Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C@@H:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH2:18][C:19]3([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:20][CH2:21][CH:22]=2)=[CH:11][CH:10]=1)[C:6]#[C:7][CH3:8].O1CCCC1.[OH-].[Na+].Cl>CO>[CH2:18]1[C:19]2([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[CH2:20][CH2:21][CH:22]=[C:17]1[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C@@H:5]([C:6]#[C:7][CH3:8])[CH2:4][C:3]([OH:28])=[O:2])=[CH:10][CH:11]=1
Reactant: CC#C[C@@H](CC(=O)OC)c1ccc(OCC2=CCCC3(CCCCC3)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#C[C@@H](CC(=O)O)c1ccc(OCC2=CCCC3(CCCCC3)C2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 97.5 %

Procedure:
To a solution of (S)-3-[4-(spiro[5.5]undec-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acid methyl ester (0.82 g) obtained in Step 8 in a mixed solvent of tetrahydrofuran (4 mL)-methanol (4 mL) was added 2N aqueous sodium hydroxide solution (2 mL), followed by stirring the reaction mixture at room temperature for 14 hours. Then, after addition of 1N aqueous hydrochloric acid solution, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:1) to give (S)-3-[4-(spiro[5.5]undec-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acid (0.77 g) as the desired compound.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=3)[C:18]([O:20]CC)=[O:19])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:26]=[CH:27][CH:28]=[CH:29][C:4]=2[NH:3]1.[OH-].[Na+].Cl>C1COCC1.O>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=3)[C:18]([OH:20])=[O:19])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:26]=[CH:27][CH:28]=[CH:29][C:4]=2[NH:3]1
Reactant: CCOC(=O)c1cccc(N2CCC(N3CCc4ccccc4NC3=O)CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(N2CCC(N3CCc4ccccc4NC3=O)CC2)c1
Temperature: 25 °C

Procedure:
650 mg (1.65 mmol) ethyl 3-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-benzoate, 10 mL THF, 2 mL water and 2 mL (8.00 mmol) of an aqueous 4M sodium hydroxide solution were stirred at RT until the reaction was complete. Then the THF was eliminated i. vac. The aqueous residue was acidified with a 4M hydrochloric acid solution. After several hours' stirring at RT the precipitate was suction filtered and dried.
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][C:27]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:25]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(=O)[O-])(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:5][CH2:9][CH:10]([NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][C:27]=2[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:25]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cn1ncc(-c2ccccc2)c1-c1csc(C(=O)NC(Cc2ccccc2)CN(C(=O)[O-])C(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1ncc(-c2ccccc2)c1-c1csc(C(=O)NC(CN)Cc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
A solution of 1,1-dimethylethyl[2-({[4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (crude from part c) in TFA-DCM (3 mL, 1:2) was stirred at 25° C. After 30 min, the solution was concentrated and the residue neutralized through a silica plug (4% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
Reaction SMILES: C(O[K])(C)(C)C.[CH2:7]([O:9][C:10](=[N:12][OH:13])[CH3:11])[CH3:8].F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22]>CN(C=O)C>[CH2:7]([O:9][C:10](=[N:12][O:13][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22])[CH3:11])[CH3:8]
Reactant: Fc1ccccc1C(F)(F)F
Reactant: CCOC(C)=NO
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Product: CCOC(C)=NOc1ccccc1C(F)(F)F
Temperature: 25 °C
Yield: 88.8 %

Procedure:
Prepared using a procedure adapted from Miyazawa et al. (Miyazawa, E.; et al. Org. Prep. Proced. Int. 1997, 29, 594-600) tBuOK (0.78 g, 6.7 mmol) was added to a stirring solution of ethyl-N-hydroxyacetimidate (1.00 g, 6.06 mmol) in anhydrous DMF (6 mL) at 0° C. under an Ar atmosphere. After tBuOK addition was completed the reaction was stirred at room temperature. After 30 min 2-fluorobenzotrifluoride (1.29 mL, 6.06 mmol) was added and the reaction was heated at 80° C. for 2 h. Upon cooling the reaction mixture was diluted with ice water (100 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (2×50 mL), dried with MgSO4, and concentrated to afford a dark oil. Flash chromatographic purification over silica (10% EtOAc in hexanes) afforded 15 as a clear liquid (1.33 g, 89%). 1H-NMR (500 MHz, CDCl3) δ 1.36 (t, J=7.1 Hz, 3H), 2.15 (s, 3H), 4.20 (q, J=7.1 Hz, 2H), 6.99 (apparent t, J=7.5 Hz, 1H), 7.47 (apparent dt, J=7.9 Hz, 1H), 7.52-7.57 (m, 2H); 13C-NMR (125 MHz, CDCl3) δ 14.3, 14.5, 63.2, 114.2, 116.2 (q, JC-F=31 Hz), 120.3, 123.7 (q, JC-F=272 Hz), 126.4 (q, JC-F=4.8 Hz), 133.2, 157.2 (q, JC-F=1.9 Hz), 167.1; LC-MS 248 m/z[MH]+, C11H13F3NO2 requires 248.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][O:35][CH2:36][CH2:37][NH:38][CH2:39][CH3:40]>>[CH2:39]([N:38]([CH2:37][CH2:36][O:35][CH3:34])[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1)[CH3:40]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(Cl)nc3)nc12
Reactant: CCNCCOC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCN(CCOC)c1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cn1

