ml), and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane/ethyl acetate=2/1) to give 3-(1,1-dimethylheptyl)benzoic acid (205 mg, 99.0%).
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:26]2[C:25]3[CH:24]=[CH:23][C:22]([Br:27])=[CH:21][C:20]=3[N:19]=[C:18]([NH2:28])[C:17]=2[N:16]=[C:15]1[CH2:29][O:30][CH2:31][CH3:32].C(N(CC)CC)C>C(Cl)(Cl)Cl>[NH2:28][C:18]1[C:17]2[N:16]=[C:15]([CH2:29][O:30][CH2:31][CH3:32])[N:14]([CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[C:26]=2[C:25]2[CH:24]=[CH:23][C:22]([Br:27])=[CH:21][C:20]=2[N:19]=1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCN
Reactant: O=C(Cl)C1CCCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCNC(=O)C1CCCC1
Reaction time: 2.5 h
Yield: 64.2 %

Procedure:
Cyclopentanecarbonyl chloride (0.80 mL, 6.6 mmol) was added dropwise over a period of five minutes to a suspension of 1-(4-aminobutyl)-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.1 mmol) and triethylamine (0.78 mL, 5.6 mmol) in chloroform (200 mL). The reaction was stirred for 2.5 hours and then stored for three days in a refrigerator. Additional cyclopentanecarbonyl chloride (0.18 mL) was added, and the reaction was stirred for 30 minutes and treated as described for Examples 558–583. The crude product was recrystallized from isopropanol (13 mL/g), isolated by filtration, and dried overnight on the filter funnel to provide 1.60 g of N-{4-[4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}cyclopentanecarboxamide as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[C:10]([CH:11]([F:13])[F:12])=[CH:9][C:8]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)=[N:7][C:6]=12.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>>[F:12][CH:11]([F:13])[C:10]1[N:5]2[N:4]=[CH:3][C:2]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[C:6]2[N:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:9]=1
Reactant: C#C[Si](C)(C)C
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc2c(Br)cnn12
Product: C[Si](C)(C)C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Yield: 88.5 %

Procedure:
Prepared from 3-bromo-7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (18.6 g, 45 mmol) and commercially available trimethylsilylacetylene (11.1 mL, 80 mmol) as described in example C.1, step 3a to give 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-3-trimethylsilanylethynyl-pyrazolo[1,5-a]pyrimidine (16.3 g, 99%) as an orange-solid. MS (ISP) 410.1[(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.[ClH:11]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:11])=[CH:5][CH:4]=1
Reactant: Cl
Reactant: COc1ccc(CO)cc1
Product: COc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Methoxybenzylalcohol (50 g, 0.36 mol) (Aldrich) was added dropwise to 100 mL of conc. HCl and stirred vigorously for 2 h at rt. The reaction mixture was extracted four times with Et2O, the Et2O extracts were combined, washed with brine, dried (Na2SO4), and concentrated. The yellow oil was distilled at 70°-73° C. (0.2 mmHg) to give 52 g (93%) as a colorless oil: 1H NMR (CDCl3) d 3.85 (s, 3H, OCH3), 4.62 (s, 2H, CH2Cl), 6.91-6.93 (d, 2H, J=8 Hz, ArH), 7.38-7.40 (d, 2H, J=8 Hz, ArH) ; MS(FD) 156(M+).
Reaction SMILES: [C:1]1([C@H:7]([CH3:11])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:15])=O>>[C:1]1([C@H:7]([CH3:11])[C:8]([Cl:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@H](C(=O)O)c1ccccc1
Product: C[C@H](C(=O)Cl)c1ccccc1

