Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:16])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17]C)(=[O:5])[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br>ClCCl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:16])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(O)cccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-butyryl-4-chloro-8-methoxyquinoline (26.3 g, 0.1 mol) in dichloromethane 250 ml) was cooled to -78° C. under nitrogen, and boron tribromide (75 g, 0.3 mol) added slowly. The solution was stirred overnight, warming gradually to room temperature, then quenched with water. The organic solution was separated and evaporated to give the crude product, which was used immediately without further purification.
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH:21]([C:33]3[CH:38]=[C:37]([CH2:39][OH:40])[CH:36]=[CH:35][N:34]=3)[CH2:22][C:23]3[CH:24]=[C:25]4[C:29](=[C:30]([CH3:32])[CH:31]=3)[NH:28][N:27]=[CH:26]4)=[O:19])[CH2:14][CH2:13]2)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:1]=[C:2]1[N:11]([CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][CH:21]([C:33]3[CH:38]=[C:37]([CH:39]=[O:40])[CH:36]=[CH:35][N:34]=3)[CH2:22][C:23]3[CH:24]=[C:25]4[C:29](=[C:30]([CH3:32])[CH:31]=3)[NH:28][N:27]=[CH:26]4)=[O:19])[CH2:16][CH2:17]2)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: Cc1cc(CC(OC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2cc(CO)ccn2)cc2cn[nH]c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1cc(CC(OC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2cc(C=O)ccn2)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To solid (±)-1-(4-(hydroxymethyl)pyridin-2-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl 4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxylate (28 mg, 0.0518 mmol, 1.0 equiv) was added Dess-Martin reagent (44 mg, 0.104 mmol, 2.0 equiv) and anhydrous methylene chloride (4 mL). The cloudy solution was stirred at room temperature for 2 h. The reaction was quenched with 0.5 N sodium hydroxide. The layers were separated and the organic layer was washed with brine, dried and concentrated to give an off-white solid. Purification by flash column chromatography (10% methanol/methylene chloride) afforded the desired product (23 mg, 82.4%) as an off-white powder. MS (ESI) [M+Na]+=559. 1H-NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 8.88 (d, J=3.2 Hz, 1H), 7.97 (s, 1H), 7.70-7.40 (m, 3H), 7.26-6.75 (m, 5H), 6.67 (br., 1H), 6.13-5.90 (m, 1H), 4.65-3.75 (m, 4H), 3.50-3.10 (m, 3H), 3.10-2.68 (m, 2H), 2.50 (s, 3H), 1.95-1.38 (m, 5H). HPLC tR=1.59 min.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:18])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[C:6]=1I.[CH2:19]([Li])CCC.IC>C1COCC1>[I:1][C:2]1[N:3]=[C:4]([CH3:18])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[C:6]=1[CH3:19]
Reactant: [Li]CCCC
Reactant: Cc1nc(I)c(I)n1-c1ccc(C(F)(F)F)cc1
Solvent: CI
Solvent: C1CCOC1
Product: Cc1nc(I)c(C)n1-c1ccc(C(F)(F)F)cc1
Temperature: -75 °C
Reaction time: 1 h

Procedure:
4,5-Diiodo-2-methyl-1-(4-trifluoromethyl-phenyl)-1H-imidazole (1.0 g, 2.1 mmol) was dissolved in 15 ml THF and cooled to −75° C. n-Butyllithium (1.6M in Hexane) (1.60 ml, 2.5 mmol) was added, and the mixture stirred for 60 min at −75° C. Iodomethane (0.19 ml, 3.0 mmol) was added and stirring was continued 30 min. at −75° C. and then 1 h without dry ice bath. The reaction mixture was quenched with sat. NaHCO3− solution and extracted with water and ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethylacetate 100:0→60:40 gradient) and by recrystallization from little ethyl acetate and cyclohexane. The desired compound was obtained as a white solid (197 mg, 26%), MS: m/e=367.0 (M+H+).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl[CH2:6][C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1>>[N:8]1[CH:9]=[CH:10][N:11]=[CH:12][C:7]=1[CH2:6][NH:3][CH2:2][CH2:1][NH2:4]
Reactant: NCCN
Reactant: ClCc1cnccn1
Product: NCCNCc1cnccn1