Procedure:
From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide with cesium carbonate and N-(2-methoxyethyl)ethylamine. ES-MS m/e (%): 472 (M+H+, 100).
Reaction SMILES: [C:1]1(=O)[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[NH:3][C:2]1=[O:14])[N:10]=[CH:9][CH:8]=[CH:7]3.[NH2:16][NH2:17]>O>[N:16](=[C:1]1[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[NH:3][C:2]1=[O:14])[N:10]=[CH:9][CH:8]=[CH:7]3)[NH2:17]
Reactant: NN
Reactant: O=C1Nc2ccc3ncccc3c2C1=O
Solvent: O
Product: NN=C1C(=O)Nc2ccc3ncccc3c21
Temperature: 100 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
3-H-Pyrrolo[3,2-f]quinoline-1,2-dione (3.89 g, 19.6 mmol) was combined with 12.0 mL of anhydrous hydrazine and 10.25 mL of water and heated at 100° C. under a condenser and nitrogen atmosphere, with stirring, for 1 hr. The reaction occasionally foamed into the condenser and heat was removed as needed to allow foaming to subside. The reaction was cooled and poured into 200 mL of water. The product was collected by filtration and dried under vacuum at 55° C. to give 2.86 g (69%) of 1-hydrazono-1,3-dihydropyrrolo[3,2-f]quinoline-2-one as a brown solid. Mass spectrum (positive ion electrospray): m/z=213. NMR (DMSO-d6): δ7.37 (d, J=8.8 Hz, 1H), 7.47 (dd, J=8.4, 4.2 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 8.71 (dd, J=4.2, 1.6 Hz, 1H), 8.80 (d, J=8.4 Hz, 1H), 9.90 (br d, J=14.7 Hz, 1H), 10.89 (br d, J=14.7 Hz, 1H), 10.95 (br s, 1H).
Reaction SMILES: [CH3:1][C@:2]12[CH2:18][CH2:17][C:16]3[C:15]4[CH:14]=[CH:13][C:12]([OH:19])=[CH:11][C:10]=4[CH:9]=[CH:8][C:7]=3[C@@H:6]1[CH2:5][CH:4]=[CH:3]2.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(OCC)(=O)C>[C:26]([O:19][C:12]1[CH:13]=[CH:14][C:15]2[C:16]3[CH2:17][CH2:18][C@@:2]4([CH3:1])[C@@H:6]([CH2:5][CH:4]=[CH:3]4)[C:7]=3[CH:8]=[CH:9][C:10]=2[CH:11]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@]12C=CC[C@H]1c1ccc3cc(O)ccc3c1CC2
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc2c3c(ccc2c1)[C@@H]1CC=C[C@@]1(C)CC3

Procedure:
A solution of estra-1,3,5(10),6,8,16-hexaen-3-ol Q8, 148.8 mg, 0.5944 mmol) in anh. pyridine (2.0 ml, 25 mmol) and acetic anhydride (0.28 ml, 3.0 mmol) was stirred 6 h, after which ethyl acetate (20 ml) was added. See FIG. 159. The mixture was washed with three 10 ml portions of 1 N hydrochloric acid+10 ml of saturated sodium bicarbonate+10 ml of brine, dried over sodium sulfate, and filtered. The residue was washed with 5 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Recrystallization from 95% ethanol gave lustrous white platelets (99.4 mg, 0.340 mmol, 55%, m.p. 9596° C. TLC (2% ethyl acetate/hazanes on silica gel) showed product (Rf 0.1) contained a trace contaminant at the origin.
Reaction SMILES: C(OC([N:8]1[CH:17]([CH3:18])[CH2:16][C:15]2[C:14]([O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[N:25]([C:29](=[O:40])[NH:30][C:31]3[NH:32][N:33]=[C:34]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:35]=3)[CH:24]=[CH:23]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:36]([C:34]1[CH:35]=[C:31]([NH:30][C:29]([N:25]2[C:26]3[C:22](=[CH:21][C:20]([O:19][C:14]4[C:15]5[CH2:16][CH:17]([CH3:18])[NH:8][CH2:9][C:10]=5[N:11]=[CH:12][N:13]=4)=[CH:28][CH:27]=3)[CH:23]=[CH:24]2)=[O:40])[NH:32][N:33]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC1Cc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(C(C)(C)C)n[nH]3)c2)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1Cc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(C(C)(C)C)n[nH]3)c2)CN1

