Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([OH:8])[CH:7]=1>CCOC(C)=O.[Pd]>[NH2:9][C:5]1[CH:4]=[C:3]([O:12][CH3:13])[C:2]([CH3:1])=[CH:7][C:6]=1[OH:8]
Reactant: COc1cc([N+](=O)[O-])c(O)cc1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(N)c(O)cc1C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
5-Methyl-4-(methyloxy)-2-nitrophenol (3.65 g, 20 mmol) was dissolved in EtOAc (100 mL) and 200 mg of 5% Pd/C was added. The reaction vessel was evacuated and filled with N2. This process was repeated twice then filled with H2 at 1 atm, and stirred for 16 h. The mixture was filtered through a pad of celite, washed with EtOAc, and the solvent was removed via rotovap to give the title compound (3.0 g, 98%) as a white solid. MS (ES) m/e 154 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:38]1[CH2:42]O[CH2:40][CH2:39]1.BrCC1CC1>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:40][CH:39]1[CH2:42][CH2:38]1)[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Reactant: C1CCOC1
Agent: BrCC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC1CC1)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Yield: 16.6 %

Procedure:
This compound was prepared according to the procedure C from ethyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.190 g; 0.5 mmol), LHMDS 1N in THF (0.55 mL; 0.55 mmol), bromomethylcyclopropane (0.096 mL; 1 mmol) in DMF (2 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (1-30%) in heptane furnished 0.036 g (16%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]1=O.B#B.Cl>O1CCCC1.O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]([CH3:12])[CH2:3]1
Reactant: Cc1nc2ccccc2n(C)c1=O
Agent: B#B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC1CN(C)c2ccccc2N1

Procedure:
To a stirred solution of 0.2 mole (34.8 g) of 1,3-dimethyl-2-oxoquinoxaline in 300 ml of dry tetrahydrofuran is added dropwise 0.24 mole (240 ml of 1 M) diborane in tetrahydrofuran. The solution is stirred one additional hour, then heated at its reflux temperature for one day. After cooling, about 40 ml of water is added, followed by 2 equivalents of 4N hydrochloric acid. The solution is heated at reflux for one hour, then evaporated to provide a solid residue. The residue is dissolved in water. The solution is basified and then extracted with diethyl ether. The ether is dried, then evaporated to provide an oil. Distillation provides 1,3-dimethyl-1,2,3,4-tetrahydroquinoxaline, b.p. 85° C/0.1 mm of Hg. Analysis: Calculated for C10H14N2 : %C, 74.0; %H, 8.7; %N, 17.4; Found: %C, 74.2; %H, 8.9; %N, 17.3.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=O)[C:7]([C:15]([O:17]CC)=[O:16])=[CH:8][N:9]2[CH2:13][CH3:14])=[CH:4][N:3]=1.O.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([CH2:6][C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH2:13][CH3:14])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn(CC)c2c(Cl)c(Cl)ncc2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCN1C=C(C(=O)O)Cc2cnc(Cl)c(Cl)c21
Temperature: 0 °C

Procedure:
6.2 g (0.0196 mol) of ethyl 7,8-dichloro-1-ethyl-1,4-dihydro-4-oxo-1,6-naphthyridine-3-carboxylate are heated at reflux in a mixture of 26 ml of acetic acid, 26 ml of water and 2.6 ml of concentrated sulphuric acid for two hours. The cooled mixture is put into ice-water, and the product is isolated and washed with water.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.C([O-])([O-])=O.[K+].[K+].F[C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[N+:35]([C:32]1[CH:33]=[CH:34][C:29]([N:10]2[CH2:9][CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)=[CH:30][CH:31]=1)([O-:37])=[O:36]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1=C(c2ccccc2)CCNC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CC=C(c3ccccc3)CC2)cc1
Temperature: 100 °C
Yield: 42 %

Procedure:
A mixture of 0.5 g (2.5 mmole) of 4-phenyl-1,2,3,6-tetrahydropyridine, 0.51 ml (2.8 mmole) of diisopropylethylamine, 0.71 g (5 mmole) of K2CO3, 0.40 g ((2.8 mmole) of 4-fluoronitrobenzene in 10 ml of DMF is heated at 100° C., for 24 hours. At the end of the reaction, the mixture is poured into 25 ml of a saturated solution of NaHCO3 and the product is extracted using 25 ml of AcOEt. After decantation, the organic solution is washed twice with 20 ml of water followed by 20 ml of brine, drying over magnesium sulphate, filtration and evaporation of the solvent under vacuum produce a yellow solid with a yield of 42%. Melting point: 185-192° C. (decomposition).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18](Cl)=[O:19])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[F:21][C:22]([F:31])([F:30])[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C@H:12]2[CH2:13][CH2:14][C@H:15]([C:18]([O:29][C:26]3[CH:25]=[CH:24][C:23]([C:22]([F:30])([F:31])[F:21])=[CH:28][CH:27]=3)=[O:19])[CH2:16][CH2:17]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)Cl)CC2)CC1
Reactant: Oc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)Oc3ccc(C(F)(F)F)cc3)CC2)CC1

