Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([CH:17]2[CH2:20][CH2:19][CH2:18]2)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[N:7]=1.[N:21]1[CH:22]=[N:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][C:25]=12>CS(C)=O>[CH:17]1([C:3]2[C:2]([N:27]3[CH2:28][CH2:29][N:24]4[N:23]=[CH:22][N:21]=[C:25]4[CH2:26]3)=[N:7][N:6]3[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Reactant: c1nc2n(n1)CCNC2
Solvent: CS(C)=O
Product: c1ccc(-c2nnc3cc(C4CCC4)c(N4CCn5ncnc5C4)nn23)cc1
Temperature: 150 °C
Yield: 26.3 %

Procedure:
A mixture of 6-chloro-7-cyclobutyl-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (150 mg, 0.53 mmol) and 5,6,7,8-tetrahydro-1,2,4-triazolo[1,5-α]pyrazine (190 mg, 1.53 mmol) in dimethyl sulphoxide (1 ml) was stirred and heated at 150° C. for 20 hours. The mixture was partitioned between dichloromethane and water. The aqueous phase was further extracted with dichloromethane (x2). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with 3→4% methanol-dichloromethane to give the title compound (52 mg, 26%) as an off-white solid (after trituration with diethyl ether). 1H NMR (360 MHz, CDCl3) δ 2.00-2.28 (4H, m), 2.48-2.55 (2H, m), 3.68-3.80 (3H, m), 4.43 (2H, t, J=5.5 Hz), 4.67 (2H, s), 7.46-7.56 (3H, m), 7.97 (1H, s), 8.09 (1H, s),8.37 (2H, br d, J=8 Hz); MS (ES+) m/e 373 [MH]+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)=O.O1CCOCC1>[OH-].[K+].CCO.O>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:20][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(C=C2CCc3cc(OCCn4ccnc4)ccc3C2=O)cc1
Yield: 10.1 %

Procedure:
6-(2-Imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.400 g, 1.56 mmol) was reacted with 4-formyl benzoic acid (0.351 g, 2.34 mmol) in 5.0 mL of 4% KOH in EtOH and 1 mL of dioxane at room temperature for 6 days. The reaction was diluted with minimal water to achieve complete solution and then extracted with DCM. The resulting aqueous solution was acidified to pH 2 with 1N HCl. After standing at room temperature for 3 weeks, 0.061 g (10%) of the title compound was isolated by filtration as a fine cream powder, nmp 267-267.5° C.: CI-MS m/e 388 (M+), 389 (M+ +1);
Reaction SMILES: S(O)(O)(=O)=O.[C:6]([C:11]1[N:15]2[C:16]([CH2:20]Cl)=[CH:17][CH:18]=[CH:19][C:14]2=[N:13][CH:12]=1)([O:8]CC)=O.C1CCN2C(=NCCC2)CC1.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([CH2:46][CH2:47][NH2:48])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].[I-].[Na+]>C(#N)C.C(N(CC)CC)C>[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([CH2:46][CH2:47][N:48]2[CH2:20][C:16]3[N:15]4[C:11](=[CH:12][N:13]=[C:14]4[CH:19]=[CH:18][CH:17]=3)[C:6]2=[O:8])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reactant: CCOC(=O)c1cnc2cccc(CCl)n12
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CCN2Cc3cccc4ncc(n34)C2=O)CC1
Yield: 37.5 %

Procedure:
In 50 ml of acetonitrile was suspended 6.73 g (20.0 mM) of 3-carbethoxy-5-chloromethylimidazo[1,2-a]pyridine sulfate followed by addition of 5.97 ml (40.0 mM) of DBU at room temperature with stirring. To the resulting solution was added 4.57 g (20.0 mM) of 2-(1-tert-butoxycarbonylpiperidin-4-yl)-1-ethylamine as well as 5.54 ml (40.0 mM) of triethylamine and 3.00 g (20.0 mM) of sodium iodide and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was extracted with 100 ml of 2-butanone. The organic layer was washed with 100 ml of saturated aqueous NaCl solution and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-ethanol=5:1) to provide 2.88 g (yield 37.5%) of the title compound as yellow oil.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](Cl)(=[O:21])[C:18]([Cl:20])=[O:19]>CCOCC>[O:21]=[C:17]([C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)[NH:13][CH:12]=1)[C:18]([Cl:20])=[O:19]
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccc(Oc2ccc3[nH]ccc3c2)cc1
Solvent: CCOCC
Product: O=C(Cl)C(=O)c1c[nH]c2ccc(Oc3ccccc3)cc12

