Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](OS(O)(=O)=O)=[C:4]2[C:9](=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[NH:8][C:7](=[O:16])[C:6]([C:17](=[O:20])[CH2:18][CH3:19])=[C:5]2C.[CH2:27]([NH2:30])[C:28]#[CH:29]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:11]=1)[NH:8][C:7](=[O:16])[C:6]([C:17](=[O:20])[CH2:18][CH3:19])=[C:5]2[NH:30][CH2:27][C:28]#[CH:29]
Reactant: C#CCN
Reactant: CCC(=O)c1c(C)c2c(OS(=O)(=O)O)c(Cl)cc(C(F)(F)F)c2[nH]c1=O
Product: C#CCNc1c(C(=O)CC)c(=O)[nH]c2c(C(F)(F)F)cc(Cl)cc12
Yield: 86.9 %

Procedure:
6-Chloro-4-methylsulfoxy-3-propionyl-8-trifluoromethyl-2-quinolinone (365 mg, 1 mmol) and propargylamine (55 mg, 1 mmol) were used and the reaction was carried out as in the above process of example 1 to obtain the desired product (310 mg, yield: 87%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[O:18])[CH:12]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:17]([C:13]1[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=1)[OH:18]
Reactant: O=Cc1cccnc1
Reactant: Fc1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OC(c1cccnc1)c1c[nH]c2ccc(F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
A stirred solution of 5-fluoroindole (4 g, 30 mmol) in methanol is treated with 3-pyridine carboxaldehyde (2.79 ml, 30 mmol), cooled to 0° C., treated with 50% NaOH (3.25 ml), stirred at 0° C. for 1 hr, warmed to room temperature, stirred for 3 hr, treated with water and extracted with ethyl acetate. The extracts are combined, dried over Na2SO4 and concentrated in vacuo. The residue is treated with ethyl acetate and filtered. The filtrate is further concentrated and filtered. The filtercakes are combined and dried to afford the title compound as a pale orange solid 5.2 g (73%) mp 131-133° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][S:10]([CH2:13][C:14]([O-:16])=[O:15])(=[O:12])=[O:11])=[CH:5][C:4]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>O.CO>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][S:10]([CH2:13][C:14]([OH:16])=[O:15])(=[O:12])=[O:11])=[CH:5][C:4]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1ncc(CS(=O)(=O)CC(=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ncc(CS(=O)(=O)CC(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
A solution of 2-((6-methoxy-5-nitropyridin-3-yl)methylsulfonyl)acetate (1.83 g, 6 mmol) and sodium carbonate (1.8 g, 15 mmol) in a mixture of water (10 mL) and methanol (10 mL) was stirred at room temperature for 4 hours. After evaporated to dryness, the residue was acidized by dropwise addition of 1N aq. HCl. White solid was precipitated gradually as pH was brought to 2 and filtrated to give the pure product (1.72 g, 98.7%). M.p. 183-186° C.; 1H-NMR (DMSO-d6): δ 4.06 (s, 3H, OCH3), 4.13 (s, 2H, CH2), 4.79 (s, 2H, CH2), 8.48 (d, 1H J=2.0 Hz, Py-H), 8.50 (d, 1H, J=2.0 Hz, Py-H); 13C-NMR (DMSO-d6): δ 55.07, 55.41, 57.15, 118.45, 133.64, 137.96, 154.26, 156.23, 164.88; HR-MS (ESI+) m/z: 289.0064 [M+H]+; C9H10N2O7S requires 290.0209
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH2:10]([O:14]C(Cl)Cl)CCC>C(=S)=S.[Ti](Cl)(Cl)(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]=[O:14])=[CH:2]1
Reactant: c1ccc2sccc2c1
Reactant: CCCCOC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: S=C=S
Product: O=Cc1csc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 15.2 %