Procedure:
A solution of 4-[1-(5-tert-butyl-2H-pyrazol-3-ylcarbamoyl)-1H-indol-5-yloxy]-6-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (300 mg, 0.55 mmol), DCM (5 mL), and TFA (5 mL) is stirred at it for 2 h. At that point the solution is concentrated and the residue separated via semi-prep HPLC (C18; 10-100% I/H2O with 0.1% NH4OH) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.CCN(CC)CC.[CH3:20][C@H:21]1[CH2:26][O:25][CH2:24][CH2:23][NH:22]1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][C@@H:21]2[CH3:20])[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: C[C@H]1COCCN1
Reactant: Clc1nc(Cl)c2c(n1)CCCS2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1SCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a solution of 2,4-dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine (500 mg, 2.26 mmol) and Et3N (457 mg, 4.52 mmol) in DMF (5.0 mL) at 0° C. was added 3-(S)-methylmorpholine (252 mg, 2.49 mmol) dropwise. The reaction was stirred overnight at rt, then the solvent removed under vacuum to give a residue which was partitioned between water and ethyl acetate. The organic layer was separated, dried and concentrated to give the crude product which was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1) to give 2-chloro-7,8-dihydro-4-((S)-3-methylmorpholino)-6H-thiopyrano[3,2-d]pyrimidine (380 mg, 87%) as a light yellow solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[N:10]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[N:8][C:7]=1[CH2:30]O.CN(C=O)C>ClCCl>[Cl:3][CH2:30][C:7]1[N:8]=[CH:9][N:10]([C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[CH3:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CO)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of thionyl chloride (1.3 ml) in dry dichloromethane (10 ml) was added over 5 min. to a stirred suspension of 5-methyl-1-(triphenylmethyl)-1H-imidazole-4-methanol (5.0 g) in a mixture of dichloromethane (100 ml) and dry DMF (2 ml) at 0°. The mixture was stirred at 0° for 30 min. and washed consecutively with 8% sodium bicarbonate (2×50 ml), water (50 ml), dried and evaporated in vacuo below 40° to give an oil (5 g). This was dissolved in ether (100 ml) and the resulting solution was filtered through a pad of silica which was further eluted with ether (2×100 ml). The combined filtrates were evaporated below 40° to give a foam which was triturated with cold hexane and filtered to give the title compound (4.2 g) as a solid, m.p. 133°-135°.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8]Cl)[N:7]=1.Cl.[CH3:11][NH:12][O:13][CH3:14].CCN(C(C)C)C(C)C>C1COCC1>[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][N:12]([CH3:11])[O:13][CH3:14])[N:7]=1
Reactant: CNOC
Reactant: Nc1nc(CCl)cs1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CON(C)Cc1csc(N)n1
Temperature: 60 °C

Procedure:
A mixture of 2-amino-4-chloromethyl-thiazole hydrochloride (27.8 g, 0.15 mol), N,O-dimethylhydroxylamine hydrochloride (87.8 g, 0.90 mol), and anhydrous THF (300 mL) was rapidly stirred and DIPEA (157 mL, 0.90 mol) was added. The resulting mixture was heated at 60° C. for 10-15 hours. The mixture was cooled in an ice/salt bath and the solid byproduct (DIPEA hydrochloride) was removed by filtration and washed with cold THF (300 mL). The combined filtrate was concentrated to afford the N-(2-amino-thiazol-4-ylmethyl)-O,N-dimethyl-hydroxylamine as a dark oil (31 g, >100% theory), which partially crystallized on standing. This product was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][NH:6]1.[CH3:15][C:16]([CH3:18])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.[OH-].[Na+]>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][N:6]1[CH:16]([CH3:18])[CH3:15]
Reactant: CC(C)=O
Reactant: COC(=O)CC1NCc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: COC(=O)CC1c2ccccc2CN1C(C)C
Reaction time: 6 h

