Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=O)[CH3:2].[NH2:13][C:14]1[C:15](=[O:24])[NH:16][C:17](=[O:23])[N:18]([CH2:21][CH3:22])[C:19]=1[NH2:20].C(N(CC)CC)C.[OH-].[Na+].Cl>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]1[NH:13][C:14]2[C:15](=[O:24])[NH:16][C:17](=[O:23])[N:18]([CH2:21][CH3:22])[C:19]=2[N:20]=1)[CH3:2]
Reactant: CCOc1ccccc1C(=O)Cl
Reactant: CCn1c(N)c(N)c(=O)[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1ccccc1-c1nc2c([nH]1)c(=O)[nH]c(=O)n2CC
Temperature: 25 °C
Reaction time: 20 h
Yield: 38.2 %

Procedure:
A solution of 2-ethoxybenzoyl chloride (12.0 g, 65 mmol) in dimethylformamide (10 mL) was added dropwise to a stirred solution of 5,6-diamino-1-ethyl-1H-pyrimidine-2,4-dione (10.4 g, 61 mmol) and triethylamine (9.8 mL, 65 mmol) in dimethylformamide (250 mL). The resulting mixture was stirred for 20 hours at room temperature, then evaporated under reduced pressure. Aqueous sodium hydroxide solution (1N, 98 mL, 98 mmol) was added and the mixture heated under reflux for 6 hours. The resulting solution was acidified with 1N hydrochloric acid and the precipitate collected and dried by suction to give 8-(2-ethoxyphenyl)-3-ethyl-3,7-dihydropurine-2,6-dione as a beige solid (7.0 g, 72%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)O.[CH2:9]([NH2:12])[CH:10]=C.C=O>C1(C)C=CC=CC=1>[O:6]1[C:5]2[CH:4]=[CH:3][CH:1]=[CH:8][C:7]=2[CH:10]=[CH:9][NH:12]1
Reactant: C=CCN
Reactant: Oc1ccc(O)cc1
Agent: C=O
Solvent: Cc1ccccc1
Product: C1=Cc2ccccc2ON1

Procedure:
Hydroquinone (8.23 g, 75 mmol), allylamine (8.57 g, 150 mmol) and toluene (100 mL) were placed in a 250 mL flask. Paraformaldehyde (9.0 grams, equivalent to 300 mmole formaldehyde) was added along with a magnetic stir bar. The flask was equipped as described in Example 1 and brought to reflux. The full theoretical amount of water was collected within forty-five minutes of reflux. The toluene solution was washed with six 25 ml portions of 5% aqueous sodium hydroxide, and three 30 ml aliquots of water. The toluene solution was then dried over anhydrous magnesium sulfate and then passed over 26 grams of activated, neutral alumina. The toluene was removed to yield 11.0 grams (54% of theory) of a red, semi-solid material.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)([O-:3])=[O:2].[C:17](#[N:20])[CH:18]=[CH2:19]>C1C=CC=CC=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>[C:17]([CH2:18][CH2:19][N:8]1[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)#[N:20]
Reactant: O=[N+]([O-])c1ccc2[nH]c3ccccc3c2c1
Reactant: C=CC#N
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: c1ccccc1
Product: N#CCCn1c2ccccc2c2cc([N+](=O)[O-])ccc21
Temperature: 50 °C

Procedure:
21.2 g (0.1 mol) 3-nitrocarbazole were suspended in 250 ml benzene in a three-necked flask equipped with stirrer, condenser and thermometer and present in an oil-bath, then mixed with 50 ml acrylonitrile, heated to 50°C and, after the addition of two drops of benzyl trimethyl ammonium hydroxide, reacted for two hours at 70°C, while stirring. After evaporation of the reaction mixture and recrystallization of the residue from aqueous acetone, there were obtained 22 g 9-(β-cyanoethyl)-3-nitrocarbazole, which was further worked up directly.
Reaction SMILES: [CH2:1]([O:7][C:8]([C:10]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:14]([C:25]([OH:27])=[O:26])=[C:13]([CH3:28])[NH:12][C:11]=1[CH3:29])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH3:6].[C:30](O)([CH3:33])([CH3:32])[CH3:31].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClC(Cl)C>[N+:22]([C:18]1[CH:17]=[C:16]([CH:15]2[C:10]([C:8]([O:7][CH2:1][CH:2]=[CH:3][CH:4]=[CH:5][CH3:6])=[O:9])=[C:11]([CH3:29])[NH:12][C:13]([CH3:28])=[C:14]2[C:25]([O:27][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:26])[CH:21]=[CH:20][CH:19]=1)([O-:24])=[O:23]
Reactant: CC=CC=CCOC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Product: CC=CC=CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)(C)C)C1c1cccc([N+](=O)[O-])c1
Yield: 73.1 %

