Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13]([F:19])=[C:12]([Cl:20])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]N1C(C)(C)CCCC1(C)C.CC1(C)CCCC(C)(C)N1.[Li]CCCC.[CH:53](=[O:56])[CH2:54][CH3:55]>C1COCC1>[NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([CH:53]([OH:56])[CH2:54][CH3:55])[C:13]([F:19])=[C:12]([Cl:20])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC=O
Reactant: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(Cl)c(F)cc12
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: C1CCOC1
Product: CCC(O)c1c(F)c(Cl)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 103.3 %

Procedure:
A −40° C. solution of 2-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg, 0.274 mmol) in THF (10 mL) was treated with LTMP (1.10 mmol, freshly prepared by mixing 2,2,6,6-Tetramethyl piperidine and n-BuLi at 0° C. for 30 min.). The mixture was then allowed to warm to 0° C. for 2 h. The reaction mixture was cooled to −30° C. and propionaldehyde (159 mg, 2.74 mmol) was added. The reaction was stirred at −30° C. for 2 h before it was slowly quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc and the organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography to afford 2-anilino-7-chloro-6-fluoro-5-(1-hydroxypropyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (120 mg, 97%) as a white solid: LCMS RT: 3.14 min, MH+: 424.2. Other electrophiles such as disulfide may be used to quench the anion.
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([N:42]=[C:43]=[S:44])=[O:41]>C1(C)C=CC=CC=1.C(O)C>[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([N:42]=[C:43]=[S:44])=[O:41].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:43]([NH:42][C:40](=[O:41])[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[F:33])=[S:44])=[CH:28][CH:27]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccccc1F
Agent: O=C(N=C=S)c1ccccc1F
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccccc4F)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
2-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-fluoro-1-benzenecarbonyl isothiocyanate (50 μl) in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (43 mg, yield 53%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[S:13][C:14]([C:16]([N:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])[CH3:19])=[O:17])=[CH:15][C:11]=3[CH2:10][CH2:9][O:8][C:7]=2[CH:27]=1.CCN(C(C)C)C(C)C.[CH2:37]([N:39]=[C:40]=[O:41])[CH3:38].[Cl-].[NH4+]>C1COCC1>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:18]([CH3:19])[C:16]([C:14]1[S:13][C:12]2[C:6]3[CH:5]=[CH:4][C:3]([NH:2][C:40]([NH:39][CH2:37][CH3:38])=[O:41])=[CH:27][C:7]=3[O:8][CH2:9][CH2:10][C:11]=2[CH:15]=1)=[O:17]
Reactant: CCN=C=O
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(N)cc1OCC2)c1ccccc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Temperature: 40 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
To a solution of 8-amino-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide HCl salt (0.25 g, 0.593 mmol) in anhydrous THF (15 mL) was added DIPEA (0.52 mL, 2.97 mmol) and ethyl isocyanate (0.1 g, 1.4 mmol). The solution was stirred at 40° C. overnight. The reaction mixture was poured into ammonium chloride aqueous solution and extracted with EtOAc. The organic phase was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated to the crude product, which was purified by preparative TLC to afford about 0.113 g of 166 (isolated yield: 42%). 1H NMR (DMSO-d6, 400 MHz): δ 8.56 (s, 1H), 7.64-7.58 (m, 2H), 7.49 (t, J=3.6 Hz, 2H), 7.22 (d, J=4.4 Hz, 1H), 7.15 (d, J=2.4 Hz, 1H), 6.92 (dd, J=2.0, 8.4 Hz, 1H), 6.44 (s, 1H), 6.13 (t, J=5.6 Hz, 1H), 4.09 (d, J=4.4 Hz, 2H), 3.22 (s, 3H), 3.06 (dd, J=6.0, 7.2 Hz, 2H), 2.85 (s, 2H), 1.01 (t, J=7.2 Hz, 3H). MS: (ESI+) 456.1
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:6]2)[CH2:3][CH2:2]1.C[O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Br)[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C(C)C>[CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:29][C:25]4[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=4)[C:22]([OH:31])=[O:21])[CH2:16][CH2:15]3)=[CH:6]2)[CH2:2][CH2:3]1
