Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:6]=1)(=[O:3])[CH3:2].[I:23](O)(=O)=O.II>C(O)C>[C:1]([NH:4][C:5]1[N:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=[C:7]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[C:6]=1[I:23])(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cn1nc(-c2ccc(F)cc2)cc1NC(C)=O
Reactant: [O-][I+2]([O-])O
Agent: II
Solvent: CCO
Product: CCOC(=O)Cn1nc(-c2ccc(F)cc2)c(I)c1NC(C)=O
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 397.9 %

Procedure:
To a solution of ethyl 2-(5-acetamido-3-(4-fluorophenyl)-1H-pyrazol-1-yl)acetate (1.1 g, 3.7 mmol) in ethanol (33 mL) were added iodic acid (170 mg, 0.95 mmol) and iodine (480 mg, 1.9 mmol). The reaction was stirred for 90 min at 60° C. The reaction mixture was concentrated in vacuo and the residue was dissolved in CH2Cl2 and washed with a 2 N Na2SO3 solution. The organic phase was dried over MgSO4, filtered and evaporated to give ethyl 2-(5-acetamido-3-(4-fluorophenyl)-4-iodo-1H-pyrazol-1-yl)acetate as a white solid (1.63 g), which was used as such in the subsequent step.
Reaction SMILES: [CH3:1][C:2]1SC(CNCC)=C(C)[N:6]=1.Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15](OC)[N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:2]([NH:6][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1)[CH3:1]
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CCNCc1sc(C)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.0 g of 2,4-dimethyl-5-ethylaminomethylthiazole, 1.5 g of 2-chloro-3-nitro-6-methoxypyridine, 5.0 g of potassium carbonate, 20 mL of N,N-dimethylformamide (DMF) were added into a 150 mL of single-neck flask equipped with a magnetic stirrer. And the reaction mixture was stirred at room temperature overnight. And then extracted with ethyl acetate, the organic layer was separated while the aqueous layer was extracted with ethyl acetate twice. The organic phases were combined, and dried over anhydrous sodium sulfate after washed with an iced aqueous sodium chloride solution twice, then remove the solvent under reduced pressure to obtain 1.5 g of crude product which was purified by a silica gel column chromatography using a petroleum ether/ethyl acetate (20/1) as an eluent to obtain 0.49 g of 6-methoxy-N-(2,4-dimethylthiazole-5-yl)methyl)-N-ethyl-3-nitropyridine-2-amine, having the content of 98%, as a yellow viscous liquid, and solidified after standing. GC-MS (M+) (EI, 70 eV, m/z) calc: 322. found: 322. 1H NMR (CDCl3/TMS, 300 MHz) δ (ppm) 1.199 (t, J=7.2 Hz, 3H, CH3), 2.383 (s, 3H, CH3), 2.603 (s, 3H, CH3), 3.303 (q, J=7.2 Hz, 2H, CH2), 3.960 (s, 3H, CH3), 4.778 (s, 2H, CH3), 6.151 (d, J=8.7 Hz, 1H, Py H), 8.141 (d, J=9.0 Hz, 1H, Py H).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:25]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)(=[O:27])[CH3:26]>C1(C)C=CC=CC=1>[C:25]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([O:1][C:2]2[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])=[CH:4][CH:3]=2)=[O:34])=[CH:31][CH:30]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccc(C(=O)Oc2ccc(C(=O)OCc3ccccc3)cc2)cc1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
A 200 ml. four-necked flask equipped with a condenser tube and a thermometer was charged with 36 g of p-acetoxybenzoic acid and 71.4 g of thionyl chloride, and they were reacted at 50° C. for 4 hours. The excess of thionyl chloride was evaporated under reduced pressure to give p-acetoxybenzoyl chloride. Then, a 300 ml four-necked flask equipped with a condenser tube, a thermometer and a dropping funnel was charged with 45.7 g of benzyl p-hydroxybenzoate, 20.2 g of triethylamine and 100 ml of toluene. The temperature of the flask was raised to 30° C., and a solution of 39.7 g of p-acetoxybenzoyl chloride in 50 g of toluene was added dropwise over 1 hour, and the reaction was carried out at 50° C. for 30 minutes. After cooling, the reaction mixture was washed with three 50 ml portions of water, and the solvent was evaporated under reduced pressure. Recrystallization of the residue from methanol gave benzyl p-(p-acetoxybenzoyloxy)benzoate.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[OH:8][C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[C:11]2[CH:20]=[CH:21][S:22][C:10]=12.[OH-].[K+]>O>[CH3:5][N:12]1[CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9](=[O:8])[C:10]2[S:22][CH:21]=[CH:20][C:11]1=2
Reactant: CCOC(=O)c1cnc2ccsc2c1O
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1cn(C)c2ccsc2c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dimethyl sulphate (3.9 ml) can be added to a stirred solution of ethyl 7-hydroxythieno[3,2-b]-pyridine-6-carboxylate (4.63 g) and potassium hydroxide (3.5 g) in water (50 ml) at 0-5° C. More water (20 ml) can be added and the mixture can be stirred at ambient temperature for 24 hours. The solid product can be collected by filtration, washed with water and dried to give the compound ethyl 4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate, m.p. 122-128° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:20]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[C:21]([C:23]3[C:27]4=[N:28][C:29]([O:34][CH3:35])=[C:30]([O:32][CH3:33])[CH:31]=[C:26]4[N:25]([CH2:36][CH2:37]I)[CH:24]=3)=[CH:22][C:15]=12>CC#N>[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:20]([S:39]([C:42]3[CH:43]=[CH:44][C:45]([CH3:48])=[CH:46][CH:47]=3)(=[O:40])=[O:41])[C:21]([C:23]3[C:27]4=[N:28][C:29]([O:34][CH3:35])=[C:30]([O:32][CH3:33])[CH:31]=[C:26]4[N:25]([CH2:36][CH2:37][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH:24]=3)=[CH:22][C:15]=12
Reactant: C1COCCN1
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCN1CCOCC1
Temperature: 60 °C
Yield: 257.1 %

