Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](O)=O.[NH2:14][NH:15][C:16]([NH2:18])=[S:17].P(Cl)(Cl)(Cl)=O>O1CCOCC1>[CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]([C:6]1[S:17][C:16]([NH2:18])=[N:15][N:14]=1)[CH3:9]
Reactant: NNC(N)=S
Reactant: Cc1ccccc1OC(C)C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Cc1ccccc1OC(C)c1nnc(N)s1
Temperature: 90 °C

Procedure:
A 100 milliliter flask adapted with a paddle stirrer, thermometer, an addition funnel, condenser and drying tube was charged with 7.2 grams (0.040 mole) of 2-(2-methylphenoxy)propanoic acid, 3.6 grams, (0.040 mole) of thiosemicarbazide and 30 milliliters of dioxane. The slurry was heated to 90° C. and the addition funnel was charged with phosphorous oxychloride (POCl3). The POCl3 (6.7 grams; 0.044 mole) was slowly added (for 20 minutes) while maintaining the temperature within 90°-95° C., a gooey white precipitate formed. When the addition was completed the mixture was refluxed for 60 minutes. The flask was evacuated by using a water aspirator to remove volatiles (HCl, POCl3 and some dioxane), and then 50 milliliters of water was added and mixture was made basic by the addition of 50 percent solution of NaOH until the pH of the solution was 10. The white precipitate was filtered off, washed with water and dissolved in the minimum amount of 95 percent ethanol, to which a small amount of a 10 percent sodium hydroxide solution was added to make the ethanol solution basic. Water was added until a precipitate formed and the solution was cooled in the refrigerator, then suctioned filtered. The precipitate was washed with water, and dried in a vacuum oven at 70° C. to white crystals of 5-[1-(2-methylphenoxy)ethyl]-2-amino-1,3,4-thiadiazole (6.8 grams--melting point 176°-179° C.)
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([F:7])([F:6])[F:5].[Br-].[Mg].C([O:12][CH3:13])=O>C1COCC1.O>[F:5][C:4]([F:7])([F:6])[CH2:3][CH2:2][CH:13]([OH:12])[CH2:2][CH2:3][C:4]([F:7])([F:6])[F:5]
Reactant: COC=O
Reactant: FC(F)(F)CCBr
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: OC(CCC(F)(F)F)CCC(F)(F)F
Temperature: 0 °C

Procedure:
3-Bromo-1,1,1-trifluoropropane (31 g, 0.175 mol) was dissolved in THF (175 mL). Mg (4.2 g, 0.175 mol) was placed in a 1 L, 3-necked round-bottom flask equipped with a condenser, nitrogen inlet and thermometer. The bromide solution (10 mL) was added to cover the magnesium and upon stirring a mild exotherm commenced. The temperature was kept <40° C. by immersing the flask in a bowl of water. The bromide was added slowly to maintain this mild exothermic reaction. When the exotherm had subsided the mixture was cooled in ice-water and methyl formate (7 mL, 0.11 mol) in THF (175 mL) was added. The mixture was stirred for 30 min and then quenched with NH4Cl (aq.soln. 100 mL). The mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried (MgSO4) and evaporated.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH2:11])[CH2:10][CH2:9]2)=[C:4]([F:12])[CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:23](=[O:24])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:9][CH2:10]2)=[C:4]([F:12])[CH:3]=1
Reactant: NC1(c2ccc(Br)cc2F)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC1(c2ccc(Br)cc2F)CC1)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a cooled solution of 1-(4-bromo-2-fluorophenyl)cyclopropanamine (2.16 mmol) in DCM (10 mL) at 0° C., was added DIEA (0.75 mL, 4.32 mmol) and benzyl chloroformate (0.37 mL, 2.59 mmol). The reaction mixture was warmed to it and stirred for 1 h until LC/MS analysis indicated the reaction was complete. The reaction was quenched with HCl (1N) and extracted with DCM. Drying over MgSO4, yielded crude product which was purified by flash chromatography (gradient EtOAc/Hexanes (0-50%). HPLC-MS tR=1.31 min (UV254 nm); mass calculated for formula C17H15BrFNO2 363.02, observed LCMS m/z 363.9 (M+H)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[O:20][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cnn2ccc(Oc3cccc(Cl)c3)nc12
Temperature: 70 °C
Yield: 92.7 %

