Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:13])[NH:5][CH:6]=[N:7]2.[CH:14]([OH:17])([CH3:16])[CH3:15]>>[F:12][C:10]1[CH:9]=[C:8]2[C:3]([C:4](=[O:13])[NH:5][CH:6]=[N:7]2)=[C:2]([O:17][CH:14]([CH3:16])[CH3:15])[CH:11]=1
Reactant: O=c1[nH]cnc2cc(F)cc(F)c12
Reactant: CC(C)O
Product: CC(C)Oc1cc(F)cc2nc[nH]c(=O)c12
Yield: 73 %

Procedure:
5,7-Difluoro-3,4-dihydroquinazolin-4-one was reacted with isopropanol to give 7-fluoro-5-isopropoxy-3,4-dihydroquinazolin-4-one in 73% yield; NMR Spectrum: (DMSOd6) 1.31 (s, 6H), 4.73 (m, 1H), 6.89 (m, 1H), 6.95 (m, 1H), 7.96 (s, 1H); Mass Spectrum: M+H+ 223.
Reaction SMILES: C[O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]3[C:27](=[O:28])[CH2:26][C:25]([CH3:30])([CH3:29])[CH2:24][C:23]3=[O:31])[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]3[C:23](=[O:31])[CH2:24][C:25]([CH3:29])([CH3:30])[CH2:26][C:27]3=[O:28])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCCCN1C(=O)CC(C)(C)CC1=O
Agent: Cl
Solvent: c1ccncc1
Product: CC1(C)CC(=O)N(CCCCCCN2CC[C@@H]3c4cccc(O)c4CC[C@@H]32)C(=O)C1
Yield: 88.8 %

Procedure:
In an analogous manner to that described in Example 20b), from 9.2 g (21.56 mmol) of rac-cis-1-[6-(6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-3-yl)-hexyl]-4,4-dimethyl-piperidine-2,6-dione using pyridine hydrochloride there were obtained 7.9 g of (89%) rac-cis-1-[6-(6-hydroxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-3-yl)hexyl]-4,4-dimethylpiperidine-2,6-dione; yellowish crystals of m.p. 98.5°-99° after crystallization from ether/hexane.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C@H:6]([C:7]#[N:8])[N:5]2[C:9](=[O:26])[C@H:10]([CH:11]([OH:25])[C:12]3[CH:17]=[CH:16][C:15]([O:18]C4CCCCO4)=[CH:14][CH:13]=3)[C@H:4]2[S:3]1>CC(C)=O.P(=O)(O)(O)O.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:27])[C@H:6]([C:7]#[N:8])[N:5]2[C:9](=[O:26])[C@H:10]([CH:11]([OH:25])[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[C@H:4]2[S:3]1
Reactant: CC1(C)S[C@@H]2[C@@H](C(O)c3ccc(OC4CCCCO4)cc3)C(=O)N2[C@H]1C#N
Agent: O=P(O)(O)O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC1(C)S[C@@H]2[C@@H](C(O)c3ccc(O)cc3)C(=O)N2[C@H]1C#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2,2-Dimethyl-3α-cyano-6α-[p-(2-tetrahydropyranyloxy)-α-hydroxybenzyl]penam (45 mg, 0.12 mmol) is dissolved in 3 ml of acetone and 0.5 ml of 10% phosphoric acid. After stirring 18 hours at room temperature, the solution is diluted with a 10 fold excess of ethyl acetate and washed with saturated sodium chloride. Purification of the crude phenol (42 mg) by PLC (35% acetone/toluene) provides 2,2-dimethyl-3α-cyano-6α-(p-hydroxy-α-hydroxybenzyl)penam.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][O:17][C:11]=2[N:10]=[C:9]1[CH2:19][CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])=O.[Na+].[Br:27]Br.O>CC(O)=O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][O:17][C:11]=2[N:10]=[C:9]1[CH:19]([Br:27])[CH2:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CCCc1nc2onc(C)c2c(=O)n1Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCC(Br)c1nc2onc(C)c2c(=O)n1Cc1ccccc1
Temperature: 55 °C
Reaction time: 72 h
Yield: 29.8 %