Procedure:
Add morpholine (3.5 equiv., 25.9 mg, 26.1 μmol, 0.30 mmol) and K2CO3 (11.7 mg, 0.085 mmol) to bisazaindole 32 (54 mg, 0.0848 mmol) in CH3CN (6.0 mL). After heating at 60° C. for 30 h, concentrate the reaction medium under vacuum and submit the residue of raw product to flash chromatography on SiO2 (MeOH at 2-4%/CH2Cl2) to obtain 33 (40 mg, 79.2%) as an ivory-colored solid: 1H NMR (CDCl3) δ 8.26 (d, 1H, J=5.4 Hz), 7.72 (d, 2H, J=8.4 Hz), 7.66 (s, 1H), 7.16 (m, 3H), 7.09 (d, 2H, J=8.1 Hz), 4.29 (t, 2H, J=6.6 Hz), 4.05 (s, 3H), 4.01 (s, 3H), 3.73 (m, 4H), 2.86 (t, 2H, J=6.6 Hz), 2.55 (m, 4H), 2.33 (s, 3H), TLC (MeOH at 4%/CH2Cl2, 0.25% of NH3) Rf=0.25, m/z obs.=597.56 (M+1)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:37]=[CH:36][C:9]([NH:10][C:11]2[N:12]=[C:13]([CH3:35])[C:14]3[CH:20]=[CH:19][C:18](=[O:21])[N:17]([C:22]4[CH:34]=[CH:33][C:25]([C:26]([O:28]C(C)(C)C)=[O:27])=[CH:24][CH:23]=4)[C:15]=3[N:16]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([NH:10][C:11]2[N:12]=[C:13]([CH3:35])[C:14]3[CH:20]=[CH:19][C:18](=[O:21])[N:17]([C:22]4[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:33][CH:34]=4)[C:15]=3[N:16]=2)=[CH:36][CH:37]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2nc(C)c3ccc(=O)n(-c4ccc(C(=O)OC(C)(C)C)cc4)c3n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(Nc2nc(C)c3ccc(=O)n(-c4ccc(C(=O)O)cc4)c3n2)cc1
Yield: 84.5 %