Procedure:
To a solution of benzothiophene (1.08 g, 8.0 mmol) in carbon disulfide (20 mL) at 0° C. was added titanium tetrachloride (3 mL, 27.3 mmol) followed by dichloromethyl n-butyl ether (1.24 g, 7.9 mmol) slowly dropwise. The reaction mixture was warmed to 25° C. and stirred for 1.5 h. The reaction was quenched with conc. hydrochloric acid solution (1 mL), diluted with chloroform (60 mL) and washed with water (50 mL), saturated sodium bicarbonate solution (2×30 mL) and brine (30 mL). The organic layer was dried (MgSO4), filtered, concentrated and flash chromatographed (silica gel, 2.5-5% diethyl ether in petroleum ether) to afford benzothiophene-3-carboxaldehyde (195 mg, 15% yield) as a yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]([CH3:23])[CH:13]=1.[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O>[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([O:31][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH3:23])[CH:13]=2)[CH2:27][CH2:26]1
Reactant: Cn1cc(-c2cc(S(C)(=O)=O)ccc2F)c2ccccc2c1=O
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2O[C@H]2CC[C@H](N)CC2)c2ccccc2c1=O
Temperature: 120 °C
Reaction time: 12 h

Procedure:
A mixture of 4-(2-fluoro-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one (200 mg, 0.60 mmol), trans-4-aminocyclohexan-1-ol (278 mg, 2.42 mmol) and Cs2CO3 (591 mg, 1.81 mmol) in DMSO (4 mL) was stirred at 120° C. for 12 hrs. Water (20 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to give the title compound (103.15 mg, 36.9%) as its hydrochloride salt. 1H NMR (DMSO-d6, 400 MHz) δ 8.28 (d, J=8.0 Hz, 1H), 8.10 (s, 3H), 7.95 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.80 (d, J=2.4 Hz, 1H), 7.63 (t, J=7.2 Hz, 1H), 7.51-7.49 (m, 3H), 7.14 (d, J=8.0 Hz, 1H), 4.50-4.44 (m, 1H), 3.56 (s, 3H), 3.22 (s, 3H), 2.95-2.85 (m, 1H), 2.00-1.94 (m, 2H), 1.84 (d, J=11.2 Hz, 2H), 1.47-1.41 (m, 2H), 1.20-1.12 (m, 2H). LCMS (M+H)+=427.1 (M+H)+
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[OH:14].[CH:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:21]([O:14][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH:1]=1)[C:18]1[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc2c(c1)[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc3c(c2)[nH]c2ccccc23)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.5 %

Procedure:
A mixture of 9H-carbazol-2-ol (8.57 g, 46.78 mmol, 1.0 eq), BnBr (5.56 mL, 46.78 mmol, 1.0 eq) and K2CO3 (6.47 g, 46.78 mmol, 2.0 eq) in DMF (70 mL) was stirred at room temperature for two days. Then water (70 mL) was added, the mixture was stirred at room temperature for another 5 minutes. The precipitate was filtered and washed with water three times first, then washed with ethyl acetate once. The collected solid was dried in air under reduced pressure to afford the desired product as a grey solid (10.68 g in 83% yield). 1H NMR (DMSO-d6, 400 MHz): δ 5.21 (s, 2H), 6.86 (dd, J=7.2, 2.0 Hz, 1H), 7.06 (d, J=1.6 Hz, 1H), 7.10-7.13 (m, 1H), 7.28-7.31 (m, 1H), 7.35 (t, J=6.0 Hz, 1H), 7.40-7.44 (m, 3H), 7.52 (d, J=5.6 Hz, 2H), 7.97-8.00 (m, 2H), 11.12 (s, 1H).
Reaction SMILES: [C-:1]#[N:2].[Na+].[Br:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[F:14])[C:8](F)=[O:9]>>[F:14][C:13]1[CH:12]=[CH:11][C:7]([C:8]([C:1]#[N:2])=[O:9])=[CH:6][C:5]=1[Br:4]
Reactant: [C-]#N
Reactant: O=C(F)c1ccc(F)c(Br)c1
Agent: [Na+]
Product: N#CC(=O)c1ccc(F)c(Br)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
177 g (3.6 moles) of sodium cyanide and 663 g (3 moles) of 3-bromo-4-fluorobenzoyl fluoride were together initially introduced into the reaction vessel and were heated. At about 80° C., an exothermic reaction started, which had to be restrained somewhat by slight cooling. The temperature was allowed to rise to 100° C. and the mixture was stirred at 100° C. for 1 hour. The exothermic reaction continued for about 10 minutes, and additional heat had then to be supplied to the mixture. The mixture was then cooled and the salts were filtered off and destroyed in saturated iron sulphate solution and the filtrate was distilled on a column. 507 g (74% of theory) of a colorless oil with a boiling point of 126° C./20 mm Hg were thus obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH2:7][CH2:8]Cl)[CH:3]=[C:4]([Cl:6])[Cl:5]>N1C2C(=CC=CC=2)C=CC=1>[Cl:5][C:4]([Cl:6])=[CH:3][C:2]([CH3:10])([CH3:1])[CH:7]=[CH2:8]
Reactant: CC(C)(C=C(Cl)Cl)CCCl
Solvent: c1ccc2ncccc2c1
Product: C=CC(C)(C)C=C(Cl)Cl
Yield: 73.3 %