Procedure:
To the compound obtained from Step A (0.50 g, 2.61 mmol) in dichloroethane (46 mL) was added acetone (1.76 mL, 24.01 mmol) and sodium triacetoxyborohydride (2.48 g., 11.74 mmol). After 6 hours, the mixture was diluted with 1.0N NaOH (100 mL), and the organic portion was separated. The aqueous layer was extracted with DCM (3×100 mL). The combined DCM extracts were dried (MgSO4) and concentrated to dryness to afford about 0.60 g (99%). EIS-MS 235 [M+1].
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([C:13]3[N:17]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH:25]=4)[C:23]#[N:24])[O:15][N:14]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[C:30](Cl)(=[O:32])[CH3:31].CCN(CC)CC>C(Cl)Cl>[C:23]([C:22]1[CH:25]=[C:18]([C:16]2[O:15][N:14]=[C:13]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH2:10][CH2:11][CH2:12][C@H:3]4[NH:2][C:30](=[O:32])[CH3:31])[N:17]=2)[CH:19]=[CH:20][C:21]=1[O:26][CH:27]([CH3:29])[CH3:28])#[N:24]
Reactant: CC(=O)Cl
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4N)no2)cc1C#N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H]1CCCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Reaction time: 1 h
Yield: 54.3 %

Procedure:
Prepared using General Procedure 4: To a stirring solution of (R)-5-(3-(5-amino-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile HCl 3 (20 mg, 0.05 mmol) in DCM (0.5 mL) were added acetyl chloride (7 μL, 0.10 mmol) and NEt3 (14 μL, 0.10 mmol). After stirring for 1 h, the solvent was evaporated and the residue was purified by preparative HPLC to provide 11.3 mg (56%) of (R)-N-(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide 21. LCMS-ESI (m/z) calculated for C24H24N4O3: 416.5; found 417.2 [M+H]+, tR=3.56 min. 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J=2.2 Hz, 1H), 8.32 (dd, J=8.9, 2.2 Hz, 1H), 7.92 (dd, J=7.7, 1.2 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.33 (t, J=7.7 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 5.83 (d, J=8.6 Hz, 1H), 5.36-5.21 (m, 1H), 4.79 (hept, J=6.0 Hz, 1H), 3.16 (dt, J=17.9, 6.0 Hz, 1H), 3.03 (dt, J=18.2, 6.3 Hz, 1H), 2.10-1.99 (m, 4H), 1.97-1.79 (m, 3H), 1.47 (d, J=6.1 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][CH:23]=[C:24]([CH2:26][C:27]([NH:29][CH:30]([CH3:32])[CH3:31])=[O:28])[N:25]=2)=[N:10]1.C1C(=O)N([Br:40])C(=O)C1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:40])[NH:12][C:11]([C:21]2[S:22][CH:23]=[C:24]([CH2:26][C:27]([NH:29][CH:30]([CH3:31])[CH3:32])=[O:28])[N:25]=2)=[N:10]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2nc(CC(=O)NC(C)C)cs2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CBr)NC(c2nc(CC(=O)NC(C)C)cs2)=NC1c1ccc(F)cc1Br
Yield: 49.8 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-2-(4-(2-(isopropylamino)-2-oxoethyl)thiazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate (1.05 g, 2 mmol) was reacted with NBS (0.39 g, 2.2 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.6 g, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH2:23][CH2:22][C@H:21]([CH3:24])[NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>C(Cl)Cl.O1CCOCC1>[CH3:24][C@@H:21]1[NH:20][C:16]2[N:17]=[CH:18][N:19]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:15]=2[CH2:23][CH2:22]1.[ClH:25]
Reactant: C[C@H]1CCc2c(ncnc2N2CCN(C(=O)OC(C)(C)C)CC2)N1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H]1CCc2c(ncnc2N2CCNCC2)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (7S)-4-(7-Methyl-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (32 mg, 0.096 mmol) in DCM (2 mL) was added HCl in dioxane (4M, 2 mL). The mixture was stirred at room temperature for 3 hours. The solvent was removed to give (7S)-7-Methyl-4-piperazin-1-yl-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine as HCl salt (22 mg, 99%). MS (APCI+) [M+H]+234.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:16].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:13]1[C:14]2[C:9](=[C:8]3[C:3](=[C:2]([O:1][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:15]=2)[CH2:4][CH2:5][CH2:6][C:7]3=[O:16])[CH2:10][CH2:11][CH2:12]1
Reactant: CCOC(=O)CBr
Reactant: O=C1CCCc2c(O)cc3c(c21)CCCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cc2c(c3c1CCCC3=O)CCCC2