Procedure:
Stir a solution of (S)-2-phenylpropanoic acid (300 mg, 2.0 mmol) in 5 mL of oxalyl chloride for 3 hours at room temperature. After removal of solvent under vacuum, (S)-2-phenylpropanoyl chloride is obtained as pole yellow oil. Dissolve the oil in 10 mL of CH2Cl2. Add (1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-(3-hydroxyphenyl)bicyclo[3.2.1]octan-3-ol (400 mg, 1.45 mmol) and Et3N (293 mg, 2.9 mmol) to the solution. Stir the resultant mixture at room temperature for additional 3 hours. After addition of 20 mL of water, basify the mixture with K2CO3 to pH=10, and extract the aqueous mixture with EtOAc (20 mL×3). The combined organic layers are washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purify the residue by silica gel chromatography (CH2Cl2:MeOH=30:1) to afford (S)-3-((1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-hydroxybicyclo[3.2.1]octan-3-yl)phenyl 2-phenylpropanoate (500 mg, 84.7%; MS (m/z): 408 (M+1)) as yellow oil. Stir (S)-3-((1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-hydroxybicyclo[3.2.1]octan-3-yl)phenyl 2-phenylpropanoate (250 mg, 0.61 mmol) with H2O (11 mg, 0.61 mmol) and TMSCl (66 mg, 0.61 mmol) in 2-butanone (5 mL) for 3 hours. Collect the precipitate by filtration to afford (S)-3-((1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-hydroxybicyclo[3.2.1]octan-3-yl)phenyl 2-phenylpropanoate hydrochlorid (215 mg, Yield: 79.3%) as white solid. The absolute configuration of its hydrochloride salt form was confirmed by x-ray analysis. 1H NMR (400 MHz, DMSO) δ 9.81 (br, 1H), 7.31-7.41 (m, 7H), 7.14 (s, 1H), 6.87-6.90 (m, 1H), 5.01 (s, 1H), 4.08-4.10 (m, 1H), 3.02-3.08 (m, 1H), 2.42-2.58 (m, 4H), 2.12-2.26 (m, 6H), 1.90-1.99 (m, 2H), 1.75-1.80 (m, 2H), 1.51-1.59 (m, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[CH:21]=[C:20]([N:22]([CH3:24])[CH3:23])[N:19]=[C:18]([S:25][CH3:26])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[CH:21]=[C:20]([N:22]([CH3:23])[CH3:24])[N:19]=[C:18]([S:25]([CH3:26])=[O:35])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(Nc2cccc(OCc3ccccc3)c2)cc(N(C)C)n1
Solvent: ClCCl
Product: CN(C)c1cc(Nc2cccc(OCc3ccccc3)c2)nc(S(C)=O)n1
Yield: 69 %

Procedure:
A solution of N4-[3-(benzyloxy)phenyl]-N6,N6-dimethyl-2-(methylsulfanyl)-4,6-pyrimidinediamine (5.5 g, 15 mmol) and m-chloroperbenzoic acid (5.19 g) in CH2Cl2 at 0° C. was stirred for 1 hour. The reaction mixture was slowly brought to room temperature and quenched with a solution of sodium sulfite. The organic layer was separated and washed with NaHCO3 solution (3×250 mL), dried over anhydrous MgSO4, concentrated, and purified by column chromatography [eluent: chloroform/methanol (94:6)], giving N4-[3-(benzyloxy)phenyl]-N6,N6-dimethyl-2-(methylsulfinyl)-4,6-pyrimidinediamine (3.98, 69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>C(O)C.[OH-].[Na+]>[C:12]([C:11](=[CH:19][C:18]1[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=1)[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)#[N:13]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(C#N)=Cc2ccc(Cl)cc2)cc1OC
Yield: 79.7 %

Procedure:
A mixture of 3,4-dimethyoxyphenylacetonitrile (1.77 g, 10.0 mmol, purchased from Tokyo Kasei,) and 4-chlorobenzaldehyde (1.4 g, 10.0 mmol, purchased from Tokyo Kasei) in 5 ml of ethanol was heated to dissolve. Two drops of 20% aqueous sodium hydroxide solution was then added and the reaction mixture was stirred over night. The resultant reaction mass was crushed in ethanol. The precipitate was Collected and washed with ethanol then with hexane, and dried to give 2.39 g (yield: 79.7%) of α-cyano-3,4-dimethoxy-4'-chlorostilbene as a greenish yellow crystalline.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH2:14])=O)[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][S:16][CH2:17][C:3]1=2.S(Cl)(Cl)=O>CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]#[N:14])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][S:16][CH2:17][C:3]1=2
Reactant: NC(=O)c1ccc2nc3c(c(=O)n2c1)CSC3
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc2nc3c(c(=O)n2c1)CSC3
Temperature: 70 °C

Procedure:
A mixture of 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxamide (2.9 g., 0.012 mol) and thionyl chloride (1.5 ml) in dimethylformamide (30 ml) is heated at 70° C. for 4 hours. The reaction mixture is cooled in an ice bath. The product, which precipitates, is filtered off and washed with water. Recrystallization from methanol gives a crystalline product (1.6 g.), mp 256°-257° C.