Procedure:
A solution of 29.3 g of trans-4-(trans-4-n-pentylcyclohexyl)-cyclohexanecarbonyl chloride in 120 ml of toluene is added dropwise in the course of 2 hours with stirring to a boiling solution of 16.2 g of p-trifluoromethylphenol and 10 ml of pyridine in 120 ml of toluene. The reaction mixture is mixture is refluxed for a further 3 hours and then evaporated. The residue is worked up as conventional. p-Trifluoromethylphenyl trans-4-(trans-4-n-pentylcyclohexyl)-cyclohexanecarboxylate is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=[O:14])=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[O:16]1[CH2:21][CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C.C(Cl)Cl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH:10]1([CH2:9][O:8][C:7]2[N:6]=[C:5]([C:13]([OH:15])=[O:14])[CH:4]=[CH:3][C:2]=2[CH:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)[CH2:12][CH2:11]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: O=C(O)c1ccc(Br)c(OCC2CC2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(O)c1ccc(C2CCOCC2)c(OCC2CC2)n1
Yield: 90.9 %

Procedure:
Under an atmosphere of nitrogen, a solution of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid (300 mg, 1.1 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (278 mg, 1.3 mmol), 1,1′-bis(diphenylphosphino) ferrocene-palladium(II)dichloride methylene chloride complex (CAN 95464-05-4, 45 mg, 0.06 mmol) and sodium carbonate (964 mg, 9.1 mmol) in DMF (10 mL) was heated to 100° C. overnight. The reaction mixture was poured into water, extracted with ethyl acetate (30 mL), the pH of the aqueous layer was adjusted to 2 by addition of 1 N hydrochloric acid and the resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed six times with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 8 g, 30% ethyl acetate in petroleum ether) to yield the title compound (0.15 g, 1 mmol, 49.4%) as white solid; MS (EI): m/e 276.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH2:28][CH3:29])[CH3:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:30][C:31]([CH3:33])=O>>[NH2:1][C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:24][N:25]([CH:31]([CH3:33])[CH3:30])[CH2:26]4)[C:15]=3[O:27][CH2:28][CH3:29])[CH3:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)=O
Reactant: CCOc1c(C(C)n2cc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Product: CCOc1c(C(C)n2cc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C(C)C)C1
Yield: 65 %

Procedure:
The desired compound was prepared according to the procedure of Example 213 using 4-[1-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile instead of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile and acetone instead of formaldehyde as the starting materials in 65% yield. The product was isolated as a single enantiomer. 1H NMR (300 MHz, dmso) δ 7.95 (s, 1H), 7.19 (s, 1H), 7.16-7.13 (m, 1H), 6.58 (s, 2H), 6.11 (q, J=7.1 Hz, 1H), 4.04-3.67 (m, 5H), 3.04-2.92 (m, 2H), 2.36 (s, 3H), 2.27-2.12 (m, 1H), 1.69 (d, J=7.1 Hz, 3H), 1.30 (t, J=6.9 Hz, 3H), 0.85 (dd, J=6.1, 1.8 Hz, 6H). LCMS for C24H30ClN6O (M+H)+: m/z=453.2; Found: 453.3.
Reaction SMILES: Cl.[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.[S:29]1[CH2:33][CH:32]([C:34]([O:36]CC)=[O:35])[NH:31][CH2:30]1.C(Cl)(Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:31]2[CH:32]([C:34]([OH:36])=[O:35])[CH2:33][S:29][CH2:30]2)=[O:25])=[CH:22][CH:21]=1
Reactant: CCOC(=O)C1CSCN1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C1CSCN1C(=O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1