Procedure:
201.5 g (1 mol) of 3,3-dimethyl-1,1,5-trichloropent-1-ene were slowly added dropwise to 1,000 ml of quinoline at from 225° to 230° C., and distillate was taken off simultaneously via the top of the column. The temperature was increased until the quinoline boiled, and a total of 126 g of distillate were isolated and again fractionated. 121 g (73% of theory) of 1,1-dichloro-3,3-dimethyl-1,4-pentadiene of boiling point 49° to 53° C./20 mm Hg were obtained. ##STR25##
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:29][O:30][C:31](=[O:45])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[C:34]([NH2:44])[CH:33]=1>CN(C=O)C.O.C(Cl)CCl>[CH3:29][O:30][C:31](=[O:45])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH:39]([CH2:40][CH3:41])[CH2:42][CH3:43])=[C:34]([NH:44][C:7](=[O:9])[CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH:33]=1
Reactant: O=C(O)Cc1ccco1
Reactant: CCC(CC)Nc1ccc(C(=O)OC)cc1N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCC(CC)Nc1ccc(C(=O)OC)cc1NC(=O)Cc1ccco1
Reaction time: 16 h
Yield: 87 %

Procedure:
To a solution of 4.48 g of 2-furylacetic acid in 30 ml of dry DMF 1.00 g of HOBT, 3.97 g of EDC and 1.8 ml of DIPEA were added at 0° C. After 30 min 3.50 g of 3-amino-4-(1-ethyl-propylamino)-benzoic acid methyl ester and 1.8 ml of DIPEA were added and the reaction was stirred at it for 16 h. The reaction was then poured into water and extracted with ethyl acetate three times. The combined organic phases were washed with saturated aqueous sodium carbonate solution and saturated aqueous ammonium chloride solution, dried over magnesium sulphate and concentrated to obtain 4.44 g (87%) of 4-(1-Ethyl-propylamino)-3-(2-furan-2-yl-acetylamino)-benzoic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[O:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[C:9](S(C(F)(F)F)(=O)=O)=[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:7]=1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[O:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([C:38]2[CH:39]=[CH:40][C:35]([C:34]([F:45])([F:44])[F:33])=[CH:36][CH:37]=2)=[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:7]=1
Reactant: COc1nc(Oc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1S(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: COc1nc(Oc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(C(F)(F)F)cc1

Procedure:
This derivative was prepared by the method described in Example 132 using 2-(3,4-difluorophenoxy)-4-methoxy-5-trifluoromethansulfonyl-6-[2,4-dichlorophenyl]pyrimidine (60 mg, 0.11 mmol) as described in Reference Example 17 and 4-trifluoromethylbenzeneboronic acid (Lancaster, 24 mg, 0.13 mmol HPLC Rt=4.76 min. 1H-NMR 500 MHz (CDCl3): 4.13 (s, 3H), 6.55 (m, 1H), 6.68 (m, 1H), 7.07 (q, J=10 Hz, 1H), 7.28 (m, 3H), (7.50 m, 3H), 7.61 (d, J=10 Hz, 2H).
Reaction SMILES: Cl[C:2]1[C:3]([CH:15]2[CH2:17][CH2:16]2)=[C:4]([CH:12]2[CH2:14][CH2:13]2)[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[O-:18][CH2:19][CH3:20].[Na+].O>C(O)C>[CH:15]1([C:3]2[C:2]([O:18][CH2:19][CH3:20])=[N:7][N:6]3[C:8]([NH2:11])=[N:9][N:10]=[C:5]3[C:4]=2[CH:12]2[CH2:14][CH2:13]2)[CH2:17][CH2:16]1
Reactant: CC[O-]
Reactant: Nc1nnc2c(C3CC3)c(C3CC3)c(Cl)nn12
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1nn2c(N)nnc2c(C2CC2)c1C1CC1
Reaction time: 1 h
Yield: 96.3 %