Procedure:
Ethylenediamine is reacted with 2-chloromethylpyrazine by the procedure of Example 34 to give N-(2-pyrazinylmethyl)ethylenediamine. Heating this compound with S-methylisothiourea in water under reflux for 3 hours by the procedure of Example 1 gives 2-(2-pyrazinylmethylamino)ethylguanidine.
Reaction SMILES: [F:1][C:2]1[N:3]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=[C:5]([CH:7]=O)[N:6]=1.[CH2:28](P(=O)(OCC)OCC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[H-].[Na+].O>COCCOC>[F:1][C:2]1[N:3]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=[C:5](/[CH:7]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:6]=1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Fc1nc(/C=C/c2ccccc2)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 18 h
Yield: 96.5 %

Procedure:
To a stirred mixture of 2-fluoro-4-formyl-1-triphenylmethylimidazole (0.356 g.) and diethyl benzylphosphonate (0.228 g.) in 1,2-dimethoxyethane under an argon atmosphere at room temperature was added sodium hydride (0,048 g.). Stirring was continued for 18 hours and then water (15 ml.) was added. The precipitate was filtered and dried to give 2-fluoro-1-triphenylmethyl-4-(2-phenyl-trans-vinyl)imidazole (0.415 g.), m.p. 167°-170°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C(=O)O)cc(C(F)(F)F)c1
Yield: 92.4 %

Procedure:
To a solution of 3-nitro-5-(trifluoromethyl)benzoic acid (9.8 gm, 41.7 mmol) in methanol (100 mL) was added 10% palladium on carbon (50% water content, 1.5 gm) and the suspension was shaken in a Parr® hydrogenation apparatus (Parr Instrument Company, Moline, Ill.) under a hydrogen atmosphere (40 psi). After 2 hours the catalyst was removed by filtration through a pad of celite, the pad rinsed through with methanol and the solvent evaporated under reduced pressure to give the title compound as a yellow solid (7.90 gm, 92%).
Reaction SMILES: [CH3:1][C:2]([CH:4]=[CH:5][CH3:6])=[CH2:3].[CH3:7][C:8]1([CH3:15])[C:13](=[O:14])[CH:12]=[CH:11][CH2:10][CH2:9]1>>[CH3:7][C:8]1([CH3:15])[CH2:9][CH2:10][CH:11]2[CH:12]([CH:5]([CH3:6])[CH:4]=[C:2]([CH3:3])[CH2:1]2)[C:13]1=[O:14]
Reactant: C=C(C)C=CC
Reactant: CC1(C)CCC=CC1=O
Product: CC1=CC(C)C2C(=O)C(C)(C)CCC2C1

Procedure:
adding 2-methyl-penta-1,3-diene to 6,6-dimethyl-cyclohex-2-en-1-one under the conditions of a Diels-Alder type reaction to give 3,4,4a,5,8,8a-hexahydro-2,2,6,8-tetramethyl-1(2H)-naphthalenone, and
Reaction SMILES: [CH3:1][S:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][C:4]1=[O:16].[Cl:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:17][C:3]1([S:2][CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][C:4]1=[O:16]
Reactant: CSC1C(=O)Nc2ccc(C(F)(F)F)cc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CSC1(Cl)C(=O)Nc2ccc(C(F)(F)F)cc21