Procedure:
Combine 5-phenoxy-indole (1.57 g, 7.5 mmol) and anhydrous ether (35 mL) and add oxalyl chloride (1.07 g, 8.25 mmol) in 8 mL ether. A precipitate forms. Stir the reaction over night. Collect the precipitate, dry in vacuo, to give the title compound: 1H NMR (300 MHz, DMSO-d6) 6.99-7.15 (m, 4H), 7.37-7.42 (m, 2H), 7.60 (d, 1H, J=8.7 Hz), 7.75 (d, 1H, J=2.4 Hz), 8.47 (d, 1H, J=3.2 Hz), 12.49, (br, 1H).
Reaction SMILES: CO[C:3]1[C:4](=O)[CH:5]=[CH:6][C:7]([CH3:10])=[CH:8][CH:9]=1.[NH2:12][C:13]([NH2:15])=[S:14].C[O-].[Na+].CO.CO>C(O)(=O)C>[SH:14][C:13]1[N:12]=[C:4]2[CH:5]=[CH:6][C:7]([CH3:10])=[CH:8][CH:9]=[C:3]2[N:15]=1
Reactant: COc1ccc(C)ccc1=O
Reactant: NC(N)=S
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc2nc(S)nc-2cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
165 g of 2-methoxy-5-methyl-2,4,6-cycloheptatrien-1-one and 84 g of thiourea were added to 255 g of 28% sodium methoxide/methanol solution and everything was stirred for 30 minutes at room temperature. Next, 60 ml of methanol was added, and then acetic acid was added until the pH value of the resulting solution became 5 or so. The crystals thus precipitated were separated by filtration, fully washed with methanol and then dried.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+]>>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CON=C(C(=O)OC)c1ccc(OC)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Product: CON=C(C(=O)O)c1ccc(OC)c(Cl)c1
Yield: 101.8 %

Procedure:
Methyl 2-methoxyimino-2-(3-chloro-4-methoxyphenyl)acetate (syn isomer) (2.7 g.) and a 2 N aqueous solution of sodium hydroxide (10.6 ml.) were treated according to a similar manner to that of Preparation (5-3) (c) to give crystals of 2-methoxyimino-2-(3-chloro-4-methoxyphenyl)acetic acid (syn isomer) (2.6 g.), mp 133° to 135° C. (dec.).
Reaction SMILES: C([O:9][CH:10]([C@@H:16]1[CH2:20][C@@H:19]([O:21]C(=O)C)[C@H:18]([N:25]2[C:29]3[N:30]=[C:31]([NH2:35])[NH:32][C:33](=[O:34])[C:28]=3[S:27][C:26]2=[O:36])[O:17]1)[CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CC(O)=O>CO>[NH2:35][C:31]1[NH:32][C:33](=[O:34])[C:28]2[S:27][C:26](=[O:36])[N:25]([C@H:18]3[C@H:19]([OH:21])[CH2:20][C@@H:16]([CH:10]([CH:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)[OH:9])[O:17]3)[C:29]=2[N:30]=1
Reactant: CC(=O)O[C@@H]1C[C@@H](C(OC(=O)c2ccccc2)C2CCCC2)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](C(O)C3CCCC3)C[C@H]2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 9.1 %

Procedure:
To a solution of [[(2S,4R,5R)-4-acetoxy-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl]-cyclopentyl-methyl] benzoate (compound 11d, 70 mg, 0.14 mmol) in methanol (10 mL) was added K2CO3 (136 mg, 1 mmol). After being stirred at room temperature for 12 hours, the reaction mixture was adjusted to pH 7.0 by addition of HOAc (120 mg, 2 mmol), concentrated in vacuo and the residue was purified by preparative HPLC to afford 4.7 mg of 5-amino-3-[(2R,3R,5S)-5-[cyclopentyl(hydroxy)methyl]-3-hydroxy-tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione (Example 11) as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Cl[CH2:14][C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:15]([CH2:14][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][CH:8]=1)#[N:16]
Reactant: Oc1ccc(-c2cccs2)cc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCOc1ccc(-c2cccs2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.3 %