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.276 mmol) in DMF was added 3-chlorophenol (42 mg, 0.331 mmol) and K2CO3 (190 mg, 1.380 mmol). The mixture was heated at 70° C. for several hours. Water was added and the solid formed was isolated by filtration and air dried to yield 70 mg 5-(3-chlorophenoxy)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde as an orange solid (93% yield). LCMS (M+1=274)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)#[N:21]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:31]1[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:20]#[N:21])[CH2:33][CH2:32]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Reactant: N#Cc1ccccc1N1CCNCC1
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2ccccc2C#N)CC1
Yield: 85 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2-cyanophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 85%). 1H NMR (200 MHz, CDCl3): δ 3.31 (s, 4H), 3.73-3.85 (m, 3H), 4.06-4.16 (m, 4H), 7.03-7.11 (m, 3H), 7.20-7.34 (m, 1H), 7.50-7.62 (m, 3H), 7.67-7.74 (m, 1H).
Reaction SMILES: Br.Br[CH:3]([C:5]1[O:6][C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:4].[NH:23]1[C:27]2=[N:28][CH:29]=[N:30][C:31]([NH2:32])=[C:26]2[CH:25]=[N:24]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:32][C:31]1[N:30]=[CH:29][N:28]=[C:27]2[N:23]([CH:3]([C:5]3[O:6][C:7](=[O:22])[C:8]4[C:13]([C:14]=3[C:15]3[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH3:4])[N:24]=[CH:25][C:26]=12
Reactant: Nc1ncnc2[nH]ncc12
Reactant: Cc1ccc(-c2c(C(C)Br)oc(=O)c3ccccc23)cn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(C(C)n3ncc4c(N)ncnc43)oc(=O)c3ccccc23)cn1
Yield: 14.9 %

Procedure:
3-(1-Bromoethyl)-4-(6-methylpyridin-3-yl)-1H-isochromen-1-one hydrobromide (intermediate C10, 120 mg, 0.282 mmol), 1H-pyrazolo[3,4-d]pyrimidin-4-amine (76 mg, 0.565 mmol), and K2CO3 (117 mg, 0.847 mmol) were stirred in DMF (1.5 ml) at 50° C. for 2.5 hrs. The reaction mixture was diluted with 1M HClaqueous (2 ml) and purified via reverse phase chromatography with a Biotage C18 SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) to give the title compound as colourless solid (16.7 mg, 15%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)(=O)=O.[C:21]([C:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1)#[CH:22].C(N(CC)CC)C.N>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[S:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[CH2:13][C:12]1[C:7]([C:22]#[C:21][C:23]2([OH:31])[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: O=S(=O)(Oc1ncccc1Cc1cccs1)C(F)(F)F
Agent: [Pd]
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC1(C#Cc2ncccc2Cc2cccs2)CN2CCC1CC2
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 98.5 %

Procedure:
A mixture of 89 mg of 3-(2-thienylmethyl)-2-pyridyl trifluoromethanesulfonate, 50 mg of 3-ethynyl-3-quinuclidinol, 64 mg of tetrakis (triphenylphosphine) palladium(0), 11 mg of cuprous iodide, 105 μl of triethylamine and 3.0 ml of N,N-dimethylformamide was heated under stirring at 70° C. for 1.5 hours in a nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia, followed by extracting with ethyl acetate. Then, the organic phase was washed with brine and the solvent was removed, and the residue was subjected to NH-silica gel (Fuji silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (15:1), to give 88 mg of the target compound.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=3[C:21]3[C:22]([O:27][CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)([O-])[O-:30].[K+].[K+].OO>CS(C)=O.C(Cl)Cl>[C:1]12([CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]([NH2:18])=[O:30])=[CH:15][C:14]=3[C:21]3[C:22]([O:27][CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C([O-])[O-]
Reactant: COc1ncccc1-c1cc(C#N)ccc1OCC12CC3CC(CC(C3)C1)C2
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ncccc1-c1cc(C(N)=O)ccc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.5 %