Procedure:
A solution of 3-methylthio-5-trifluoromethyloxindole (1.40 g, 0.0057 mol) and N-chlorosuccinimide (800 mg, 0.006 mol) in 100 ml of carbon tetrachloride was stirred at room temperature for 1 hour. The precipitated succinimide was removed by filtration, and the filtrate was evaporated to give 3-chloro-3-methylthio-5-trifluoromethyl oxindole as a yellow solid which was dissolved in 30 ml of tetrahydrofuran and added to a vigorously stirred slurry of red mercuric oxide (1.30 g, 5.8 mmol) and boron trifluoride etherate (860 mg, 5.8 mmol) in 100 ml of 20 percent aqueous tetrahydrofuran. The resulting mixture was stirred for 2 hours at room temperature, filtered through a pad of Celite and the filtrate was extracted with four 100-ml portions of methylene chloride. The methylene chloride extracts were dried over anhydrous magnesium sulfate, filtered, and evaporated to give a residue which was chromatographed on silica gel. Elution with methylene chloride gave 5-trifluoromethylisatin as yellow needles (860 mg, 73%), mp 191°-193° (recrystallized from benzene); ir (KBr) 3200 (NH), 1750 (C=O), 1710 cm-1 (C=O); nmr (DMSO-d6), τ-1.20 (b s, 1H, NH), 2.15 (d, 1H, H6), 2.30 (s, 1H, H4), 2.90 (d, 1H, J6,7 =8 Hz, H7); mass spectrum m/e obs. 215.0196 (calc. 215.0194).
Reaction SMILES: [C:1]([NH:4][C:5]1([CH2:10][C:11]([OH:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].N[C@H:15](C1C=CC=CC=1)[CH2:16]C(O)=O.CC#N.O.CC#N>O>[C:1]([NH:4][C@H:5]([C:9]1[CH:8]=[CH:7][CH:6]=[CH:16][CH:15]=1)[CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: N[C@@H](CC(=O)O)c1ccccc1
Reactant: CC(=O)NC1(CC(=O)O)CCCC1
Solvent: O
Solvent: CC#N
Product: CC(=O)N[C@@H](CC(=O)O)c1ccccc1

Procedure:
The title compound is prepared analogously as described for (1-acetylamino-cyclopentyl)-acetic acid from (S)-3-amino-3-phenylpropionic acid. MS (LC-MS): [M+H]+=208.2. tR (HPLC, -Waters Symmetry C18 column, 10-95% CH3CN/H2O/3.5 min, 95% CH3CNIH2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 0.79 min.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[N:24]([CH3:50])[C:25]([C:27]1[S:49][C:30]2[C:31]3[CH:39]=[CH:38][C:37]([C:40](=[O:48])[NH:41][CH2:42][CH2:43][S:44]([CH3:47])(=[O:46])=[O:45])=[CH:36][C:32]=3[O:33][CH2:34][CH2:35][C:29]=2[CH:28]=1)=[O:26]>CCOC(C)=O>[Cl:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[N:24]([CH3:50])[C:25]([C:27]1[S:49][C:30]2[C:31]3[CH:39]=[CH:38][C:37]([C:40]([NH:41][CH2:42][CH2:43][S:44]([CH3:47])(=[O:45])=[O:46])=[O:48])=[CH:36][C:32]=3[O:33][CH2:34][CH2:35][C:29]=2[CH:28]=1)=[O:26]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(C(=O)NCCS(C)(=O)=O)cc1OCC2)c1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C(=O)c1cc2c(s1)-c1ccc(C(=O)NCCS(C)(=O)=O)cc1OCC2)c1cc(C(=O)N2CCNCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
A solution of HCl in EtOAc (4M, 20 mL) was slowly added into a solution of tert-butyl 4-(4-chloro-3-(N-methyl-8-(2-(methylsulfonyl)ethylcarbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoyl)piperazine-1-carboxylate (350 mg, 0.48 mmol) in EtOAc (5 mL) at 0° C. The mixture was stirred at room temperature for overnight. The solids were filtered and washed with EtOAc, dried to give 334 (176.6 mg, yield: 55%). 1H NMR (MeOD, 400 MHz): δ7.77-7.44 (m, 7H, ArH, NH), 6.93 (s, 1H, ═CH), 4.24-3.04 (m, 23H). LC-MS: (ESI, m/z)=631 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[N:16]1([CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[N:25]1[CH2:24][CH2:23][CH:22]([CH2:21][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:27][CH2:26]1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: C1CCN(CC2CCNCC2)C1
Product: CC(=O)c1cnc2ccc(Br)cc2c1N1CCC(CN2CCCC2)CC1
Yield: 79.6 %