Procedure:
A solution of the compound of Example 1, Step 3 (525 mg, 1.85 mmol) in HOAc (20 mL) at room temperature was treated with NaOAc (182 mg, 2.22 mmol) followed by Br2 (296 mg, 1.85 mmol). The mixture was stirred at 55° C. for 72 h then cooled and poured into water. The resulting precipitate was collected and air dried to afford the desired product as a white solid (200 mg, 30%); 1H NMR (DMSO-d6) δ 7.35 (m, 5H), 5.71 (d, J=16.5 Hz, 1H), 5.21 (d, J=16.5 Hz, 1H), 5.16 (t, J=7.5 Hz, 1H), 2.51 (s, 3H), 2.49 (m, 1H), 2.28 (m, 1H), 0.78 (t, J=7.5 Hz, 3H); LC/MS (ESI): 284 (M+H)+.
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([C:13](=[O:25])[NH:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)=[O:17])C1)=O)(C)(C)C.[C:26]([O:30][C:31]([N:33]1C(C(O)=O)C2C[CH:34]1[CH2:35][CH2:36]2)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH:10]([C:13](=[O:25])[NH:14][CH2:15][C:16]([C:18]2[CH:19]=[CH:20][C:21]([Br:24])=[CH:22][CH:23]=2)=[O:17])[CH:11]2[CH2:12][CH:34]1[CH2:35][CH2:36]2)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2ccc(Br)cc2)C1
Product: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)NCC(=O)c1ccc(Br)cc1

Procedure:
Following the procedure used to prepare compound 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester, except that 2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester was used instead of pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester.
Reaction SMILES: [N+]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-])=O.[CH3:13][N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH2:19][OH:20].[ClH:21]>CCOCC>[ClH:21].[ClH:21].[CH3:13][N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH2:19][O:20][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1
Reactant: CN1CCC[C@H]1CO
Reactant: O=[N+]([O-])c1cncc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCOCC
Product: CN1CCC[C@H]1COc1cncc([N+](=O)[O-])c1

Procedure:
A sample of 3,5-dinitro pyridine from step 93a above is reacted with (S)-(-)-1-methyl-2-pyrrolidinemethanol according to the procedure of Example 3a, and the product is converted into the title compound by treatment with HCl in ether according to Example 14c.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14].[Cl:15][C:16]1[CH:31]=[CH:30][C:19]2[N:20]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:21](=[O:23])[NH:22][C:18]=2[CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[Cl:15][C:16]1[CH:31]=[CH:30][C:19]2[N:20]([CH:24]3[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][CH2:4][N:5]4[C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=5[O:7][C:6]4=[O:14])[CH2:28][CH2:29]3)[C:21](=[O:23])[NH:22][C:18]=2[CH:17]=1
Reactant: O=c1oc2ccccc2n1CCCCl
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1oc2ccccc2n1CCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Yield: 47 %

Procedure:
A mixture of 4.7 parts of 3-(3-chloropropyl)-2(3H)-benzoxazolone, 5 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 6.4 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. After cooling, water is added and the layers are separated. The 4-methyl-2-pentanone phase is dried, filtered and evaporated. The residue is boiled in a mixture of 4-methyl-2-pentanone, 2-propanol and methanol. The whole is cooled and the product is filtered off and dried, yielding 4 parts (47%) of 5-chloro-1-{1-[3-(2-oxo-3(2H)-benzoxazolyl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 212.3° C.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](OC)=O)[C:3]=1[C:4]([OH:6])=O.[N+](C1C=CC=[C:20]([C:21](O)=[O:22])[C:19]=1C(O)=O)([O-])=O.C(O)(C(F)(F)F)=O>CO>[OH:6][CH2:4][C:3]1[CH:2]=[CH:10][CH:9]=[C:8]2[C:7]=1[CH:11]=[CH:19][CH:20]=[C:21]2[OH:22]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Reactant: COC(=O)c1cccc(N)c1C(=O)O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: OCc1cccc2c(O)cccc12