Procedure:
A mixture of 4-(2-thienyl)phenol (1.30 g), chloroacetonitrile (668 mg) and potassium carbonate (1.53 g) in DMF (7 ml) was stirred for 5 hours at ambient temperature. The mixture was diluted with H2O and the separated solid was recovered to give 1.45 g of 2-(4-cyanomethoxyphenyl)thiophene.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl:23][C:24]([Cl:29])([Cl:28])[C:25](Cl)=[O:26].O>O1CCCC1>[C:8]([C:7]1[C:2]([NH:1][C:25](=[O:26])[C:24]([Cl:29])([Cl:28])[Cl:23])=[N:3][CH:4]=[CH:5][CH:6]=1)(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Nc1ncccc1C(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccccc1)c1cccnc1NC(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
To a solution of 11.0 g (55 mmol) of 2-amino-3-benzoylpyridine and 6.1 g (60 mmol) of triethylamine in 200 mL of tetrahydrofuran was added dropwise 10.0 g (55 mmol) of trichloroacetyl chloride at temperature of 5° to 15° C. After being stirred for 3 hours at ambient temperature, the reaction mixture was poured into water, and then the mixture was extracted with ethyl acetate. The organic layer separated was washed with water and then with brine, dried on anhydrous sodium sulfate and then concentrated in vacuo. The resulting crude crystals were recrystallized from ethanol to give 14.0 g (40 mmol) of the title compound.
Reaction SMILES: [Cl-:1].[Li+].[C:3]([O:6][C:7]1[C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:25])[C@H:17](Br)[CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=[C:9]([O:27][CH3:28])[CH:8]=1)(=[O:5])[CH3:4].O>CN(C)C=O>[C:3]([O:6][C:7]1[C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:25])[C@@H:17]([Cl:1])[CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=[C:9]([O:27][CH3:28])[CH:8]=1)(=[O:5])[CH3:4]
Reactant: [Cl-]
Reactant: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)[C@H](Br)C[C@H]3[C@@H]1CC2
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)[C@@H](Cl)C[C@H]3[C@@H]1CC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of lithium chloride (1.3 g, 31 mM) in 9 ml of anhydrous dimethylformamide is heated to 70° and then cooled to room temperature. 1-Acetoxy-16α-bromo-3-methoxyestra-1,3,5(10)-trien-17-one (0.50 g) is added to the solution as a solid using Gooch tubing. The resulting suspension is heated to 50° to effect solution. The solution is then stirred at room temperature for 5 hr, poured into 100 ml of H2O, filtered and dried in vacuo to give a white solid. Recrystallization from methanol gives 1-acetoxy-16β-chloro-3-methoxyestra-1,3,5(10)-trien-17-one, yield 0.40 g (89%); m.p. 164°-166°.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH3:13])[C:6]=2[C:5](=[O:14])[NH:4][C:3]1=[O:15].Cl[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:24]=[C:22]([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:4]1[C:5](=[O:14])[C:6]2[N:7]([CH2:11][CH2:12][CH3:13])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:15]
Reactant: CC(=O)CCCCCCl
Reactant: CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1cnc2c1c(=O)n(CCCCCC(C)=O)c(=O)n2C
Yield: 162.4 %

Procedure:
2.1 g of 3-methyl-7-propylxanthine, 0.7 g of 1-chloro-heptan-6-one and 1.4 g of potassium carbonate are heated at 120° C. in 15 ml of dimethylformamide for 7.5 hours, while stirring. After the mixture has been concentrated under reduced pressure, the residue is poured into 100 ml of H2O, the mixture is extracted three times with 100 ml of CHCl3 each time, and the combined chloroform extracts are treated with 1 N sodium hydroxide solution and water in succession and dried over sodium sulfate. The concentration residue is chromatographed in a column using silica gel 60 and chloroform/ethanol (9:1) as the mobile phase. After recrystallization from petroleum ether/diisopropyl ether (3:1), 2.45 g (=76.6% yield) of 1-(6-oxoheptyl)-3-methyl-7-propylxanthine of melting point 69-70° C. are obtained.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)[O:12][C@H:13]([C:15](=[O:43])[NH:16][C@@H:17]2[C:23](=[O:24])[N:22]([CH2:25][CH2:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:21]3[CH:35]=[CH:36][CH:37]=[CH:38][C:20]=3[C:19]3[CH:39]=[CH:40][CH:41]=[CH:42][C:18]2=3)[CH3:14])=CC=1)([O-])=O.[F:45][C:46]([F:54])([C:50]([F:53])([F:52])[F:51])[CH2:47][CH2:48][NH2:49]>>[CH2:28]([O:27][CH2:26][CH2:25][N:22]1[C:23](=[O:24])[C@@H:17]([NH:16][C:15]([C@@H:13]([O:12][C:11](=[O:10])[NH:49][CH2:48][CH2:47][C:46]([F:54])([F:45])[C:50]([F:53])([F:52])[F:51])[CH3:14])=[O:43])[C:18]2[CH:42]=[CH:41][CH:40]=[CH:39][C:19]=2[C:20]2[CH:38]=[CH:37][CH:36]=[CH:35][C:21]1=2)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: NCCC(F)(F)C(F)(F)F
Product: C[C@H](OC(=O)NCCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using carbonic acid (S)-1-[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl]-ethyl ester 4-nitro-phenyl ester and 3,3,4,4,4-pentafluorobutylamine, the title compound was prepared in the same manner as described for example 5c. White solid (97%). MS: m/e=620(M+H+).
Reaction SMILES: Br[C:2]1[C:3]([O:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]2.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][N:33]([CH:35]3[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]3)[CH:34]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[C:42]([O:41][C:39]([N:37]1[CH2:38][CH:35]([N:33]2[CH:34]=[C:30]([C:2]3[C:3]([O:17][CH:18]4[CH2:21][CH2:20][CH2:19]4)=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]4)[CH:31]=[N:32]2)[CH2:36]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Reactant: COC(=O)N1c2ccc(Br)c(OC3CCC3)c2CC[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)N1c2ccc(-c3cnn(C4CN(C(=O)OC(C)(C)C)C4)c3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 100 °C
Yield: 104.6 %