Reactant: c1ccc2c(c1)c(C1CCNCC1)cn2CC1CC1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: O=C(O)c1cccc(CN2CCC(c3cn(CC4CC4)c4ccccc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in Example 157 (part D) starting with 1.5 g (6 mmol) of 1-cyclopropylmethyl-3-piperidin-4-yl-1H-indole, 1.8 g (7.8 mmol) of 3-bromomethyl-benzoic acid methyl ester, 1.2 g (9 mmol) of potassium carbonate and 0.9 g (4.5 mmol) of potassium iodide in 25 mL of iso-butylmethylketone. The crude mixture was purified by flash chromatography over silica gel affording 0.63 g (27% of yield) of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH2:12][N:13]1C(=O)C3=CC=CC=C3C1=O)[CH2:7]2.O.NN>C(O)C>[NH2:13][CH2:12][CH:6]1[CH2:5][CH2:4][C:3]2[C:2]([OH:1])=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:7]1
Reactant: O=C1c2ccccc2C(=O)N1CC1CCc2c(O)cccc2C1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCC1CCc2c(O)cccc2C1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
A solution of N-[(1,2,3,4-tetrahydro-5-hydroxy-2-naphthyl)methyl]phthalimide (634 mg) and hydrazine monohydrate (309 mg) in ethanol (14 ml) was refluxed for 3 hours, cooled to room temperature, and evaporated in vacuo. The residue was chromatographed (methylene chloride-methanol) over basic alumina to afford 6-(aminomethyl)-5,6,7,8-tetrahydro-1-naphthol (281 mg) as a colorless powder. mp: 183°-192° C.
Reaction SMILES: C[O-].[Na+].Cl.[F:5][CH2:6][C:7]([NH2:9])=[NH:8].[C:10](OCC)(=[O:17])[CH2:11][C:12](OCC)=[O:13]>CO>[F:5][CH2:6][C:7]1[N:9]=[C:12]([OH:13])[CH:11]=[C:10]([OH:17])[N:8]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N=C(N)CF
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Oc1cc(O)nc(CF)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of fluoroacetonitrile (11 g) in ethanol (10.9 mL)-diethyl ether (186 mL) was bubbled with hydrogen chloride under ice-cooling until the solution was saturated with hydrogen chloride with stirring, and the mixture was stirred at the same temperature for 4 hours. The precipitated crystals were collected by filtration. The collected crystals were washed with diethyl ether, and dried under reduced pressure to give ethyl 2-fluoroacetimidate hydrochloride (24.9 g). This material was suspended in ethanol (50 mL). To the suspension was added ethanol (130 mL) containing ammonia (about 5 g), and the mixture was stirred at room temperature overnight. The crystals were collected by filtration. The collected crystals were washed with diethyl ether, and dried under reduced pressure to give 2-fluoroacetamidine hydrochloride (16.3 g). To a mixture of sodium methoxide (28% methanol solution, 83.6 mL) and methanol (145 mL) was added 2-fluoroacetamidine hydrochloride (16.3 g), followed by adding diethyl malonate (22.0 mL), and the mixture was heated at reflux for 11 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added water (145 mL). The mixture was acidified by adding concentrated hydrochloric acid (18 mL), and the mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration. The collected crystals were washed with water and diethyl ether, and dried under reduced pressure to give 2-fluoromethyl-4,6-dihydroxypyrimidine (20.1 g). To a mixture of fuming nitric acid (36 mL) and acetic acid (18 mL) was added 2-fluoromethyl-4,6-dihydroxypyrimidine (20.1 g) slowly under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled in ice. To the mixture was added cold water, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration. The collected crystals were washed with water and diethyl ether, and dried under reduced pressure to give the title compound (16.8 g).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=4)(=[O:20])=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>[OH-].[Na+]>[O:4]=[C:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=3)(=[O:19])=[O:20])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC4(CC3)OCCO4)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
N-{4-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 215) (2.2 g, 5.1 mmol) was treated with concentrated hydrochloric acid (50 mL) at 0° C. and then allowed to warm to room temperature. After 30 min., ˜20 mL of 5 N NaOH was added dropwise and the precipitate was collected by filtration, and dried over P2O5 to give the title compound as a white solid (1.2 g); 1H NMR (300 MHz, DMSO-d6) δ 2.06 (s, 3 H), 2.43 (t, J=5.8 Hz, 4 H), 3.53 (t, J=5.8 Hz, 4 H), 6.85–7.05 (m, 4 H), 7.62 (d, J=9.0 Hz, 2 H), 7.71 (d, J=9.0 Hz, 2 H), 9.81 (s, 1 H), 10.35 (s, 1 H); MS (ES) m/z: 388.3 (MH+); HRMS Calcd. for C19H21N3O4S(M+):387.1253. Found: 387.1272.