Procedure:
2-Amino-6-(methoxycarbonyl) benzoic acid (1) was made from 3-nitrophthalic acid using the procedure first reported by Rogers and Averill (Rodgers, M. E. and Averill, B. A., J. Org. Chem., 1986, 51, 3308) and then used immediately to make Diels Alder cycloadduct 2 via the 3-(methoxhycarbonyl)dehydrobenzene intermediate that is generated under aprotic diazotization reaction conditions (based on modified conditions first reported by Giles, R. G. F., Sargent, M. V., and Sianipar, H., J. Chem. Soc. Perkin Trans I, 1991, 1571). Treatment of cycloadduct 2 with TFA in refluxing methanol yielded a 1:2 mixture of regioisomeric naphthols 3a and 3b which were separated by column chromatography on silica gel. The 1,5-naphthol regioisomer (3a) was then reduced with LAH to produce 5-hydroxymethyl naphthol 4, which was then coupled to carbapenem intermediate 5 (CPI 5) with catalytic palladium to produce the 1-carbon naphthol coupled CPI 6.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][NH2:17].C(OCC)(=O)C>CO.[Pd]>[CH3:16][NH:17][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: CN
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CNCc1ccc(Oc2ccccc2)cc1
Yield: 80 %

Procedure:
4-Phenoxybenzaldehyde (10.0 g, 0.05 mol), excess methylamine and 1.5 g of 10% Pd/C in 200 mL of methanol were stirred under an atmosphere of hydrogen for 16 hours. After removal of the catalyst by filtration through Celite®, the filtrate was concentrated under reduced pressure to give the crude product as an oil. Chromatography on silica gel eluting with ethyl acetate gave the title compound in 80% yield.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][C:8](=[O:26])[C:9]=1[N:10]2[S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].[Li+].[CH3:28][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([CH3:28])[C:8](=[O:26])[C:9]=1[N:10]2[S:16]([C:19]1[CH:20]=[CH:21][C:22]([CH3:23])=[CH:24][CH:25]=1)(=[O:18])=[O:17]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4c(Cl)c(Cl)ccc42)CCCC3=O)cc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c3c(c4c(Cl)c(Cl)ccc42)CCC(C)C3=O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 328.9 %

Procedure:
5,6-Dichloro-9-tosyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (intermediate 5b) (0.15 g, 0.036 mmol) was dissolved in dry THF, cooled to −78° C. and LiHMDS (0.8 mL, 0.88 mmol, 1M solution in THF) was added dropwise. The reaction mixture was slowly warmed to 0° C. and stirred for an additional 30 min. The reaction mixture was cooled to −78° C. and MeI (0.05 ml, 0.88 mmol) was added slowly, and the reaction mixture was slowly, warmed to room temperature and stirred for 4 h. The reaction was cooled to 0° C. and quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (2×50 ml). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude material obtained was purified by column chromatography using [EtOAc-hexane (1:9) as eluant] to afford the title compound (0.05 g, 32%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.22 (d, J=8.5 Hz, 1H), 8.02 (d, J=8.5 Hz, 2H), 7.54 (d, J=9 Hz, 1H), 7.34 (d, J=8.5 Hz, 2H), 3.55-3.49 (m, 1H), 3.22-3.15 (m, 1H), 2.68-2.64 (m, 1H), 2.42 (s, 3H), 2.27-2.22 (m, 1H), 1.95-1.87 (m, 1H), 1.25-1.17 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][CH:10]=O)([CH3:4])([CH3:3])[CH3:2].[N+](=[C:21](P(=O)(OC)OC)C(=O)C)=[N-].C(=O)([O-])[O-].[K+].[K+]>CO>[C:12]1([CH:8]([NH:7][C:6](=[O:18])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9][C:10]#[CH:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: CC(C)(C)OC(=O)NC(CC=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CCC(NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
To the solution of 1.2 g of tert-butyl 3-oxo-1-phenylpropylcarbamate (Formula 12) and 1.38 g of dimethyl 1-diazo-2-oxopropylphosphonate (Formula 15) in 60 mL of methanol at 0° C. was added 1.32 g of potassium carbonate. The mixture was stirred at room temperature for 16 hours then quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Column chromatography (5% ethyl acetate/hexane) gave 1.03 g (87%) of tert-butyl 1-phenylbut-3-ynylcarbamate (Formula 16) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.43 (s, 9H), 1.98-2.00 (m, 1H), 2.6-2.8 (m, 2H), 4.88 (br, 1H), 5.16 (br, 1H), 7.23-7.37 (m, 5H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([F:13])=[C:6]([CH:9]=[CH:10][C:11]=1[F:12])[C:7]#[N:8])([O-])=O.Cl>[Pd].CO>[NH2:1][C:4]1[C:5]([F:13])=[C:6]([CH:9]=[CH:10][C:11]=1[F:12])[CH2:7][NH2:8]
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1ccc(F)c(N)c1F
Temperature: 25 °C
Reaction time: 13 h