Procedure:
One-tenth mole of 4-(16-bromohexadecylamino)benzoyl chloride hydrochloride in methylene chloride is added to a solution of 0.1 mole of ethyl thiazolidine-4-carboxylate in chloroform containing two equivalents of triethylamine. After 5 hours at 20° C. the solution is filtered and evaporated to a white solid which is recrystallized from acetonitrile to yield 3-[4-(16-bromohexadecylamino)benzoyl]-4-carboxythiazolidine. By means of the alkaline hydrolysis method of Example 10, the ethyl ester is converted to the subject carboxylic acid. This acid is also prepared using the procedure of this Example except that the acylation of the thiazolidine-4-carboxylic acid is carried out in aqueous acetone sodium bicarbonate solution.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.[Li]CCCC.CCCCCC.CN([CH:30]=[O:31])C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[C:3]=1[CH:30]=[O:31]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)ccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)Nc1nccc(Cl)c1C=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Dissolve tert-butyl 4-chloropyridin-2-ylcarbamate (1.95 g, 0.00855 moles) in dry THF (50 mL) and cool to −78° C. under nitrogen atmosphere. Add dropwise 1.6 M n-BuLi/hexane (12.8 mL, 0.02053 moles) over a period of 15 minutes while maintaining the reaction temperature below −70° C. Stir the resulting red orange solution at −78° C. for 2 hours. Add DMF (3.3 mL, 0.04275 moles) dropwise to the reaction mixture while maintaining the reaction temperature below −70° C. Stir further at −78° C. for 2 hours and then quench the reaction mixture with saturated ammonium chloride (50 mL). Warm the reaction mixture to room temperature, extract with EtOAc (3×50 mL) and dry with MgSO4. Filter and concentrate under reduced pressure to afford a yellow viscous oil. Purify the crude product by flash column chromatography using 15-20% EtOAc/hexane to afford the title product as a white solid.
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5](=[O:15])[C@@H:6]([NH3+:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:3].[C:16]([O-])(O)=[O:17].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[N:14]([C@@H:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])[C:5]([O:4][CH2:2][CH3:3])=[O:15])=[C:16]=[O:17]
Reactant: CCCCCCC[C@H]([NH3+])C(=O)OCC
Reactant: O=C([O-])O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CCCCCC[C@H](N=C=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (2S)-1-ethoxy-1-oxononan-2-aminium chloride (4.00 g, 16.97 mmol) and DCM (80 ml) was cooled to 0° C. A solution of saturated NaHCO3 (80.0 ml, 84 mmol) was added, and then triphosgene (1.662 g, 5.60 mmol) was added. The reaction mixture was stirred at 0° C. for 1 hour, and then the layers were separated. The aqueous layer was extracted with DCM (3×). The combined organic portions were washed with brine, dried with MgSO4 and filtered and concentrated. The crude product was subjected to silica gel chromatography (80:20 hexane/EtOAc) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=[C:4]2[C:3]=1[NH:13][CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22].[C:23](OC(=O)C)(=[O:25])[CH3:24].C(N(CC)CC)C>C(Cl)Cl>[CH3:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=1[CH2:14][NH:13][C:3]1[C:4]2[N:5]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:6]=[CH:7][C:2]=1[NH:1][C:23](=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C)c1CNc1c(N)ccn2c(C)c(C)nc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccn2c(C)c(C)nc2c1NCc1c(C)cccc1C
Temperature: 25 °C

Procedure:
7-amino-2,3-dimethyl-8-(2,6-dimethylbenzylamino)-imidazo[1,2-a]pyridine (example 77) (0.16 g, 0.53 mmol) was dissolved in methylene chloride (5 ml) and acetic anhydride (60 mg) was added. The mixture was stirred over night at ambient temperature. A small amount of triethylamine was added and the solvent was removed under reduced pressure. Chromatography first with methylene chloride:methanol, 95:5 and secondly with methylene chloride:ethyl acetate, 50:50 gave after trituration with diethyl ether 87 mg (47%) as white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[C:15]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:14][C:13]([Cl:30])=[CH:12][N:11]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:31](Cl)(=[O:33])[CH3:32]>N1C=CC=CC=1.O1CCOCC1>[C:26]([C:23]1[CH:22]=[CH:21][C:20]([S:17]([NH:16][C:15]2[C:10]([C:8]([C:6]3[N:7]=[C:2]([NH:1][C:31](=[O:33])[CH3:32])[CH:3]=[CH:4][CH:5]=3)=[O:9])=[N:11][CH:12]=[C:13]([Cl:30])[CH:14]=2)(=[O:18])=[O:19])=[CH:25][CH:24]=1)([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2cccc(N)n2)cc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
N-[2-(6-amino-pyridine-2-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide (52 mg, 0.1 mmol) in pyridine/1,4-dioxane (1:1, 4 mL) was treated with acetyl chloride (100 mg) and then stirred at 60° C. for 2 h. After evaporation of solvent under reduced pressure, to the mixture was added THF (5 mL), followed by NaOH (2 N, 2 mL) and stirred at room temperature for another 2 h. The mixture was diluted with EtOAc and the organics were washed with 1 N HCl, NaHCO3 (saturated), and brine; dried over MgSO4, concentrated under reduced pressure, and purified through automated normal-phase chromatography to afford the title compound: 1H NMR (400 MHz, CDCl3) δ 10.80 (s, 1H), 8.37 (d, 1H), 8.22 (m, 2 H), 8.14 (s, 1H), 7.80 (m, 3H), 7.46 (m, 3H), 2.20 (s, 3H), 1.23 (s, 9H); MS (ES) (M+H)+ expected 487.1, found 487.1.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:5]=1[C:6]([NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:10])=[O:7].O.[C:25]1([CH:31](Br)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[Cl:3][C:4]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:5]=1[C:6]([NH:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:16][CH:17]=1)=[O:10])=[O:7]
Reactant: CCCCCCC(Br)c1ccccc1
Reactant: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCC(Oc1ccc(NC(=O)NC(=O)c2c(Cl)cccc2Cl)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
0.24 g of 55% sodium hydride dispersion in mineral oil were added to a solution of 1.63 g of N-(2,6-dichlorobenzoyl)-N'-(4-hydroxyphenyl)urea in 15 ml of dimethylformamide; the reaction mixture was stirred for 20 minutes with external cooling with water until a bright solution was obtained. 1.6 ml of 77% 1-phenylheptylbromide were added to this solution after which the reaction mixture was left to stand at room temperature for approximately 2 days. After pouring the reaction mixture on a mixture of ice water and petroleum ether a crystalline product was obtained which was sucked off, washed with successively water and little isopropanol and dried in air. The desired product was obtained in a yield of 0.87 g; melting point 146°-149° C. The product was identified by means of its NMR spectrum. The following compounds were prepared in a corresponding manner:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:5]=[CH:4][CH:3]=1.[C:21]1([P:27](Cl)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH:19]1[C:20]2[N:8]([C:6]3[N:7]=[C:2]([P:27](=[O:28])([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:3]=[CH:4][CH:5]=3)[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: Brc1cccc(-n2c3ccccc3c3ccccc32)n1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Product: O=P(c1ccccc1)(c1ccccc1)c1cccc(-n2c3ccccc3c3ccccc32)n1