Procedure:
199 mg (0.5 mM) of 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid mono (2,4-hexadienyl) ester, 44 mg (0.6 mM) of tert-butanol, 113 mg (0.55 mM) of dicyclohexylcarbodiimide and 61 mg (0.5 mM) of 4-dimethylaminopyridine were dissolved in 5 ml of dichloroethane, and refluxed for 2 hours. After the reaction mixture was chilled, insoluble matters were filtered off. The solvent was evaporated under reduced pressure, and the residue was purified by silicas gel column chromatography to obtain 198 mg of a crude material. This material was recrystallized with methanol, and 166 mg of tert-butyl 2,4-hexadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate was obtained (yield 73%).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8]C2C=CC(Cl)=C(NC(=O)C3C=CC=C(Cl)C=3)C=2)=[O:7])=[CH:4][N:3]=1.C([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>>[N:35]1([C:2]2[CH:27]=[CH:26][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2cccc(Cl)c2)c1)c1ccc(Cl)nc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc(N2CCNCC2)nc1

Procedure:
6-chloro-N-(4-chloro-3-(3-chlorobenzamido)phenyl)nicotinamide (0.16 mmol) was used in general procedure 3 with Boc-piperazine (0.868 mmol). The product was deprotected by treatment with TFA and purified by RP-HPLC to give N-(4-chloro-3-(3-chlorobenzamido)phenyl))-6-(piperazin-1-yl)nicotinamide. MS (Q1) 470.1 (M)+
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5][C:4]([CH2:25][CH2:26][CH2:27][C:28]([O-:30])=[O:29])=[N:3]1.[K+].S(=O)(=O)(O)O.[CH2:37](O)[CH3:38]>>[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)[CH:13]=2)=[N:5][C:4]([CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:37][CH3:38])=[O:29])=[N:3]1
Reactant: CCO
Reactant: Cn1nc(CCCC(=O)[O-])nc1NCCCOc1cccc(CN2CCCCC2)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)CCCc1nc(NCCCOc2cccc(CN3CCCCC3)c2)n(C)n1

Procedure:
Potassium 1-methyl-5[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazole-3-butanoate (2.0 g) and concentrated sulphuric acid (1 ml) in anhydrous ethanol (200 ml) was heated under reflux for 16 h. The suspension was filtered, the filtrate evaporated, and saturated aqueous sodium bicarbonate (50 ml) added. The mixture was extracted with ethyl acetate, the extract washed with brine, dried, and evaporated to give the title compound (1.0 g) as an oil.
Reaction SMILES: [CH2:1]([OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[H-].[Na+].C(Cl)C(=C)C.ClC1C=C[CH:27]=[C:26]([C:30]([O:32]O)=O)[CH:25]=1>ClCCl.O.CN(C)C=O>[O:32]1[C:26]([CH3:27])([CH2:25][O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:30]1
Reactant: CCCCCCCCCCCCCCO
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: C=C(C)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOCC1(C)CO1
Temperature: 60 °C
Reaction time: 15 h
Yield: 79.5 %

Procedure:
A 200-ml flask equipped with a stirrer was charged with 10 g (46.6 mmol) of tetradecanol, 50 ml of dimethylformamide, 2.86 g (71.5 mmol) of 60% NaH and 5.96 g (65.8 mmol) of methallyl chloride. The contents were stirred at 60° C. for 15 hours. After completion of the reaction, the reaction mixture was added with water and subjected to extraction with hexane, and the solvent was distilled off under reduced pressure. The resultant residue was charged into a 300-ml flask equipped with a stirrer, and 12.24 g (70.9 mmol) of m-chloroperbenzoic acid and 200 ml of dichloromethane were added thereto. The resultant mixture was stirred at room temperature for 19 hours. Solids formed were separated by filtration, and the resultant solution was concentrated under reduced pressure and then purified by column chromatography on silica gel, thereby obtaining 10.54 g (yield: 79.4%) of 1,2-epoxy-2-methyl-3-tetradecyloxypropane as an intermediate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[O:8][C@H:7]1[C:9]([O-:11])=O)=[O:5])[CH3:2].[K+].S(Cl)(Cl)=O.[CH3:17][CH:18]([CH3:28])[CH2:19][CH:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>>[CH3:17][CH:18]([CH3:28])[CH2:19][CH:20]([NH:27][C:9]([C@@H:7]1[O:8][C@H:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:11])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)CC(N)c1ccccc1
Reactant: CCOC(=O)[C@@H]1O[C@H]1C(=O)[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@@H]1O[C@H]1C(=O)NC(CC(C)C)c1ccccc1
Yield: 95.9 %