Reaction SMILES: [C:1]([O:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([C:16]([OH:18])=[O:17])([CH2:9]3)[CH2:7]1)[CH2:13]2)(=[O:4])[CH:2]=[CH2:3].[CH2:19]=[C:20]([CH3:22])[CH3:21].S(=O)(=O)(O)O>ClCCl>[C:1]([O:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([C:16]([O:18][C:20]([CH3:22])([CH3:21])[CH3:19])=[O:17])([CH2:9]3)[CH2:7]1)[CH2:13]2)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=C(C)C
Reactant: C=CC(=O)OC12CC3CC(C1)CC(C(=O)O)(C3)C2
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: C=CC(=O)OC12CC3CC(C1)CC(C(=O)OC(C)(C)C)(C3)C2
Temperature: 0 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
A mixture of 5 mmole of the above-prepared 1-acryloyloxy-3-carboxyadamantane, 50 mmole of isobutene, 0.5 mmole of sulfuric acid and 50 ml of dichloromethane was stirred at 0° C. for 24 hours. After concentrating the reaction mixture, the concentrate was subjected to column chromatography on a silica gel to thereby yield the title compound in a yield of 81%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>CN(C)C=O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([N:1]=[CH:22][N:23]([CH3:25])[CH3:24])=[CH:7][CH:6]=3)[N:9]=[CH:10][N:11]=2)=[CH:14][CH:15]=1
Reactant: Nc1ccc(-n2ncnc2-c2ccc(F)cc2)cc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Nc1ccc(-n2ncnc2-c2ccc(F)cc2)cc1
Reaction time: 1.5 h

Procedure:
A 1.7 g. portion of 1-(p-aminophenyl)-5-(p-fluorophenyl)-1H-1,2,4-triazole is gently refluxed in a mixture of 5.0 ml. of dimethylformamide dimethylacetal and 2.5 ml. of dimethylformamide. Heating is continued for 1.5 hours, then the mixture is evaporated under high vacuum (70° C.) to a brown oil. This oil is triturated with 50 ml. of ether. The solid is collected by filtration, dried and recrystallized from 25 ml. of hot cyclohexane, giving 1.1 g. of the desired product as a light tan solid, mp. 90°-93° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4](S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.C[O-].[Na+]>CO>[Cl:1][C:2]1[C:10]2[C:5]([NH:6][CH:7]=[N:8][C:9]=2[N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13][CH2:12]2)=[N:4][CH:3]=1
Reactant: O=C(NC1CCN(c2ncnc3c2c(Cl)cn3S(=O)(=O)c2ccccc2)CC1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(NC1CCN(c2nc[nH]c3ncc(Cl)c2-3)CC1)c1ccccc1
Temperature: 75 °C

Procedure:
N-{1-[5-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-piperidinyl}benzamide D41 (240 mg) and sodium methoxide (157 mg, 2.9 mmol) were dissolved in MeOH (15 ml). The reaction mixture was heated at 75° C. for 30 min and then extracted with EtOAc (150 ml); washed with water (60 ml), brine (2×60 ml). Yellow oil obtained, solvent removed to afford a yellow solid which was purified by prep HPLC (mobile phase: A: 0.01% NH4HCO3/H2O B; ACN. Column shimazu PRC-ODS 10.0 uM, 20×250 mm. Method 07.8 min 40-50% ACN 8-10 min 95˜95% ACN. Flow rate 30 mL/min to give product E44 as an ashen solid in 73 mg. LCMS [MH+] 356.0@1.58 min (5 min run)