Procedure:
A solution of compound 3 (0.12 g; 0.2397 mmol) and trifluoroacetic acid (0.2 mL; 2.62 mmol) in 3 mL of methylene chloride was stirred at room temperature for 2 h. The reaction mixture was concentrated and the crude product taken up with ethyl acetate and n-hexane to yield compound 9 (0.09 g; 84%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([N+:18]([O-])=O)[C:15]([F:21])=[CH:14][C:13]=2[F:22])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[C:3]([C:12]2[C:13]([F:22])=[CH:14][C:15]([F:21])=[C:16]([NH2:18])[CH:17]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:9])([F:8])[F:10]
Reactant: Cn1nc(-c2cc([N+](=O)[O-])c(F)cc2F)c(Cl)c1C(F)(F)F
Agent: [Fe]
Solvent: CC(=O)O
Product: Cn1nc(-c2cc(N)c(F)cc2F)c(Cl)c1C(F)(F)F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
A solution of 3.4 g (0.01 mole) 4-chloro-3-(2,4-difluoro-5-nitrophenyl)-1-methyl-5-(trifluoro-methyl)-1H-pyrazole in 50 mL acetic acid was heated to 80° C. under a nitrogen atmosphere. The heat and nitrogen were removed and 1.7 g (0.03 mole) iron powder was added in 3 portions over 5 min. The solution was stirred at 80° C. for an additional 30 min. The solution was cooled and filtered through Celite®. The filtrate was diluted with 100 mL water and extracted three times with ethyl acetate. The ethyl acetate extracts were washed with a saturated NaHCO3 solution, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified chromatographically using 35% ethyl acetate in hexane as the eluent to give 2.46 g (79%) of 5-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4-difluorobenzenamine as a white solid, mp 82° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8](OCC)=[O:9])=[C:4]([N+:15]([O-])=O)[CH:3]=1>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][CH2:7][C:8](=[O:9])[NH:15][C:4]=2[CH:3]=1
Reactant: CCOC(=O)COc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1COc2ccc(Cl)cc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Iron powder (1.4 g) was added to a solution of the product from step (i) (1.4 g) in acetic acid (30 ml) and the mixture stirred at RT for 1 h. The mixture was filtered and the filtrate evaporated under reduced pressure. Yield 0.44 g
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH:7]=[CH:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11](=[O:12])[C:2]=12.ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)(Cl)Cl>[N+:1]1([O-:25])[CH:6]=[CH:5][CH:4]=[C:3]2[CH:7]=[CH:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11](=[O:12])[C:2]=12
Reactant: O=c1c2ccccc2ccc2cccnc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=c1c2ccccc2ccc2ccc[n+]([O-])c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.2 %

Procedure:
To a solution of 1.04 grams (0.005 mole) of benzo[5,6]cyclohepta[1,2-b]pyridin-11-one in 20 milliliters of chloroform was added 1.19 grams (0.0055 mole) of m-chloroperbenzoic acid and the resulting solution stirred at room temperature for 24 hours. At this time an additional 0.6 gram of m-chloroperbenzoic acid was added and the mixture stirred for 5 hours; thereafter, another 0.3 gram of m-chloroperbenzoic acid was added and the mixture stirred overnight. The resulting reaction mixture was then washed twice with 10 percent aqueous sodium hydroxide, twice with water and the washed solution dried over magnesium sulfate. The mixture was filtered to remove drying agent and the solvent removed under reduced pressure to obtain 0.75 gram of benzo[5,6]cyclohepta[1,2-b]pyridin-11-one N-oxide intermediate as residue.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].CN1C=CN=C1.[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:20][C:17]1[CH:18]=[CH:19][C:14]([S:13][CH3:12])=[CH:15][CH:16]=1
Reactant: CSc1ccc(O)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cn1ccnc1
Product: CSc1ccc(OP(=O)(Cl)Cl)cc1
Yield: 42.8 %

Procedure:
To a solution of freshly distilled phosphoryl chloride (45 ml, 0.5 mol) and 1-methylimidazole (0.15 ml), is added 4-(methylthio)phenol (14, 0.1 mol) and the solution is heated under reflux for 20 h. The excess of phosphoryl chloride is removed by distillation and the residue distilled under reduced pressure to give the product (11 g, 42% yield); bp 135°-142° C. (2 mm Hg) 1H NMR (CDCl3) δ 2.39 (3H, S, SCH3), 7.22 (4 H, s, phenyl).
Reaction SMILES: Cl[C:2]1[N:13]=[C:12]([NH:14][CH:15]2[CH2:20][CH2:19][CH:18]([N:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)[C:11]2[C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:22][N:21]([CH3:23])[CH:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:12]2[C:11]3[C:10]4[CH2:9][CH2:8][CH2:7][C:6]=4[S:5][C:4]=3[N:3]=[C:2]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:13]=2)[CH2:16][CH2:17]1
Reactant: Nc1ccccc1
Reactant: CN(C)C1CCC(Nc2nc(Cl)nc3sc4c(c23)CCC4)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN(C)C1CCC(Nc2nc(Nc3ccccc3)nc3sc4c(c23)CCC4)CC1
Temperature: 110 °C
Reaction time: 8 h
Yield: 14.4 %