Procedure:
A mixture of methyl (S)-6-bromo-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.096 g, 0.254 mmol), tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (0.113 g, 0.325 mmol), and cesium carbonate (0.264 g, 0.811 mmol) in dioxane (2.0 mL) and water (0.40 mL) was purged with nitrogen to remove any oxygen. XPhos Precatalyst 2nd Generation (0.020 g, 0.027 mmol) was added and the reaction was purged with nitrogen and then heated at 100° C. for 16 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous phase was separated and extracted with ethyl acetate, and the combined organic phases were concentrated to afford an oil. This material was purified via column chromatography on silica gel (Biotage 10 g column, gradient elution with 25-50% ethyl acetate-hexane) to afford methyl (S)-6-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.132 g, 98%) as a colorless oil. MS (ESI, pos. ion) m/z 497 [M+H]+.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)=[O:3].[CH3:20][N:21]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[CH2:30][CH2:31][CH2:32][NH2:33])[CH3:22].C(OC(C)C)(C)C>>[CH3:20][N:21]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[CH2:30][CH2:31][CH2:32][NH:33][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)=[O:3])[CH3:22]
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ccccc21
Reactant: CN(C)CC1CCCCN1CCCN
Solvent: CC(C)OC(C)C
Product: CN(C)CC1CCCCN1CCCNC(=O)N1c2ccccc2NC(=O)c2ccccc21
Yield: 80 %

Procedure:
Prepared analogously to Example 2 from 5-(chlorocarbonyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 3-[2-[(dimethylamino)methy]-piperidin-1-yl]propanamine in a yield of 80% of theory. Colourless crystals, m.p. 131°-133° C. (diisopropyl ether).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH:21]([CH2:29][CH2:30][CH3:31])[CH2:22][CH:23]=[CH:24][CH2:25][C:26]([OH:28])=[O:27])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1.[C:32](OCC)(=O)C>O.[Pt](=O)=O>[CH3:32][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH:21]([CH2:29][CH2:30][CH3:31])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1
Reactant: CCCC(CC=CCC(=O)O)C1c2ccc(O)cc2SCC1(C)c1ccc(OC)cc1
Reactant: CCOC(C)=O
Agent: O=[Pt]=O
Solvent: O
Product: CCCC(CCCCC(=O)O)C1c2ccc(OC)cc2SCC1(C)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
To a solution of 6-[7-hydroxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-yl]-3-nonenoic acid (254 mg, 0.56 mmol) in ethyl acetate (5 ml) was added platinum(IV) oxide hydrate (130 mg, 0.56 mmol) and the mixture was stirred for 16 h at room temperature under hydrogen atmosphere. The catalyst was filtered off and washed with methanol. The filtrate was concentrated and the residue was subjected to flash chromatography on silica gel (ethyl acetate) to give the title compound (222 mg, yield: 87%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH:25]4[CH2:27][CH2:26]4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:28][C@@H:29]1[CH2:33][O:32][C:31](=[O:34])[NH:30]1>>[C:7]([C:6]1[CH:9]=[C:2]([N:30]2[C@H:29]([CH3:28])[CH2:33][O:32][C:31]2=[O:34])[CH:3]=[CH:4][C:5]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH:25]3[CH2:27][CH2:26]3)=[CH:20][N:19]=2)[CH2:14][CH2:13]1)=[O:11])#[N:8]
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2C#N)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C)cc2C#N)CC1