Reaction SMILES: [C:1]1([CH:7]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([OH:23])=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][OH:29].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]1([CH:7]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(c1ccccc1)c1c[nH]c2cc(O)ccc12
Reactant: OCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CC(c1ccccc1)c1c[nH]c2cc(OCCCCO)ccc12

Procedure:
Analogously to Example 1.4, 1.2 g (3.88 mmol) of ethyl 3-phenyl-3-(6-hydroxyindol-3-yl)propionate are reacted with 1.16 g (7.6 mmol) of 4-bromo-1-butanol in the presence of 2.1 g (15.2 mmol) of potassium carbonate in 30 ml of acetone, giving ethyl 3-phenyl-3-[6-(4-hydroxybutoxy)indol-3-yl]propionate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]([CH:16]1[CH2:20][CH2:19][C:18](=[O:21])[O:17]1)[CH2:9][CH:10]([CH3:15])[CH2:11][CH2:12][CH:13]=[O:14])([CH3:4])([CH3:3])[CH3:2].CC([OH:27])(C)C.CC(=CC)C.[O-]Cl=O.[Na+]>CCOC(C)=O.[Cl-].[Na+].O.C1COCC1.O>[C:1]([O:5][C:6]([NH:7][CH:8]([CH:16]1[CH2:20][CH2:19][C:18](=[O:21])[O:17]1)[CH2:9][C@H:10]([CH3:15])[CH2:11][CH2:12][C:13]([OH:27])=[O:14])=[O:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)O
Reactant: CC(CCC=O)C[C@@H](NC(=O)OC(C)(C)C)C1CCC(=O)O1
Agent: CC=C(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](CCC(=O)O)CC(NC(=O)OC(C)(C)C)C1CCC(=O)O1
Reaction time: 0.17 h

Procedure:
A mixture of 2.09 g (6.67 mmol) [(R)-3-Methyl-6-oxo-1-(5-oxo-tetrahydro-furan-2-yl)-hexyl]-carbamic acid tert-butyl ester, 1.2 g (10 mol) NaH2PO4, 50 ml tBuOH and 10 ml water is subsequently treated with 20 ml of a 2M THF solution of 2-methyl-2-butene and 2.35 g (20.6 mmol) NaClO2 (technical, 80%). After stirring for 10 min the mixture is diluted with EtOAc and brine. The organic phase is dried with MgSO4, filtered and evaporated to yield the title compound as a resin which is used in the next step without purification.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[C:6]([CH3:14])[CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].[Cl:15][C:16]1[CH:21]=[C:20]([N:22]=[C:23]=[O:24])[CH:19]=[C:18]([Cl:25])[N:17]=1>>[Cl:15][C:16]1[CH:21]=[C:20]([NH:22][C:23]([NH:2][NH:1][C:3]2[CH:12]=[C:11]([CH3:13])[C:10]3[C:5](=[C:6]([CH3:14])[CH:7]=[CH:8][CH:9]=3)[N:4]=2)=[O:24])[CH:19]=[C:18]([Cl:25])[N:17]=1
Reactant: Cc1cc(NN)nc2c(C)cccc12
Reactant: O=C=Nc1cc(Cl)nc(Cl)c1
Product: Cc1cc(NNC(=O)Nc2cc(Cl)nc(Cl)c2)nc2c(C)cccc12

Procedure:
A solution of 2-hydrazinyl-4,8-dimethylquinoline (110 mg, 0.60 mmol) and 111 mg (1.0 eq) of 2,6-dichloro-4-isocyanatopyridine was reacted as outlined in Scheme 1 above to give the desired title compound. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.50 (s, 3 H) 2.56 (s, 3 H) 6.79 (s, 1 H) 7.18 (t, J=7.62 Hz, 1 H) 7.41 (d, J=7.03 Hz, 1 H) 7.70 (d, J=8.20 Hz, 2 H) 8.72 (s, 2 H).