Procedure:
To a solution of 4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzonitrile (1.15 g, 3.07 mmol) in dimethylsulfoxide (25 mL) and methylene chloride (25 mL) was added potassium carbonate (0.85 g, 6.15 mmol) followed by addition of 35% hydrogen peroxide aqueous solution (5.30 mL, 61.60 mmol) dropwise. The mixture was stirred at ambient temperature for 4 h, the volatiles were removed by evaporation in vacuo. The residue was diluted with water (100 mL). The precipitate was collected by filtration and washed with water to give the title compound as a colorless solid (0.97 g, 80%): 1H NMR (300 MHz, CDCl3) δ 8.18-8.15 (m, 1H), 7.84-7.79 (m, 1H), 7.71-7.69 (m, 1H), 7.54-7.50 (m, 1H), 6.95-6.91 (m, 2H), 5.85 (br s, 2H), 3.87 (s, 3H), 3.49 (s, 2H), 1.89 (br s, 3H), 1.68-1.37 (m, 12H); MS (ES+) m/z: 393.2 (M+1).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[F:12][C:13]1[C:14](B(O)O)=[CH:15][C:16]([O:19][CH3:20])=[N:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.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>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:14]2[C:13]([F:12])=[CH:18][N:17]=[C:16]([O:19][CH3:20])[CH:15]=2)=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Reactant: COc1cc(B(O)O)c(F)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2ncc(Br)cc2[N+](=O)[O-])c(F)cn1
Temperature: 90 °C
Reaction time: 21.5 h

Procedure:
A mixture of 2,5-dibromo-3-nitropyridine, commercially available from Matrix Scientific (0.72 g, 2.55 mmol), 5-fluoro-2-methoxypyridin-4-ylboronic acid, commercially available from Asymchem (0.39 g, 2.34 mmol), dichlorobis(triphenyl-phosphine)palladium (II) (90 mg, 0.13 mmol), and 1.0M sodium carbonate (3.5 mL, 7.0 mmol) in 1,4-dioxane (10 mL) was degassed by nitrogen. The mixture was heated to 90° C. After 21.5 h, the reaction was cooled to rt then treated with water. After extracting twice with EtOAc, the organic layer was combined and dried over anhydrous magnesium sulfate. After filtration and concentration, the yellowish brown residue was treated with MeOH and placed on the rotoevaporator (without vac.) in a 45° C. water bath. After 30 min, the solid was filtered and rinsed twice with MeOH to afford a tan solid as 5-bromo-5′-fluoro-2′-methoxy-3-nitro-2,4′-bipyridine. 1H NMR (500 MHz, CDCl3) δ ppm 9.01 (1H, d, J=2.0 Hz), 8.56 (1H, d, J=2.0 Hz), 8.06 (1H, d, J=1.2 Hz), 7.02 (1H, d, J=4.6 Hz), 4.04 (3H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:36][CH2:37][CH2:38][CH2:39][C:40]([NH:42][CH3:43])=[O:41])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([NH:17][C@@H:18]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:19][N:20](C)[C:21](=O)OC(C)(C)C)=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:36][CH2:37][CH2:38][CH2:39][C:40]([NH:42][CH3:43])=[O:41])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([NH:17][C@H:18]([CH2:19][NH:20][CH3:21])[CH2:29][CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)CCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@H](OCCCC(=O)NC)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.9 %

Procedure:
tert-butyl (S)-2-((R)-3-((R)-(3-chlorophenyl)(4-(methylamino)-4-oxobutoxy)methyl)piperidine-1-carboxamido)-3-cyclohexylpropyl(methyl)carbamate (50 mg, 0.08 mmol) was dissolved in a solution of 20% (V/V) TFA/CH2Cl2 (10 mL). The reaction mixture was stirred at rt for 1 h, a solution of saturated sodium bicarbonate was added dropwise to adjust pH=7-8. The resulting mixture was extracted with CH2Cl2 (3×15 mL), washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative HPLC to afford (R)-3-((R)-(3-chlorophenyl)(4-(methylamino)-4-oxobutoxy)methyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide (3.30 mg, yield 8%). 1H NMR (CD3OD, 400 MHz) δ 7.30-7.34 (m, 3H), 7.20 (d, 1H), 4.30 (d, 1H), 4.05 (m, 1H), 3.97 (m, 2H), 2.76 (m, 3H), 2.69 (s, 3H), 2.53 (s, 3H), 2.27 (m, 3H), 1.83 (m, 3H), 1.71 (m, 5H), 1.13-1.28 (m, 10H), 0.89 (m, 4H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[CH3:27][CH:28]1[NH:33][C:32](=[O:34])[CH2:31][NH:30][CH2:29]1>CN1C(=O)CCC1>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:30]4[CH2:29][CH:28]([CH3:27])[NH:33][C:32](=[O:34])[CH2:31]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: CC1CNCC(=O)N1
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC1CN(c2ccc3ncc(C(C)c4c(F)cc5ncccc5c4F)n3n2)CC(=O)N1
Temperature: 180 °C
Reaction time: 16 h