Procedure:
6-Chloro-7,8-dicyclopropyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.016, 0.1 g) was dissolved in ethanol (20 ml) while stirring and under argon. Thereafter, the reaction mixture was admixed with sodium ethoxide (110 mg) and stirred at RT for 1 h, then at 55° C. for 1 h. Subsequently, the mixture was left to stand overnight and then heated to reflux for 7.5 h. After standing over the weekend, the solvent was drawn off, and the residue was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 100 mg of the title compound were obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:24][CH2:25][O:26][CH3:27])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[CH2:28][CH2:29][CH3:30])[CH:7]=1.O.[CH3:32][N:33](C)C=O>[C-]#N.[Zn+2].[C-]#N>[F:19][C:16]([F:17])([F:18])[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[N:4][CH:3]=[C:2]([CH:7]=2)[C:32]#[N:33])=[C:10]([CH2:28][CH2:29][CH3:30])[CH:11]=1)([O:24][CH2:25][O:26][CH3:27])[C:20]([F:21])([F:22])[F:23]
Reactant: CN(C)C=O
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cncc(Br)c1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cncc(C#N)c1
Yield: 84 %

Procedure:
To a solution of 3-bromo-5-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy) pyridine (320 mg, 637 μmol) in N,N-dimethylformamide (5 mL), zinc cyanide (112 mg) and tetrakis triphenylphosphine palladium complex (74 mg) were added at room temperature under an argon atmosphere, and the resultant mixture was allowed to react in a microwave (80 watts, 10 minutes). After completion of the reaction, the reaction solution was added with water at room temperature, extracted with ethyl acetate, and then concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (239 mg, yield 84%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:24][CH3:25])=[N:8][NH:9][C:10]=1[O:11][CH:12]([CH3:23])[C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])=O)=[O:5])[CH3:2].[NH4+].[Cl-]>ClCCCl.Cl[Ti](Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:24][CH3:25])=[N:8][N:9]2[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])=[C:12]([CH3:23])[O:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CC)n[nH]c1OC(C)C(=O)c1ccc(Cl)cc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Product: CCOC(=O)c1c(CC)nn2c(-c3ccc(Cl)cc3Cl)c(C)oc12
Temperature: 80 °C

Procedure:
To a stirred solution 5-[2-(2,4-dichloro-phenyl)-1-methyl-2-oxo-ethoxy]-3-ethyl-1H-pyrazole-4-carboxylic acid ethyl ester (2.48 g, 6.44 mmol) in 1,2-dichloroethane (40 ml) at RT is added TiCl4 (0.86 ml, 7.73 mmol). The reaction mixture is heated to 80° C. for 2 hrs. On cooling, the mixture is poured into a stirred sat. aq. NH4Cl (150 ml), (stirring continued for 5-10 mins following addition). Celite® (filter material) is added to this mixture and then filtered through a Celite® bed. The filter-cake is washed with EtOAc (30 ml) and the filtrate is extracted with EtOAc (approx. 90 ml). The combined organics are washed with 2N Na2CO3 (30 ml), brine and dried with sodium sulphate. On evaporation the resultant solid residue is triturated in 3/1 v/v iso-hexane/diethyl ether (15 ml) at RT for ½ h; the solid is filtered and dried in vacuo to give the title compound as a white solid yield: MS: m/z 367.20 [M+H]+
Reaction SMILES: [SH:1][C:2]1[N:6]2[CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.BrC1C=CC2N(C(S[C:25]3[CH:26]=[CH:27][C:28]4[N:29]([CH:31]=[C:32]([NH:34][C:35]([CH:37]5[CH2:39][CH2:38]5)=[O:36])[N:33]=4)[N:30]=3)=NN=2)C=1>>[CH:37]1([C:35]([NH:34][C:32]2[N:33]=[C:28]3[CH:27]=[CH:26][C:25]([S:1][C:2]4[N:6]5[CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=[CH:10][C:5]5=[N:4][N:3]=4)=[N:30][N:29]3[CH:31]=2)=[O:36])[CH2:38][CH2:39]1
Reactant: O=C(O)c1ccc2nnc(S)n2c1
Reactant: O=C(Nc1cn2nc(Sc3nnc4ccc(Br)cn34)ccc2n1)C1CC1
Product: O=C(O)c1ccc2nnc(Sc3ccc4nc(NC(=O)C5CC5)cn4n3)n2c1