Procedure:
Following general procedure B, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (200 mg, 0.703 mmol) was reacted with 4-(pyrrolidin-1-ylmethyl)piperidine (168 mg, 1.00 mmol) to afford the desired product (233 mg, 80%) as a yellow solid: ESI MS m/z 416 [C21H26BrN3O+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].[CH2:12]([CH:14](OS(C)(=O)=O)[CH2:15][CH3:16])[CH3:13].CC([O-])(C)C.[K+].Cl>CS(C)=O.CC([O-])(C)C.[K+].C(OCC)(=O)C>[CH2:12]([CH:14]([O:11][C:4]1[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH2:15][CH3:16])[CH3:13]
Reactant: COc1cccc(OC)c1O
Reactant: CCC(CC)OS(C)(=O)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCC(CC)Oc1c(OC)cccc1OC
Temperature: 50 °C
Yield: 100.2 %

Procedure:
To a yellow solution of 38.5 g 2,6-dimethoxy phenol (0.25 mol) and 83.1 g methanesulfonic acid 1-ethyl-propyl ester (0.50 mol) in 500 ml dimethylsulfoxide was added under stirring at 50° C. a solution of 56,1 g potassium tert-butylate (0.50 mol) in 500 ml dimethylsulfoxide over 4 h. After additional 2.8 g potassium tert-butylate (0.025 mol) were added, stirring at 50° C. was continued for lh. The reaction mixture was distributed between 500 ml ethyl acetate and 600 ml 1N HCl. The organic layer was washed twice with 250 ml, a total of 500 ml deionized water and the aqueous layers were extracted sequentially with 250 ml ethyl acetate. The combined organic layers were dried over ca. 25 Na2SO4, filtered and the solvent was evaporated by rotary evaporation (50° C./≧1 mbar) affording 56.2 g (100.2%) of the title product as an orange oil, which was used without purification in the next step (bp. 90° C./0.03 mbar).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:11])[N:6]([CH2:8][CH2:9]Br)[CH:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[OH:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:11])[N:6]([CH2:8][CH2:9][N:20]2[C:21]3[C:16](=[CH:15][C:14]([O:13][CH3:12])=[C:23]([O:24][CH3:25])[CH:22]=3)[C:17](=[O:26])[CH:18]=[CH:19]2)[CH:7]=1
Reactant: O=c1ccc(Br)cn1CCBr
Reactant: COc1cc2nccc(O)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2c(=O)ccn(CCn3cc(Br)ccc3=O)c2cc1OC
Temperature: 23 °C
Reaction time: 18 h

Procedure:
A suspension of 5-bromo-1-(2-bromoethyl)pyridin-2(1 H)-one (100 mg, 356 μmol), 6,7-dimethoxyquinolin-4-ol (88 mg, 427 μmol), and cesium carbonate (290 mg, 890 μmol) in DMF (2 mL) was stirred at 23° C. for 18 h. The reaction mixture was partitioned between CH2Cl2 and 5% NaHCO3. The aqueous was extracted with CH2Cl2 (2×10 mL) and the combined organics were dried over MgSO4. The solvents were concentrated to an oil from toluene and purified on silica (12 g) eluting with 0-100% of 6% (2M NH3 in MeOH/CH2Cl2). MS (ESI pos. ion) m/z (MH+): 405/407. Calc'd exact mass for C18H17BrN2O4: 404. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.84 (s, 3 H) 4.00 (s, 3 H) 4.25 (t, J=7.04 Hz, 2 H) 4.47 (t, J=7.04 Hz, 2 H) 5.97 (d, J=7.63 Hz, 1 H) 6.44 (d, J=9.59 Hz, 1 H) 7.41 (s, 1 H) 7.50-7.60 (m, 2 H) 7.74 (d, J=7.63 Hz, 1 H) 7.87 (d, J=2.54 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ ppm 47.43, 49.21, 55.39, 56.01, 96.58, 98.22, 105.09, 108.26, 120.40, 120.95, 135.41, 139.10, 142.58, 142.96, 146.31, 153.03, 160.30, 175.10.
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][CH2:5][CH2:6][SH:7].[F:8][C:9]([F:23])([F:22])[CH2:10][N:11]=[C:12]([NH2:21])[NH:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=1>C(O)C>[F:8][C:9]([F:23])([F:22])[CH2:10][N:11]=[C:12]([NH2:21])[NH:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([S:7][CH2:6][CH2:5][NH2:4])[N:15]=1
Reactant: NCCS
Reactant: NC(=NCC(F)(F)F)Nc1cncc(Cl)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: NCCSc1cncc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C