Procedure:
(rac)-6-[1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate C, 50 mg, 0.145 mmol), KF (42.1 mg, 0.725 mmol), 6-methylpiperazin-2-one (49.7 mg, 0.435 mmol) were suspended in NMP (483 μL). The RM was stirred at 180° C. for 16 h. The mixture was purified by preparative UPLC with acetonitrile and water (+0.1% TFA) The fractions were collected and acetonitrile was removed. It was taken up with MeOH and passed through an SPE cartridge of PL-HCO3 MP from polymer lab. The solvent was removed and a brown solid was obtained (tR 0.9 min (conditions 4), MH+=423).
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:6][S:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)(=[O:9])=[O:8])[CH2:5][CH2:4]1.Br[CH2:22][C:23]#[N:24].O>CN(C)C=O>[CH:3]1([N:6]([CH2:22][C:23]#[N:24])[S:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)(=[O:9])=[O:8])[CH2:5][CH2:4]1
Reactant: O=S(=O)(Cc1cccc(C(F)(F)F)c1)NC1CC1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCN(C1CC1)S(=O)(=O)Cc1cccc(C(F)(F)F)c1
Reaction time: 0.25 h
Yield: 28.3 %

Procedure:
0.26 g of sodium hydride was added portion-wise to a solution containing 2.79 g of N-cyclopropyl-3-trifluoromethylbenzylsulfonamide in 50 ml of dimethylformamide over an ice bath. The mixture was stirred 15 minutes at 0l° C. and then 1.26 g of bromoacetonitrile was added drop-wise with cooling. The mixture was stirred overnight at room temperature. Water was then added resulting in the formation of a precipitate and oil. Addition of water was continued until no further precipitate or oil was formed. (About 150 ml of water was used.) The mix was cooled over an ice bath and then filtered. The filter cake was dissolved in hot cyclohexane and then recrystallized affording 0.9 g of the title compound as a solid m.p. 70.1°-71.0° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>>[Br:15][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([CH3:14])=[CH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ncc(C)cn2)cc1
Product: Cc1cnc(-c2ccc(CBr)cc2)nc1

Procedure:
Reaction of the above 2-(4-methylphenyl)-5-methylpyrimidine with N-bromosuccinimide, as described in Example 15, affords 2-(4-bromomethylphenyl)-5-methylpyrimidine with a melting point of 129°-131° C. (recrystallisation from ligroin). With stirring, a mixture of 184 g of 2-(4-bromomethylphenyl)-5-methylpyrimidine and 465 g of triethylphosphite is slowly heated to 150° C., while simultaneously distilling off ethyl bromide, and then stirred for 5 hours at this temperature. Excess triethylphosphite is distilled off, affording 220 g of the phosphonate in the form of a light brown viscous oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.F[C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: Oc1ccc(Cl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(=O)c1ccc(Oc2ccc(Cl)c3ccccc23)cc1
Temperature: 150 °C

Procedure:
A mixture of 42.86 g of 4-chloro-1-naphthol, 27.6 g of p-fluoroacetophenone, 33.12 g of potassium carbonate and 200 ml of dimethylacetamide was heated at 150° C., under argon for 18 hours, then poured into ice water, stirred and extracted with ethyl acetate. The extract was washed with 0.5N sodium hydroxide, 0.5N hydrochloric acid, water and brine, dried and evaporated to a residue. This residue was boiled in hexane, then cooled and the intermediate collected to yield the product as white crystals, mp 95°-99° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:18]=2[NH:19][C:20]2[C:21]([CH3:30])=[C:22]3[C:26](=[C:27]([Cl:29])[CH:28]=2)[NH:25][CH:24]=[CH:23]3)[C:16]#[N:17])=[CH:7][CH:6]=1.[CH3:31][NH:32][CH3:33]>C1COCC1.COCCOC>[Cl:29][C:27]1[CH:28]=[C:20]([NH:19][C:18]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[CH:12][C:11]=2[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:32]([CH3:33])[CH3:31])=[CH:6][CH:7]=2)[C:21]([CH3:30])=[C:22]2[C:26]=1[NH:25][CH:24]=[CH:23]2
Reactant: CNC
Reactant: Cc1c(Nc2c(C#N)cncc2-c2ccc(OCCCl)cc2)cc(Cl)c2[nH]ccc12
Solvent: COCCOC
Solvent: C1CCOC1
Product: Cc1c(Nc2c(C#N)cncc2-c2ccc(OCCN(C)C)cc2)cc(Cl)c2[nH]ccc12
Temperature: 25 °C
Yield: 74 %