Procedure:
Compound 33 was prepared from 3-mercapto-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid following the procedure described in the synthesis of compound 4. 1H NMR (400 MHz, CDCl3—CD3OD 10:1) δ ppm 9.03 (bs, 1 H), 8.01 (d, J=9.1 Hz, 1 H), 7.87 (d, J=9.6 Hz, 1 H), 7.68 (d, J=9.4 Hz, 1 H), 7.36 (m, 1H), 7.09 (d, J=9.3 Hz, 1 H), 2.84 (m, 1 H), 1.72 (m, 1 H), 0.97 (m, 2 H), 0.84 (m, 2H) ESI-MS:m/z 396.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[C:15](=O)[C:14](=[CH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[CH2:13][S:12](=[O:29])(=[O:28])[CH2:11]2)[CH:6]=[CH:7][CH:8]=1.[CH2:32]([NH:35][NH2:36])[CH2:33][CH3:34]>CO>[CH2:32]([N:35]1[CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:31])([F:30])[F:1])[CH:4]=2)[CH:10]2[CH2:11][S:12](=[O:29])(=[O:28])[CH2:13][C:14](=[CH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:15]2=[N:36]1)[CH2:33][CH3:34]
Reactant: CCCNN
Reactant: O=C1C(=Cc2cccc(C(F)(F)F)c2)CS(=O)(=O)CC1=Cc1cccc(C(F)(F)F)c1
Solvent: CO
Product: CCCN1N=C2C(=Cc3cccc(C(F)(F)F)c3)CS(=O)(=O)CC2C1c1cccc(C(F)(F)F)c1

Procedure:
A mixture of 2.5g of tetrahydro-3,5-bis[[3-(trifluoromethyl)phenyl]methylene]-4H-thiopyran-4-one-1,1-dioxide and n-propyl hydrazine in 100ml of methanol is heated at reflux temperature for 1 hour. The crystals obtained on cooling to 5°-10°C are collected and dried in vacuo over phorphorus pentoxide at 50°C to yield 1.7g of the title compound, melting point 190°-191°C. The filtrate is diluted with water giving additional crude material which is recrystallized from methanol to give 400mg of the title compound, melting point 191°-193.5°C.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([CH3:28])[CH2:27][O:26]2)=[CH:21][CH:20]=1.O>C1COCC1.CN(C=O)C.CCOC(C)=O>[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([OH:26])([CH3:27])[CH2:28][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:23][CH:24]=1
Reactant: CC1(c2ccc(F)cc2)CO1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc(F)cc2)CCN(C)C1
Temperature: 120 °C