Procedure:
Sodium hydride (50% w/w dispersion in oil; 0.114 g.) was added portionwise to ethanol (2 ml.). To the resulting solution was added 2-aminoethanethiol hydrochloride (0.134 g.) and the mixture stirred at room temperature. 2-[2-(2,2,2-Trifluoroethyl)guanidino]-6-chloropyrazine (0.1 g.) was added and the mixture heated under reflux on a steam bath for 22 hours. The mixture was cooled, evaporated, water added and extracted with ethyl acetate. The extracts were dried over magnesium sulphate, filtered and the filtrate evaporated to yield 2-[2-(2,2,2-trifluoroethyl)guanidino]-6-[(2-aminoethyl)thio]pyrazine as a gum (0.16 g.) which was used without further purification.
Reaction SMILES: [Cl-].[CH3:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([CH3:9])[N:4]1[CH2:10][CH2:11][NH3+:12].[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[F:24])[C:17](OC)=[O:18]>C1COCC1>[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[F:24])[C:17]([NH:12][CH2:11][CH2:10][N:4]1[C@H:5]([CH3:9])[CH2:6][CH2:7][CH2:8][C@@H:3]1[CH3:2])=[O:18]
Reactant: C[C@@H]1CCC[C@H](C)N1CC[NH3+]
Reactant: COC(=O)c1ccc(F)c(N)c1
Agent: [Cl-]
Solvent: C1CCOC1
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)c1ccc(F)c(N)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture comprising 2-(2,6-cis-dimethylpiperidin-1-yl)ethanaminium chloride (4 g, 20.75 mmol) and methyl 3-amino-4-fluorobenzoate (3.51 g, 20.75 mmol) in THF (50 ml) was treated with TBD (2.89 g, 20.75 mmol) and stirred at 80° C. for 16 hrs. A further portion of methyl 3-amino-4-fluoro benzoate (1 g) and TBD (0.5 g) were added and heating continued for 24 hrs. The resulting mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate. The mixture was extracted once with ethyl acetate and once with chloroform. The combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Purification of the residue by chromatography on silica eluting with 0-20% MeOH in DCM afforded the title compound;
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16]=3[C:29]([C:28]3[CH:32]=[CH:33][C:25]([F:24])=[CH:26][CH:27]=3)=[O:30])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: c1ccc2sc(-c3ccc(OCCN4CCCC4)cc3)cc2c1
Product: O=C(c1ccc(F)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Yield: 65 %