Procedure:
A solution of 5-[4-(2-chloroethoxy)phenyl]-4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]nicotinonitrile (144 mg, 0.3 mmol) and dimethyl amine (1.7 mL of a 2.0 M solution in THF, 3.4 mmol) in DME (3 mL) in a sealed tube was stirred at 110° C. for 48 h and cooled to room temperature. After the resulting solution was concentrated, 1 N aqueous HCl was added and the aqueous phase was extracted with ethyl acetate and the aqueous solution was adjusted to pH of 10 by adding sodium carbonate and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over magnesium sulfate, and concentrated to give 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-{4-[2-(dimethylamino)ethoxy]phenyl}nicotinonitrile as a yellow solid (109 mg, 74%). HPLC retention time: 5.1 min.(g); MS: 446.3 (M+H); and HRMS: 446.1743.
Reaction SMILES: [Mg].CI.[CH3:4][C:5]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:6]=1C#N.CC[O:16][CH2:17][CH3:18]>>[Br:11][C:10]1[C:5]([CH3:4])=[C:6]([C:17](=[O:16])[CH3:18])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOCC
Reactant: Cc1c(Br)cccc1C#N
Agent: [Mg]
Solvent: CI
Product: CC(=O)c1cccc(Br)c1C
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a stirred and refluxing Grignard-complex, previously prepared starting from 7.3 parts of magnesium, 52.6 parts of methyl iodide in 160 parts of ether, is added dropwise a solution of 19.6 parts of 3'-bromo-2'-methylbenzonitrile in 40 parts of ether. Upon completion, stirring at reflux is continued for 20 hours. The reaction mixture is cooled to 0° C and poured onto 500 parts of ice-water while stirring vigorously. The ethereal phase is separated, dried and evaporated. The residue is boiled in 60 parts of a 6N hydrochloric acid solution for 10 minutes. The separated oil is extracted with ether. The extract is washed with water, dried and evaporated. The residue is distilled, yielding 3'-bromo-2'- methylacetophenone; bp. 125°-128°C at 10 mm. pressure.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][CH2:9][S:10][C:11]1[O:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2].[CH2:18]([NH2:20])[CH3:19]>>[N+:1]([CH:4]=[C:5]([NH:20][CH2:18][CH3:19])[NH:6][CH2:7][CH2:8][CH2:9][S:10][C:11]1[O:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCCSc1ncco1
Reactant: CCN
Product: CCNC(=C[N+](=O)[O-])NCCCSc1ncco1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[3-(2-oxazolylthio)propylamino]ethylene (see Example 19 (iv)) with ethylamine by the procedure of Example 8(ii) gives the title product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:24])=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:13]=[C:12]([C:21]#[N:22])[CH:11]=1)=[O:8].C([O-])([O-])=[O:26].[K+].[K+].OO>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:24])=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:13]=[C:12]([C:21]([NH2:22])=[O:26])[CH:11]=1)=[O:8]
Reactant: N#Cc1cc(NC(=O)c2cc(Br)ccc2Cl)n(-c2ccccc2)n1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1cc(NC(=O)c2cc(Br)ccc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
To a solution of 5-bromo-2-chloro-N-(3-cyano-1-phenyl-1H-pyrazol-5-yl)benzamide (Preparation 15, 500 mg, 1.24 mmol) in DMSO (5 mL) was added K2CO3 (340 mg, 2.48 mmol) followed by H2O2 (50% by weight, aqueous solution, 1.69 mL, 24.9 mmol). The reaction was stirred at room temperature for 3 hours. The reaction was quenched by the addition of saturated aqueous KHSO4 solution (5 mL) followed by water (15 mL) and EtOAc (40 mL). The mixture was filtered and separated. The organic layer was washed with brine (40 mL), dried over MgSO4, and concentrated in vacuo. The residue was slurried in water and filtered to afford the title compound (457 mg, 88%).