Procedure:
A mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (2.6 g, 13.1 mmol, 1 equiv.) and NaH (55%, 750 mg, 17.2 mmol, 1.3 equiv.) in 60 mL of THF was heated to 120° C. for 1 h. The reaction mixture was cooled to RT and compound 2-(4-fluorophenyl)-2-methyloxirane (4 g, 26 mmol, 2 equiv.) in DMF (25 mL) was added dropwise for 5 min. at RT followed by heating at 120° C. for 2 h. The reaction mixture was cooled to RT and water (10 mL) was added followed by dilution with EtOAc (800 mL), which was washed with water (3×150 mL) and then brine, dried over sodium sulfate and concentrated under vacuum. The product was purified using column chromatography over 230-400 Silica gel (flash) using 15% MeOH in EtOAc as eluent. Yield: 3 g (66%). 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 7.5 (m, 2H), 7.3 (d, 1H), 7.12 (m, 3H), 6.8 (d, 1H), 4.3 (bs, 1H), 4.2 (m, 2H), 4.0 (m, 3H), 3.4 (bs, 1H), 3.0 (m, 1H), 2.9 (s, 3H), 2.3 (s, 3H), 1.5 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][C@@H:13]1[NH:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.C(N(C(C)C)CC)(C)C.BrC1C=CC=CC=1S(Cl)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([N:18]2[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][C@@H:13]2[CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=C([O-])O
Agent: O=S(=O)(Cl)c1ccccc1Br
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
3-bromobenzene-1-sulfonyl chloride and (S)-tert-butyl 3-methylpiperazine-1-carboxylate was coupled following as follows: Dissolve 1 g (5 mmol) of the amine in 10 mL of methylene chloride. Add 2.0 eq. of diisopropyl ethylamine. Cool to 0° C. and add 1.5 equivalents of bromobenzene sulfonyl chloride dropwise (ca. 1 min) and stir for 5 min. Warm to rt and stir for an additional 16 h. Work up by adding a saturated solution of NaHCO3 and extracting with EtOAc. Wash the organic layer with HCl (1 N) followed by NaHCO3 and brine. Remove the solvent to afford crude, yellow oil. Purification of the sulfonamide derivative by Biotage on silica gel (99% MeOH/DCM) affords the desired product as a yellow oil. The yield was 55%. LC-MS showed the product was >95% pure and had the expected M+H+ of 420. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 7.9 (d, 1H) 7.72-7.65 (m, 2H) 7.4 (t, 1H), 3.7 (m, 2H) 3.6 (m, 1H), 3.13-3.0 (m, 2H) 2.92-2.77 (m, 2H), 1.4 (s, 12H) 1.0 (d, 3H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]3=[O:17])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.I[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[CH3:25].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][C:13]([CH3:15])([CH3:16])[N:12]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][C:24]=4[CH3:25])[C:11]3=[O:17])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Cc1ccncc1I
Reactant: CC1(C)CN(c2ccc3ncsc3c2)C(=O)N1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1C(=O)N(c2ccc3ncsc3c2)CC1(C)C
Yield: 4.4 %

Procedure:
1-Benzothiazol-6-yl-4,4-dimethyl-imidazolidin-2-one (I-201b: 100 mg, 0.4048 mmol) was reacted with 3-iodo-4-methyl-pyridine (115 mg, 0.525 mmol), 1,4-dioxane (10 mL), copper iodide (7 mg, 0.0368 mmol), trans-1,2-diamino cyclohexane (18 mg, 0.1197 mmol) and potassium phosphate (214 mg, 1.0094 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in CHCl3) afforded 6 mg of the product (4.8% yield).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1Br.[CH2:21]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)P(=O)(N(C)C)N(C)C>[F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:31]1[CH2:32][CH2:33][CH:28]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:29][CH2:30]1
Reactant: CC1CCc2c(Br)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1CCc2c(N3CCC(Cc4ccccc4)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.1 %

Procedure:
In a 50 ml flask were placed 2.5 g of 9-fluoro-8-bromo-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 6.4 g of 4-benzylpiperidine and 25 ml of hexamethylphosphoric triamide and the mixture was stirred at 160° C. in an argon gas atmosphere for 7 hours. After disappearance of the starting materials was confirmed by thin layer chromatography, hexamethylphosphoric triamide was removed using a vacuum pump followed by cooling to room temperature. To the residue was added ethyl acetate and then several drops of concentrated hydrochloric acid and the mixture was allowed to stand in a refrigerator for 1 day. The crystals which formed were collected by filtration and recrystallized from dimethylformamide to give 0.45 g of 9-fluoro-8-(4-benzyl-1-piperidyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. m.p. 230°-232° C., white rhombic crystals.