Procedure:
The reactions and treatments of Example 5 were repeated using potassium (2R,3R)-3-ethoxycarbonyloxirane-2-carboxylate (3.97 g, 20.0 mmol.), thionyl chloride (2.86 g, 24.0 mmol), 3-methyl-1-phenylbutylamine (4.25 g, 26.0 mmol), and triethylamine (2.63 g, 26.0 mmol.), to give the desired compound as a colorless viscous oil (5.86 g, yield: 96%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[O:7]=[C:8]1[NH:17][CH:16]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[C:15]2[C:14](=[O:26])[CH2:13][CH2:12][CH2:11][C:10]=2[N:9]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1.Br[CH:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40].O>CN(C)C=O>[C:22]([C:21]1[CH:20]=[CH:19][C:18]([CH:16]2[C:15]3[C:14](=[O:26])[CH2:13][CH2:12][CH2:11][C:10]=3[N:9]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)[C:8](=[O:7])[N:17]2[CH:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])=[CH:25][CH:24]=1)#[N:23]
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)cc1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
Cesium carbonate (713 mg, 2.19 mmol) is added to a solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)1,2,3,4,5,6,7,8octahydroquinazolin-4-yl)-benzonitrile (example 1, 300 mg, 0.73 mmol) and methyl 2-bromopropanoate (244 mg, 1.46 mmol) in N,N-dimethylformamide (10 mL), and the mixture is stirred at 50° C. for 6 h and at room temperature over night. Water is added, and the mixture is extracted with dichloromethane. The organic layer is extracted with water and brine, dried over MgSO4 and concentrated under reduced pressure. Yield: 353 mg; ESI mass spectrum [M+H]+=498; Retention time HPLC: 0.97 min (Z018_S04).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[CH:31]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C1COCC1>[CH:31]1([NH:37][C:12]2[N:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[CH3:30])[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1F
Reactant: NC1CCCCC1
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NC2CCCCC2)nc2c1ccc(=O)n2-c1ccccc1F
Reaction time: 18 h

Procedure:
The product of Example 59 (200 mg, 0.47 mmol) and cyclohexylamine (100 mg, 1 mmol) were combined in THF (10 mL) and stirred under Ar at 23° for 18 h. The solvents were removed in vacuo, and the residue was flash chromatographed on silica gel eluted with 50-100% CH2Cl2/hexane. Recrystallization from CH2Cl2/hexane gave the title compound as a white-crystalline solid. mp 181-182°, LC MS m/z=447 (MH+) Retention time=2.71 min.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])([CH3:5])[CH3:4].FC(F)(F)C(O)=O.CCOCC>ClCCl>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])([CH3:4])[CH3:5]
Reactant: Cc1ccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)CO)cn3COCC[Si](C)(C)C)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Cc1ccc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)CO)c3n2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.1 %