Reaction SMILES: CC(C)(OC([NH:7][N:8]1[CH2:12][CH2:11][N:10]([C:13](=[O:36])[CH2:14][O:15][P:16]([OH:35])([N:18]2[C:21](=[O:22])[C@@H:20]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@@H:19]2[CH3:34])=[O:17])[C:9]1=[O:37])=O)C.[K].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>O>[NH2:7][N:8]1[CH2:12][CH2:11][N:10]([C:13](=[O:36])[CH2:14][O:15][P:16]([OH:35])([N:18]2[C:21](=[O:22])[C@@H:20]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@@H:19]2[CH3:34])=[O:17])[C:9]1=[O:37]
Reactant: C[C@H]1[C@H](NC(=O)OCc2ccccc2)C(=O)N1P(=O)(O)OCC(=O)N1CCN(NC(=O)OC(C)(C)C)C1=O
Agent: O=C([O-])O
Agent: [K]
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1[C@H](NC(=O)OCc2ccccc2)C(=O)N1P(=O)(O)OCC(=O)N1CCN(N)C1=O
Reaction time: 6 h

Procedure:
(2S-trans)[1-[[2-[3-[[(1,1-Dimethylethoxy)-carbonyl]amino]-2-oxo-1-imidazolidinyl]-2-oxoethoxy]hydroxyphosphinyl]-2-methyl-4-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, monopotassium salt (5.9 g, 10 mmol) was treated at 0° C. sequentially with anisole (25 ml) and trifluoroacetic acid (60 ml), and the solution was stirred for six hours. The solution was evaporated in vacuo at ambient temperature and then co-evaporated with toluene (10 ml). The residue was triturated with hexane (50 ml) and diethyl ester (2×50 ml) to give a white solid. The solid was dissolved in water (10 ml) and the pH adjusted to 2.5 with sodium bicarbonate. This solution was chromatographed on a column of CHP20P reverse phase resin and eluted with an acetonitrile/water gradient. The appropriate fractions were combined and evaporated in vacuo to ~100 ml. This was lyophilized to give the title compound as a white solid, 2.520 g.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[Cl:20][C:21]1[N:26]=[CH:25][C:24]([C:27](Cl)=[O:28])=[CH:23][CH:22]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:27](=[O:28])[C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[N:26][CH:25]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccc(Cl)nc1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 6-chloropyridine-3-carbonyl chloride were combined to provide N3-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-6-chloronicotinamide as an off white crystalline solid, m.p. 144.0-148.0° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ 8.77 (dd, J=2.5, 0.6 Hz, 1H), 8.73 (t, J=5.6 Hz, 1H), 8.22 (s, 1H), 8.16 (dd, J=8.3, 2.5 Hz, 1H), 8.03 (m, 1H), 7.63 (d, J=0.5 Hz, 1H), 7.60 (d, J=0.5 Hz, 1H), 7.45-7.40 (m, 1H), 7.23-7.18 (m, 1H), 6.61 (broad s, 2H), 4.63 (t, J=6.9 Hz, 2H), 3.30 (m, 2H), 1.92 (m, 2H), 1.58 (m, 2H). MS (EI) m/e 394.1298 (394.1309 calcd for C20H19N6OCl).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[CH:4][C:3]1=[O:8].[F:9][CH:10]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:11]([O:14][C:15]([CH:17]1[CH2:22][CH:21]2[CH2:23][CH:18]1[CH:19]=[CH:20]2)=[O:16])([F:13])[F:12].[F:29][CH:30]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:31]1([CH3:43])[CH2:32]C(=C)C([O-])=O.CC(N=NC(C#N)(C)C)(C#N)C>O1CCCC1>[CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[CH:4][C:3]1=[O:8].[F:9][CH:10]([CH2:24][C:25]([F:26])([F:27])[F:28])[C:11]([O:14][C:15]([CH:17]1[CH2:22][CH:21]2[CH2:23][CH:18]1[CH:19]=[CH:20]2)=[O:16])([F:13])[F:12].[F:42][CH:38]1[CH:39]=[CH:40][CH:41]=[C:30]([F:29])[C:31]1([CH3:43])[CH2:32][C:18]12[CH2:23][CH:21]([CH:20]=[CH:19]1)[CH2:22][CH:17]2[C:15]([O-:14])=[O:16]