Procedure:
A mixture of 3-Nitro-2,4-difluoro-benzonitrile (0.50 g, 2.7 mmol), MeOH (25 ml), 37% HCl (1.5 ml) and Pd/C (200 mg) was stirred for 13 h at rt under a hydrogen atmosphere (3 bar). The catalyst was removed by filtration and the filtrate was concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12](O)([CH3:14])[CH3:13])=[N:7][N:6]=[CH:5]2.CCN(S(F)(F)[F:22])CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([F:22])([CH3:14])[CH3:13])=[N:7][N:6]=[CH:5]2
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(O)c1nncc2cc(Cl)ccc12
Solvent: ClCCl
Product: CC(C)(F)c1nncc2cc(Cl)ccc12
Temperature: 25 °C
Yield: 54.2 %

Procedure:
A mixture of 2-(6-chlorophthalazin-1-yl)propan-2-ol (154 mg, 0.69 mmol) in 5 mL of DCM at −78° C. was treated with DAST (0.11 mL, 0.76 mmol) slowly. It was warmed slowly to room temperature overnight, then quenched with saturated NaHCO3 solution and extracted with CH2Cl2. The DCM layer was dried over MgSO4, filtered and concentrated. Purification on an ISCO (12 g column, 10-35% EtOAc:Hexanes) afforded 6-chloro-1-(2-fluoropropan-2-yl)phthalazine (84 mg, 54% yield) as a pale yellow, viscous oil. MS (ESI, pos. ion) m/z: 225.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH:10]([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:8][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)Oc1cccc(Br)c1

Procedure:
3-Bromophenol was combined with an equal molar amount of 2-bromopropane in ethanol and in the presence of potassium carbonate to provide 3-bromoisopropoxybenzene.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[H-].[Na+].Cl[C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH:24]=[N:25][N:26]=2)[N:23]=1>CN(C=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH:24]=[N:25][N:26]=2)[N:23]=1
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: Clc1ccc2nncn2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1COc1ccc2nncn2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.1 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (100 mg, 0.53 mmol) in DMF (2 mL) was added sodium hydride (55% dispersion in mineral oil, 25.4 mg, 0.58 mmol). The mixture was stirred at room temperature for 15 min. After addition of 6-chloro-1,2,4-triazolo[4,3-b]pyridazine (90 mg, 0.58 mmol) the mixture was stirred at room temperature for another 2 h. Then the mixture was evaporated, extracted (ethyl acetate/water) and the organic phase was dried with sodium sulfate and concentrated. Chromatography (SiO2, dichloromethane:methanol=100:0 to 9:1) afforded the title compound (80 mg, 51%) as a white solid. MS: m/e=308.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.Cl>C(=S)=S>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Clc1ccc(Cl)cc1
Reactant: ClC1CCCCC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: Clc1ccc(Cl)c(C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.3 %