Procedure:
To a solution of N-(1-hydroxy-2-methylpropan-2-yl)-2-(5-methylpyridin-2-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (66 mg, 140 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (320 mg, 216 μL, 2.8 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo then the residue was dissolved in dichloromethane (2 mL), methanol (0.5 mL) and ammonium hydroxide (0.3 mL). After stirring at room temperature for 30 min, the mixture was concentrated in vacuo and triturated with ether and water. The yellow precipitate was collected by filtration and washed with water then ether to give N-(1-hydroxy-2-methylpropan-2-yl)-2-(5-methylpyridin-2-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (31 mg, 91.1 μmol, 65%) as a yellow solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.38 (s, 1H), 9.86 (s, 1H), 8.39 (s, 1H), 8.12 (d, J=2.5 Hz, 1H), 8.04 (d, J=3.3 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.74 (s, 1H), 7.54 (dd, J=8.6, 2.3 Hz, 1H), 5.06 (s, 1H), 3.58 (s, 2H), 2.25 (s, 3H), 1.39 (s, 6H); MS (EI/CI) m/z: 341.1 [M+H].
Reaction SMILES: [OH-].[Na+].BrBr.[CH2:5]([O:12][C:13]1[CH:32]=[CH:31][C:16]([CH2:17][C@H:18]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@H:19](O)[CH2:20][OH:21])=[CH:15][C:14]=1[F:33])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[CH2:5]([O:12][C:13]1[CH:32]=[CH:31][C:16]([CH2:17][C@H:18]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C@H:19]2[CH2:20][O:21]2)=[CH:15][C:14]=1[F:33])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(F)c1)[C@H](O)CO
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(F)c1)[C@H]1CO1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 49.6 %

Procedure:
To an ice-cold solution of sodium hydroxide (228 mg, 5.7 mmol) in water (2.5 mL) was added bromine (94 μL, 1.84 mmol) dropwise. After stirring for 5 min at 0° C., amide 16 (336 mg, 1.5 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 20 min and then heated at 75° C. for 5 h. The reaction mixture was diluted with water and extracted with methylene chloride. The organic layer was washed with saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to give a yellow solid. Purification by flash column chromatography (silica, 95:5 methylene chloride/methanol) gave amine 17 (288 mg, 98%) as a light yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.35 (s, 1H), 2.79 (d, J=7.2 Hz, 2H), 2.08 (m, 1H), 1.13 (m, 1H), 1.06-0.97 (m, 8H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:19][C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]1>CS(C)=O.O>[S:19]1[C:14]2=[CH:15][N:16]=[CH:17][CH:18]=[C:13]2[CH:12]=[C:11]1[C:8]1[N:6]2[N:7]=[C:2]([NH:32][C@H:33]3[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Clc1ccc2ncc(-c3cc4ccncc4s3)n2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: O
Product: O[C@H]1CC[C@H](Nc2ccc3ncc(-c4cc5ccncc5s4)n3n2)CC1
Temperature: 100 °C

Procedure:
To a solution of 6-chloro-3-(thieno[2,3-c]pyridin-2-yl)imidazo[1,2-b]pyridazine (50 mg, 0.174 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonic acid monohydrate (25 mg, 0.174 mmol, 1.0 equiv) and trans-4-aminocyclohexanol (0.870 mmol, 5.0 equiv) and heated to 100° C. for 24 h. The reaction mixture was diluted with water and extracted with ethyl acetate. Purification by column chromatography using 5% methanol in dichloromethane elution gave 42 mg of the yellow solid, 67%.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7]1([C:13]#[CH:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=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)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:14]#[C:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Brc1cccs1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C(#Cc1cccs1)c1ccccc1
Yield: 57.5 %

Procedure:
1 g (0.00142 mol) of bis-(triphenylphosphine)palladium chloride, 5 g (0.0262 mol) of copper iodide and 8.5 g (0.0324 mol) of triphenylphosphine were added in succesion to a solution of 163 g (1 mol) of 2-bromothiophene and 127.5 g (1.25 mol) of phenylacetylene in 850 ml of triethylamine at 25° C. Stirring was carried out for twelve hours under a nitrogen atmosphere at 80° C., after which the mixture was filtered and the filtrate was evaporated down under reduced pressure. 600 ml of methylene chloride were added to the residue and the solution was washed with three times 200 ml of water, dried over Na2SO4 and evaporated down under reduced pressure, after which 200 ml of n-pentane were added. The crystals thus obtained were filtered off under suction and dried. 106 g (57.6% of theory) of 1-(2-thienyl)-2-phenylacetylene were obtained as pale yellow crystals of melting point 49°-59 ° C. (Active Ingredient Example 1.001).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:42])C=1>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19]([CH3:20])=[O:42])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(C(F)(F)F)cc3)c[nH]c12
Solvent: CO
Solvent: ClCCl
Product: CS(=O)Cc1cccc2c(C(c3ccc(F)cc3)c3ccc(C(F)(F)F)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
75 mg (0.18 mmol) of the compound from Example 99 were introduced into 25 ml of dichloromethane at 0° C., 43 mg (0.18 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The residue was purified twice by preparative HPLC (mobile phase: acetonitrile/water gradient). 65 mg (84% of theory) of the title compound were obtained as mixture of diastereomers.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[N:29]1([CH:27]([C:3]2[N:4]=[C:5]([CH2:24][CH2:25][CH3:26])[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[C:7](=[O:8])[CH:2]=2)[CH3:28])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: C1COCCN1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Product: CCCc1nc(C(C)N2CCOCC2)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g) and morpholine (8 mL) was stirred at 90° C. for 12 hr. The solvent was evaporated from the reaction mixture under reduced pressure. The residue was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.43 g, 83%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[C:4]([Cl:15])[C:3]=1[N+:16]([O-:18])=[O:17].[NH2:19][C:20]1[C:21]([S:28][CH3:29])=[N:22][CH:23]=[N:24][C:25]=1[S:26][CH3:27].CC([O-])(C)C.[K+]>CS(C)=O>[Cl:15][C:4]1[C:3]([N+:16]([O-:18])=[O:17])=[C:2]([N:24]2[C:25]([S:26][CH3:27])=[C:20]([NH2:19])[C:21]([S:28][CH3:29])=[N:22][CH2:23]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12]
Reactant: CSc1ncnc(SC)c1N
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CSC1=NCN(c2c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c2[N+](=O)[O-])C(SC)=C1N
Temperature: 20 °C
Reaction time: 15 h
Yield: 9737.8 %