Procedure:
A solution of 4-N-[10-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine (120 mg, 0.34 mmol, 1.00 equiv) in dioxane (5 mL), was added aniline (60 mg, 0.72 mmol, 2.00 equiv), XantPhos (20 mg, 0.03 mmol, 0.10 equiv) and Pd2(dba)3 (20 mg, 0.02 mmol, 0.06 equiv) subsequently under nitrogen. The resulting solution was stirred overnight at 110° C. After completion of the reaction, the solids were filtered out and the filtrate was diluted with DCM, washed with brine. The organic layer was concentrated under vacuum and the crude product (80 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH4HCO3 and CH3CN (25% CH3CN up to 100% in 15 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the 12-N-[4-(dimethylamino)cyclohexyl]-10-N-phenyl-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene-10,12-diamine (20 mg) as a grey solid. LCMS (ES, m/z): 408 [M+H]+;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22]CC)=O)[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH:26]1[CH:30]=[C:29]([CH2:31][CH2:32][NH2:33])[N:28]=[CH:27]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:33][CH2:32][CH2:31][C:29]4[N:28]=[CH:27][NH:26][CH:30]=4)=[O:22])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: NCCc1c[nH]cn1
Product: O=C(NCCc1c[nH]cn1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-(1H-imidazol-4-yl)ethylamine employing methods similar to those described in Example 11 and was obtained as an off-white solid: 1H NMR (CF3CO2D) δ 8.66 (1H, s), 8.60 (1H, s), 8.43 (1H, s), 7.39 (1H, s), 7.22 (2H, m), 7.08 (2H, t, J=8.4 Hz), 4.36 (2H, s), 4.00 (2H, br, t, J=6 Hz), 3.29 (2H, br t, J=6 Hz); ES+ MS: 408 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[NH:6]2.[Br:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]2[O:22][C:23]([CH2:26]Cl)=[N:24][N:25]=2)[CH:20]=1>>[Br:14][C:15]1[CH:20]=[C:19]([C:21]2[O:22][C:23]([CH2:26][N:6]3[C:7]4[C:3](=[C:2]([Cl:1])[C:10]([C:11]#[N:12])=[CH:9][CH:8]=4)[CH:4]=[C:5]3[CH3:13])=[N:24][N:25]=2)[CH:18]=[N:17][CH:16]=1
Reactant: ClCc1nnc(-c2cncc(Br)c2)o1
Reactant: Cc1cc2c(Cl)c(C#N)ccc2[nH]1
Product: Cc1cc2c(Cl)c(C#N)ccc2n1Cc1nnc(-c2cncc(Br)c2)o1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-methyl-1H-indole-5-carbonitrile and 3-bromo-5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyridine: 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.94 (s, 1H), 8.48 (s, 1H), 7.96 (s, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 5.96 (s, 2H), 2.47 (s, 3H); MS (ES) m/z 429 (M+1).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:15]([CH2:22][CH3:23])[C:16](N(OC)C)=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:24]([N:14]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C@@H:15]([CH2:22][CH3:23])[CH:16]=[O:17])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC[C@@H](C(=O)N(C)OC)N(Cc1ccccc1)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Temperature: -30 °C
Reaction time: 2.5 h

Procedure:
Under an atmosphere of argon, at −20 to −30° C., LiAlH4 (2.34 g, 61.8 mmol, Eq: 1.2) was combined with THF (150 ml) to give a light grey suspension. Then (S)-2-(dibenzylamino)-N-methoxy-N-methylbutanamide (24 g, 51.5 mmol, Eq: 1.00), diluted in THF (50 ml) was added at −30° C. The reaction was stirred for 2.5 h at −30° C. The excess reagent was quenched by the dropwise addition of ethyl acetate and water (1/1, ˜30 ml). The reaction was vigorously stirred for 15 min at RT. After filtration through dicalite, the mixture was diluted with water (100 ml) and extracted with ethyl acetate. The organic layers were dried over Na2SO4 and concentrated in vacuo. The title compound was obtained as a light brown liquid (13.41 g, 97.5%, MS (m/e)=268.3 [M+H+]).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[CH:21][N:20]=1>>[Cl:18][C:19]1[CH:24]=[C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)[CH:22]=[CH:21][N:20]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1ccnc(Cl)c1
Product: N#Cc1cc(-c2ccnc(Cl)c2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (68 mg, 84%), MS (ISN) m/z=323.5 [(M+H)+], mp 286° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 2-chloro-pyridin-4-ylboronic acid (51.1 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH:12]([C:16]1[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[C:13]([OH:15])=[O:14])=[O:4].[N:24]12[CH2:31][CH2:30][CH:27]([CH2:28][CH2:29]1)[C@@H:26](O)[CH2:25]2.O.N1(O)C2C=CC=CC=2N=N1.C(=NC1CCCCC1)=NC1CCCCC1>C1COCC1>[CH3:23][O:22][C:19]1[N:18]=[CH:17][C:16]([CH:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])[C:13](=[O:15])[O:14][C@@H:26]2[CH:27]3[CH2:30][CH2:31][N:24]([CH2:29][CH2:28]3)[CH2:25]2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccccc1NC(C(=O)O)c1ccc(OC)nc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(2-(methoxycarbonyl)phenylamino)-2-(6-methoxypyridin-3-yl)acetic acid (I79) (118 mg, 0.37 mmol), (R)-quinuclidin-3-ol (52.2 mg, 0.41 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (62.8 mg, 0.41 mmol), and N,N′-methanediylidenedicyclohexanamine (85 mg, 0.41 mmol) was dissolved in dry THF (10 ml) and stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the crude product was taken up with EtOAc and washed twice with 2M K2CO3. The organic phase was dried over Na2SO4, filtered and evaporated to dryness to obtain the title compound, which was used in the next step without any further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:6](=[O:20])[C:5]2=O.Cl.[NH2:23][NH:24][C:25]([NH2:27])=[O:26]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:6](=[O:20])/[C:5]/2=[N:23]/[NH:24][C:25]([NH2:27])=[O:26]
Reactant: CC(C)N(CCN1C(=O)C(=O)c2cc(Br)ccc21)C(C)C
Reactant: NNC(N)=O
Agent: Cl
Product: CC(C)N(CCN1C(=O)/C(=N/NC(N)=O)c2cc(Br)ccc21)C(C)C
Yield: 72.6 %