Procedure:
To a solution of 1,4-dichlorobenzene (294 g) in anhydrous carbon disulfide (400 ml) was added anhydrous aluminum chloride (16.0 g). To the mixture was added dropwise chlorocyclohexane (96 g) with stirring at ambient temperature during 3 hours. After the stirring was continued for 3 hours at ambient temperature, the reaction mixture was allowed to stand overnight at ambient temperature. To the reaction mixture was added dil.hydrochloric acid with stirring. The organic layer was separated, washed with water, dried over magnesium sulfate, concentrated under reduced pressure and allowed to stand at ambient temperature for a while to give precipitates. The precipitates were removed by filtration. The filtrate was distilled under reduced pressure to give 1,4-dichloro-2-cyclohexylbenzene (47.0 g).
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3](OCC)=[O:4].[Na].[O:13]1[CH2:17][CH2:16][CH:15]([CH:18]=[CH:19][C:20](=[O:22])[CH3:21])[CH2:14]1.[OH-].[Na+]>C(O)C.C(O)(C)C>[O:13]1[CH2:17][CH2:16][CH:15]([CH:18]2[CH2:2][C:3](=[O:4])[CH2:21][C:20](=[O:22])[CH2:19]2)[CH2:14]1
Reactant: CC(=O)C=CC1CCOC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCO
Product: O=C1CC(=O)CC(C2CCOC2)C1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Diethyl malonate (6.50 ml, 43 mmol) is added dropwise to a cooled (ice-bath) solution of sodium (1.07 g, 46 mmol) in anhydrous ethanol (60 ml) and once the addition is complete the cooling bath is removed and the reaction mixture is stirred at room temperature for 25 minutes. The mixture is cooled in an ice bath and a solution of 4-(tetrahydrofuran-3-yl)-3-buten-2-one (5.0 g, 36 mmol) in ethanol (30 ml) is added dropwise. Once the addition is complete the cooling bath is removed and the reaction mixture is stirred at room temperature for 19 hours. The reaction mixture is acidified to pH 3 by dropwise addition of 2M aqueous hydrochloric acid, water added to dissolve any precipitate formed and the reaction mixture is extracted into dichloromethane. The organic extracts are dried over anhydrous magnesium sulphate, filtered and the filtrate is concentrated in vacuo to afford a yellow oil which is taken up in isopropanol (35 ml) and a 2M aqueous solution of sodium hydroxide (100 ml) is added. The reaction mixture is stirred at room temperature for 20 hours. The reaction mixture is concentrated in vacuo to remove isopropanol then heated to 70° C. A solution of 2M aqueous hydrochloric acid is added carefully until the reaction mixture reached pH 1. The reaction mixture is heated for 1½ hours at 70° C., then cooled to room temperature, diluted with water and the product is extracted into ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and the filtrate is concentrated in vacuo to give 5-(tetrahydrofuran-3-yl)cyclohexane-1,3-dione as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2].Br[CH:31]([CH3:39])[C:32]([O:34]C(C)(C)C)=[O:33]>>[CH2:1]([C:3]1[CH:8]=[N:7][C:6]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][CH:21]=2)[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH:31]([CH3:39])[C:32]([OH:34])=[O:33])=[CH:16][CH:17]=2)=[N:5][CH:4]=1)[CH3:2]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: CCc1cnc(N(CCc2ccc(O)cc2)Cc2ccc(C(F)(F)F)cc2)nc1
Product: CCc1cnc(N(CCc2ccc(OC(C)C(=O)O)cc2)Cc2ccc(C(F)(F)F)cc2)nc1

Procedure:
Similarly prepared from 4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenol and t-butyl 2-bromopropionate.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:14](Br)[CH:15]=[CH2:16].O>CN(C=O)C>[CH2:16]([N:2]1[C:3]([CH:6]=[O:7])=[CH:4][CH:5]=[N:1]1)[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: O=Cc1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1nccc1C=O
Yield: 10.1 %

Procedure:
Pyrazole-3-carbaldehyde (3.00 g, 31.2 mmol) was dissolved in DMF (20 ml), and thereto were added potassium carbonate (6.47 g, 46.8 mmol) and allyl bromide (3.50 g, 32.8 mmol) with stirring. The mixture was stirred at room temperature for 6 hours, and thereto was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (429 mg, 10%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Br:22]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:22])[N:6]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrBr
Reactant: CCCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCSc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 16 %

Procedure:
6-Amino-9-benzyl-2-propylthiopurine (290 mg, 0.97 mmol) and bromine (0.7 ml) were dissolved in 160 ml of methylene chloride and the solution was stirred at room temperature for 4.5 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on magnesium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (58 mg, yield 16%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:20]([OH:22])=O>>[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:20]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:22]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: Cc1cc(C(=O)O)cc(C(F)(F)F)c1
Product: Cc1cc(C(=O)N(C)c2cnccc2-c2ccccc2C)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-methyl-5-(trifluoromethyl)benzoic acid (CAS RN 117186-02-4) after a reaction time of 67 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 30:70). Light brown oil (9%). MS (ESI): m/z=385.15[M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][CH:29]([N:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:16])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Br)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(Br)cc1
Yield: 43.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-bromophenyl)-5-methylpyrazole-4-carboxylic acid (0.6 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (0.6 g), the title compound (0.5 g) was obtained, melting point: 250–252° C.