Reactant: C=C(CC1(C)C(F)=CC=CC1F)C(=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CN1C(=O)C=CC1=O
Agent: O=C(OC(F)(F)C(F)CC(F)(F)F)C1CC2C=CC1C2
Solvent: C1CCOC1
Product: CC1(CC23C=CC(CC2C(=O)[O-])C3)C(F)=CC=CC1F

Procedure:
To 20 mL of tetrahydrofuran was added 50 mmole of N-methylmaleimide, 10 mmole of hexafluorobutyl-5-norbornene-2-carboxylate, 40 mmole of 2,6-difluoro-1-methylbenzylacrylate and 0.3 g of AIBN, and the resulting solution was reacted at about 65° C. for about 12 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[Si]([C:24]#[N:25])(C)C>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][CH:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:10][CH:9]=2)[C:24]#[N:25])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(C=Nc2ccc(Cl)cc2)cc1
Reactant: C[Si](C)(C)C#N
Product: N#CC(Nc1ccc(Cl)cc1)c1ccc(S(N)(=O)=O)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using 4-chloro-N-(4-sulfamoylbenzylidene)aniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a white powder (yield 93%).
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([CH3:8])[O:5][C:4](=[O:9])[CH:3]=1.[C:10](O)(=[O:12])[CH3:11].C1(N=C=NC2CCCCC2)CCCCC1.CC1CC(OC(=O)C)=CC(=O)O1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C.C(Cl)Cl.CC(C)=O.C(Cl)Cl>[C:10]([C:3]1[C:4](=[O:9])[O:5][CH:6]([CH3:8])[CH2:7][C:2]=1[OH:1])(=[O:12])[CH3:11]
Reactant: CC1CC(O)=CC(=O)O1
Reactant: CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(=O)OC1=CC(=O)OC(C)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(=O)C1=C(O)CC(C)OC1=O
Temperature: 60 °C
Yield: 38.4 %

Procedure:
4-Hydroxy-6-methyl-5,6-dihydro-pyran-2-one (2 g, 15.6 mmol) was combined with methylene chloride (50 mL) in a 250 mL flask and then acetic acid (17.5 M, 2 eq, 31 mmol, 1.77 mL) was added to the mixture. The mixture was cooled in an ice bath and then dicyclohexylcarbodiimide (1.3 eq, 20.3 mmol, 4.19 g) was added portionwise, followed by the addition of 4-(dimethylamino)pyridine (0.05 eq, 0.78 mmol, 88 mg) to the mixture. A sufficient amount of methylene chloride was added to ensure easy stirring and the reaction was monitored by TLC (silica gel, hexane-ethyl acetate-methylene chloride-acetone (3:3:3:1 v/v)), HPLC and LCMS as the intermediate acetic acid 2-methyl-6-oxo-3,6-dihydro-2H-pyran-4-yl ester was formed. The mixture was stirred overnight at room temperature and then toluene (20 ml) was added. The mixture was heated to 60° C. and after 48 hours the mixture was filtered, concentrated and purified by flash column chromatography to provide 3-acetyl-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one (1.02 g, 38%) as a white solid, mp 96-98° C. (lit., mp 97-98° C.). LCMS: MH+ 171.0.