Procedure:
By reaction and treatment in the same manner as in Example 110 and using 5-bromo-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (425 mg) described in Preparation Example 194 and (R)-4-methyloxazolidin-2-one. (121 mg) described in Preparation Example 25, the title compound (363 mg) was obtained.
Reaction SMILES: [CH:1]1([C:7]([N:9]2[CH2:14][CH2:13][N:12](CC3C=CC=CC=3)[CH2:11][CH2:10]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:22].[H][H]>C(O)C.[Pd]>[ClH:22].[CH:1]1([C:7]([N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: O=C(C1CCCCC1)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C(C1CCCCC1)N1CCNCC1

Procedure:
14.3 g (0.05 mole) of 1-cyclohexanecarbonyl-4-benzylpiperazine dissolved in 250 ml of ethanol and acidified with conc. HCl was treated with hydrogen over a palladium catalyst at 1500 psi and 100° C. The catalyst was removed by filtration and the solvent removed under reduced pressure. The residue was dissolved in isopropanol. On short standing a white crystalline precipitate appeared which was collected by filtration to give 10.0 g of 1-cyclohexanecarbonylpiperazine hydrochloride.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:15][NH2:16]>>[NH:15]([C:2]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:16]
Reactant: CC(C)c1cc(Cl)nc2ccccc12
Reactant: NN
Product: CC(C)c1cc(NN)nc2ccccc12

Procedure:
A solution of 2-chloro-4-isopropylquinoline (1.80 g, 8.8 mmol) in NH2NH2 was reacted as outlined in Scheme 1 above to give the desired title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 1.41 (d, J=6.74 Hz, 6 H) 3.51-3.76 (m, 1 H) 7.20-7.35 (m, 1 H) 7.44-7.60 (m, 2 H) 7.61-7.79 (m, 1 H) 7.84-8.06 (m, 1 H).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11]1)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.[NH2:29][C:30]1[C:38]([Cl:39])=[CH:37][C:33](C(O)=O)=[C:32]([O:40][CH3:41])[CH:31]=1>>[NH2:29][C:30]1[C:38]([Cl:39])=[CH:37][C:33]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][C:20]([CH3:19])=[CH:21][CH:22]=3)[CH2:11]2)=[O:7])=[C:32]([O:40][CH3:41])[CH:31]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCN)C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCNC(=O)c2ccc(C)cc2)C1

Procedure:
3-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)propylamine (1.08 g) as starting compound was reacted and treated in the same manner as in Example 1 using 4-methylbenzoyl chloride (0.56 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.48 g) to give 4-amino-5-chloro-2-methoxy-N-(1-(3-(4-methylbenzoylamino)propyl)pyrrolidin-3-ylmethyl)benzamide.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][CH:13]=[C:12]([CH3:15])[C:11]=2[CH:16]=1>C(Cl)(Cl)Cl>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13]([S:2]([Cl:1])(=[O:5])=[O:3])=[C:12]([CH3:15])[C:11]=2[CH:16]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1csc2ccc(Br)cc12
Solvent: ClC(Cl)Cl
Product: Cc1c(S(=O)(=O)Cl)sc2ccc(Br)cc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 15820.2 %

Procedure:
Chlorosulfonic acid (2.20 ml, 0.033 mmol) was added dropwise at −5° C. to a solution of 5-bromo-3-methylbenzothiophene (Intermediate 9) (3.0 g, 13.2 mmol) in CHCl3 (30 mL). The reaction mixture was stirred at 0° C. for 3 h, and then poured into a mixture of ice/NaHCO3 and stirred vigorously for 5 min. The organic phase was immediately separated, dried and concentrated to give the title compound (1.70 g, 39%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[C:8]([C:13]#[N:14])=[CH:9][NH:10]2)=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17].P(Cl)(Cl)(Cl)(Cl)[Cl:20]>>[Cl:20][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([N+:16]([O-:18])=[O:17])[CH:5]=2)[N:10]=[CH:9][C:8]=1[C:13]#[N:14]
Reactant: COc1cc2[nH]cc(C#N)c(=O)c2cc1[N+](=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: COc1cc2ncc(C#N)c(Cl)c2cc1[N+](=O)[O-]
Temperature: 165 °C

Procedure:
A mixture of 5.3 g (21.6 mmol) of 1,4-dihydro-7-methoxy-6-nitro-4-oxo-3-quinolinecarbonitrile and 9 g (43.2 mmol) of phosphorous pentachloride was heated at 165° C. for 2 hours. The mixture was diluted with hexanes and the solid was collected. The solid was dissolved in 700 ml ethyl acetate and washed with cold dilute sodium hydroxide solution. The solution was dried over magnesium sulfate and filtered through a pad of silica gel giving 5.2 g of 4-chloro-7-methoxy-6-nitro-3-quinolinecarbonitrile as a tan solid.