Procedure:
7.32 g (0.24 mmole) of 1,3-dichloro-2,6-dinitro-4-trifluoromethylbenzene are dissolved in 30 ml of dimethylsulfoxide and then a solution of 3.75 g (20 mmoles) of 5-amino-4,6-dimethylthiopyrimidine in 20 ml of dimethylsulfoxide and a solution of 2.69 g of potassium tert-butylate in 20 ml of dimethylsulfoxide are added simultaneously dropwise at 15° C. with cooling. The reaction solution is stirred for 15 hours at 20° C. and then poured into ice-water and, after neutralisation with acetic acid, extracted three times with chloroform. The extracts are washed with water, dried over sodium sulfate, and the chloroform is removed, affording 10.7 g of a yellow oil. The crude product is purified by chromatography through a solumn of silica gel, affording 2.04 g of starting 5-amino-4,6-di(methylmercapto)pyrimidine and 2.8 g of a yellow product which is recrystallised from 1 ml of toluene and 5 ml of cyclohexane to give 2.03 g of compound 1.2 of m.p. 146°-147° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([NH2:6])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([C:11]([F:14])([F:12])[F:13])=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1cc(C(F)(F)F)cnc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1cc(C(F)(F)F)cnc1Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-chloro-5-(trifluoromethyl)nicotinamide (as prepared in the previous step, 788 mg, 3.51 mmol) in dry DCM was added TEA (1.1 mL, 7.89 mmol). After cooling to 0° C. under argon, trifluoroacetic anhydride (0.54 mL, 3.88 mmol) was added dropwise. After stirring for 1.5 hours at 0° C., DCM (30 mL) and saturated aqueous sodium bicarbonate were introduced. The organic layer was removed and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica gel, DCM) to afford the product as a tan solid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH3:7])=[C:2]=[S:3].[CH3:8][N:9]([CH2:11][C:12]1[O:16][C:15]([CH2:17][S:18][CH2:19][CH2:20][NH2:21])=[CH:14][CH:13]=1)[CH3:10]>C(#N)C>[CH3:10][N:9]([CH2:11][C:12]1[O:16][C:15]([CH2:17][S:18][CH2:19][CH2:20][NH:21][C:2]([NH:1][CH2:4][CH2:5][O:6][CH3:7])=[S:3])=[CH:14][CH:13]=1)[CH3:8]
Reactant: COCCN=C=S
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CC#N
Product: COCCNC(=S)NCCSCc1ccc(CN(C)C)o1

Procedure:
1-(Isothiocyanato)-2-methoxyethane (1.17 g) and 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.14 g) in acetonitrile were stood overnight. Solvent was removed and the residual oil chromatographed (silica/methanol) to give N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-(2-methoxyethyl)thiourea as a pale oil Rf 0.45. Analysis Found: C, 50.64; H, 7.51; N, 12.58. C14H25N3O2S2 requires: C, 50.75; H, 7.55; N, 12.69%.