Procedure:
By using 5-bromo-1-(2-diisopropylaminoethyl)isatin and semicarbazide hydrochloride, a method analogous to that described in Example 4 was carried out to obtain (E)-5-bromo-1-(2-diisopropylaminoethyl)isatin 3-semicarbazone having a melting point of 149°-153° C. (yield: 72.6%, recrystallizing solvent: chloroform-hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([CH:17](C(O)=O)[C:18]([OH:20])=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCCCCC(c1ccc(OC)cc1OC)C(C(=O)O)C(=O)O
Solvent: Cc1ccccc1C
Product: CCCCCC(CC(=O)O)c1ccc(OC)cc1OC
Yield: 74 %

Procedure:
A solution of 6.57 g of 2-[1-(2,4-dimethoxyphenyl)hexyl]malonic acid [prepared as described in step (i) above] in 60 ml of xylene was heated under reflux for 3 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 100 g of silica gel, using a gradient elution method, with mixtures of methylene chloride and methanol ranging from 1:0 to 10:1 by volume as the eluent, to give 4.55 g (a total yield of 74% over the two steps) of the title compound as crystals, melting at 52-53° C. (from hexane).
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[C:11]([O:13]CC)=O.O=S(Cl)[Cl:18]>C1(C)C=CC=CC=1.[OH-].[Na+]>[F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[C:11]([Cl:18])=[O:13]
Reactant: CCOC(=O)c1c(C(F)F)nn(C)c1F
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Temperature: 80 °C

Procedure:
A solution of 22.3 g (100 mmol) of ethyl 5-fluoro-1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylate in 100 ml of toluene and 50 ml of 10% NaOH are stirred at AT for 3 hours. The aqueous phase is separated and adjusted to pH 5 with HCl. After extracting the product with chlorobenzene and azeotropically drying the organic phase, 23.8 g (200 mmol) of SOCl2 are added to the solution and the mixture is heated at 80° C. for 2 hours. After evaporating the reaction mixture, 20.1 g of the product are obtained as an oil with a purity (GC) of 98%.
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[S:7][N:6]=1)(=O)=O.[CH2:17]([OH:21])[C:18]#[C:19][CH3:20].[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[Cl:16][C:12]1[CH:11]=[C:10]([C:8]2[S:7][N:6]=[C:5]([O:21][CH2:17][C:18]#[C:19][CH3:20])[N:9]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CC#CCO
Reactant: CS(=O)(=O)c1nsc(-c2cccc(Cl)c2)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC#CCOc1nsc(-c2cccc(Cl)c2)n1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
In 2.5 ml of N,N-dimethylformamide, 350 mg of 3-methylsulfonyl-5-(3-chlorophenyl)-1,2,4-thiadiazole and 98 mg of 2-butyne-1-ol were dissolved, to the resulting solution was added 56 mg of sodium hydride (60% oily) with ice-cooling, and the mixture was stirred for 30 minutes, and further stirred at room temperature for 1 hour. Then, the reaction mixture was poured into an aqueous saturated sodium chloride solution, and the mixture was extracted with t-butyl methyl ether. The residue obtained by concentration of the organic layer was subjected to silica gel column chromatography to obtain 290 mg of 5-(3-chlorophenyl)-3-(2-butynyloxy)-1,2,4-thiadiazole (the compound (9) of the present invention).