Procedure:
The title compound was prepared in 65% yield from 2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene and 4-fluorobenzoyl chloride by essentially following the procedure detailed in Example 129, Part A.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([F:13])([F:12])[CH2:10][OH:11])=[C:4]([CH3:14])[CH:3]=1.N1C=CN=C1.[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]([C:9]([F:12])([F:13])[CH2:10][O:11][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Br)cc(C)c1C(F)(F)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cc(C)c1C(F)(F)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
To a solution of Intermediate 7B (2.68 g, 10.11 mmol) and imidazole (1.376 g, 20.22 mmol) in DMF (30 ml) was added tert-butyl dimethylchlorosilane (1.828 g, 12.13 mmol). The mixture was stirred at rt overnight, diluted with EtOAc and sat. NaHCO3. The organic layer was extracted by EtOAc (3×20 ml). The combined organic layer was washed with water and brine, dried (MgSO4) and concentrated. The crude product was purified by flash chromatography to give Intermediate 7C (2.56 g, 66.8% yield) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ ppm −0.01 (s, 6H) 0.84 (s, 9H) 2.42 (t, J=4.61 Hz, 6H) 4.00 (t, J=13.18 Hz, 2H) 7.20 (s, 2H). 19F NMR (376 MHz, chloroform-d) δ ppm −95.94 (br. s., 2F).
Reaction SMILES: Cl.[NH2:2][NH2:3].[C:4]12[C:12](=[O:13])O[C:9](=[O:10])[C:5]=1[CH2:6][CH2:7][CH2:8]2>O>[C:9]1(=[O:10])[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[C:12](=[O:13])[NH:3][NH:2]1
Reactant: NN
Reactant: O=C1OC(=O)C2=C1CCC2
Agent: Cl
Solvent: O
Product: O=c1[nH][nH]c(=O)c2c1CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
A solution of hydrazine hydrochloride (2.4 g, 22.8 mmol) and 1-cyclopentene-1,2-dicarboxylic anhydride (3.0 g, 21.7 mmol) in water (10 mL) is heated to reflux for 3 h. The reaction mixture is cooled down to room temperature and the precipitate is collected by filtration. The yellow solid is mixed with 15 mL 1N NaOH and stirred for 2 h, filtered and dried under vacuum to give 2,3,6,7-tetrahydro-5H-cyclopenta[d]pyridazine-1,4-dione (38) (2.2 g, 67%).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C1(=O)[NH:21]C(=O)C2=CC=CC=C12.[K]>CN(C=O)C.O>[NH2:21][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(CCBr)CC1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
The compound (0.77 g) obtained in the above (4) is dissolved in DMF (5 ml), and thereto is added potassium phthalimide (0.537 g), and the mixture is stirred at 100° C. for 1.5 hour. The reaction mixture is diluted with water, and extracted three times with ethyl acetate. The extract is washed successively with 1N hydrochloric acid (twice), a saturated brine (once), a saturated aqueous sodium hydrogen carbonate solution (twice) and a saturated brine (twice), and dried over anhydrous magnesium sulfate. The desiccant is removed by the filtration, and the filtrate is concentrated under reduced pressure. The residue is dissolved in ethanol (20 ml) and thereto is added hydrazine monohydrate (2.3 g) and the mixture is stirred at room temperature for 48 hours. The mixture is diluted with ether, and the insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure to give the title compound (0.63 g) as an oily product.
Reaction SMILES: Br[C:2]1C=NC=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[CH:7]=1.[Br:18][C:19]1[N:24]=C(CP(=O)(OCC)OCC)C=C[N:20]=1>>[Br:18][C:19]1[N:24]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[CH:7]=[CH:2][N:20]=1
Reactant: CCOP(=O)(Cc1ccnc(Br)n1)OCC
Reactant: Fc1ccc(F)c(/C=C/c2cncc(Br)c2)c1
Product: Fc1ccc(F)c(/C=C/c2ccnc(Br)n2)c1

Procedure:
Prepared according to the same procedure as (E)-3-bromo-5-(2,5-difluorostyryl)pyridine, starting with diethyl (2-bromopyrimidin-4-yl)methylphosphonate. 1H NMR (500 MHz, DMSO-d6) δ 8.70 (d, J=5.2 Hz, 1H), 7.93 (d, J=16.2 Hz, 1H), 7.83 (ddd, J=9.3, 5.8, 3.2 Hz, 1H), 7.72 (d, J=5.2 Hz, 1H), 7.46 (d, J=16.2 Hz, 1H), 7.43-7.30 (m, 2H), Mass spec.: 299.1 (MH)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])=[C:5]([Br:7])[N:6]=1.[C:16]1([C:22]#[CH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:7][C:5]1[N:6]=[C:2]([C:23]#[C:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:3][C:4]=1[C:8]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: C#Cc1ccccc1
Reactant: O=C(c1sc(Br)nc1Br)N1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: O=C(c1sc(C#Cc2ccccc2)nc1Br)N1CCCCC1
Temperature: 90 °C
Yield: 17.4 %

Procedure:
To a stirred solution of a mixture of intermediate 49 (2,4-Dibromo-thiazol-5-yl)-piperidin-1-yl-methanone (325 mg, 0.918 mmol), bis(triphenylphosphine)palladium(II) chloride (12.9 mg, 0.0184 mmol), copper(I) iodide (8.74 mg, 0.0459 mmol) and phenylacetylene (0.101 mL, 0.918 mmol) was added triethylamine (3.0 mL, 22 mmol) and the reaction was heated at 90° C. for 30 minutes in a microwave (150 watts). The solvent triethylamine was removed and the crude product was extracted with dichloromethane and washed the organic portion with aqueous citric acid solution, water and brine. Purification of the crude product afford the titled compound (4-Bromo-2-phenylethynyl-thiazol-5-yl)-piperidin-1-yl-methanone (60 mg, 20%) as a pale brown color solid