Procedure:
40.44 g (0.19 mol) of the compound from Example 6 is heated to reflux with 38.64 g (0.23 mol) of ethyl bromoacetate and 31.97 g (0.23 mol) of potassium carbonate in 190 ml of butanone for 5 h. After cooling, the precipitate is filtered off and washed well with acetone and the solution is evaporated. The residue is taken up in 100 ml of CH2Cl2, shaken 3 times with 50 ml of 10% strength NaOH solution each time, dried over Na2SO4 and evaporated. The residue is dried in a high vacuum.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].C(=O)([O-])[O-].[K+].[K+].[OH:21][C:22]1([CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.O>CN(C)C=O>[OH:21][C:22]1([CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](=[O:8])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:24][CH2:23]1
Reactant: O=C(CCCCCBr)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC1(O)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCC1(O)CCN(CCCCCC(=O)c2ccccc2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
6-Bromo-1-phenyl-1-hexanone (2.9 g) and potassium carbonate (3 g) were added to a solution of 4-hydroxy-4-tert-butoxycarbonylaminomethylpiperidine (2.5 g) in dimethylformamide (40 ml), and the mixture was stirred at 60° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give 3.74 g of 4-hydroxy-1-(6-oxo-6-phenylhexyl)-4-tert-butoxycarbonylaminomethylpiperidine.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C@@H:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH2:9][CH2:8][C:7]=2[CH:20]=1)=[O:2].CC(C)([O-])C.[K+].[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br.O>CN(C=O)C>[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C@H:10]2[CH2:9][CH2:8][C:7]3[CH:20]=[C:3]([CH:1]=[O:2])[CH:4]=[CH:5][C:6]=3[O:11]2)=[CH:14][CH:15]=1
Reactant: O=Cc1ccc2c(c1)CC[C@H](Cc1ccc(O)cc1)O2
Reactant: Fc1cccc(CBr)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc2c(c1)CC[C@H](Cc1ccc(OCc3cccc(F)c3)cc1)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3,4-dihydro-6-formyl-2-(4-hydroxybenzyl)-2H-benzopyran (1.8 g, 6.7 mmol) in DMF (10 ml) at 0° C. was added potassium tert-butoxide (0.83 g, 7.4 mmol). After 30 minutes m-fluorobenzyl bromide (0.91 ml), 7.4 mmol) was added and the resulting slurry was warmed to room temperature and stirred for 2 hours. Water was added and the precipitate was collected, washed with water and air dried (2.5 g).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([NH:20][CH2:21][CH3:22])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:23]>CO>[NH2:23][C:2]1[C:11]2[N:12]=[C:13]([NH:20][CH2:21][CH3:22])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCNc1nc2c(Cl)nc3ccccc3c2n1CC(C)(C)O
Reactant: N
Solvent: CO
Product: CCNc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O
Temperature: 150 °C

Procedure:
1-[4-Chloro-2-(ethylamino)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (2.49 g, 7.81 mmol) and ammonia (70 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated overnight in an oven at 150° C. An analysis by HPLC indicated the presence of starting material, and additional ammonia in methanol (10 mL) was added. The reaction was heated for four hours at 150° C. and cooled to ambient temperature. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (eluting with 2-2.5% methanol in dichloromethane with 1% ammonium hydroxide added.) A portion of the product was recrystallized from methanol, isolated by filtration, and washed with cold methanol to provide 496 mg of 1-[4-amino-2-(ethylamino)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as white needles, mp 233-235° C.
Reaction SMILES: [C:1]([S:4][CH2:5]/[C:6](=[CH:10]\[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)/[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>>[O:9]=[C:7]([NH:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])/[C:6](/[CH2:5][S:4][C:1](=[O:3])[CH3:2])=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: CC(=O)SC/C(=C\c1ccccc1)C(=O)O
Product: CC(=O)SC/C(=C\c1ccccc1)C(=O)NCCC(=O)OCc1ccccc1
Yield: 78 %

Procedure:
The (Z)-2-acetylthiomethyl-3-phenylpropenoic acid described in Example 1 (step B) is coupled with benzyl β-alaninate according to the experimental procedure described in Example 1 (step D). Yield: 78% (after recrystallization in ether) m.p. 80° C. IR: 3380, 1720, 1670, 1630, 1600 cm-1 1H NMR (CDCl3): 7.60 (s, 1H); 7.45 to 7.15 (m, 10H); 6.90 (broad t, 1H; 5.15 (s, 2H); 3.95 (s, 2H); 3.65 (q. app., J:6.1 Hz); 2.65 (t, 2H, J=6.1 Hz); 2.35 (s, 3H). Microanalysis: C22H23NO4S Calc. % C=60.48 H=5.83 N=3.52 Found. % C=66.29 H=5.78 N=3.51