Procedure:
Compound 58 was synthesized from 9-(6-bromo-2-pyridyl)carbazole and diphenylphosphinic chloride as in Synthetic Example 1.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:10][N:11]=2)[N:8]=1)=[O:2].[CH3:21][Mg]Br.[NH4+].[Cl-]>C1COCC1>[OH:2][CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[N:10][N:11]=2)[N:8]=1)[CH3:21]
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)NCc1nnc2ccc(C=O)nn12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc2nnc(CNC(=O)OC(C)(C)C)n2n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
In a 10 mL round bottom flask under N2 was dissolved tert-butyl (6-formyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (200 mg, 721 μmol) in 3 mL of THF then cooled at −78° C. and treated with methylmagnesium bromide (721 μl, 2164 μmol). After 30 minutes, the reaction mixture was warmed to 0° C. over 1 h. After 1 h the reaction mixture based on LC-MS was neutralized with NH4Cl (sat.). The aqueous phase was extracted 3× with DCM then the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude tert-butyl (6-(1-hydroxyethyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (202 mg, 95.5% yield) was used without further purification in the next step. MS m/z=294.4 [M+1]+. Calc'd for C13H19N5O3: 293.3.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH2:6][C:7](Br)=[O:8].[CH3:10][C:11]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:12]=1[NH:13][C:14](=[O:16])[CH3:15]>C(=S)=S>[Br:5][CH2:6][C:7]([C:19]1[C:18]([CH3:21])=[CH:17][C:12]([NH:13][C:14](=[O:16])[CH3:15])=[C:11]([CH3:10])[CH:20]=1)=[O:8]
Reactant: O=C(Br)CBr
Reactant: CC(=O)Nc1cc(C)ccc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)Nc1cc(C)c(C(=O)CBr)cc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of aluminum chloride (13.4 g) in carbon disulfide (68 ml) was added bromoacetyl bromide (8.8 ml) under ice-cooling, and the mixture was stirred for 30 minutes. 2′,5′-Dimethylacetanilide (5.57 g) was added to the stirred mixture, and the mixture was heated under reflux for 12 hours. After cooling, the reaction mixture was poured into ice-water, and the resulting precipitate were collected by filtration and washed with water. The cake was dissolved in ethyl acetate, and the solution was dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was washed with diethyl ether to give 4′-(2-bromo-acetyl)-2′,5′-dimethylacetanilide (5.65 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:14])[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[C@H:3]1[C:15]([OH:17])=[O:16].[C:19]([C@@H:21](O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=1)#[CH:20]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:14])[O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[C@H:3]1[C:15]([O:17][C@H:21]([C:19]#[CH:20])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=1)=[O:16]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)OCC(F)(F)F
Reactant: C#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: C#C[C@@H](OC(=O)[C@@H]1[C@H](/C=C\C(=O)OCC(F)(F)F)C1(C)C)c1cccc(Oc2ccccc2)c1

Procedure:
Using the orocedure of Step F of Example 9, the acid of Step D of Example 1 and (R)α-ethynyl-3-phenoxy-benzyl alcohol were reacted to obtain (R)α-ethynyl-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3[(Z) 3-oxo-3(2,2,2-trifluoroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+42°±1.5° (c=1% in CHCl3).
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([Cl:11])[N:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14](B(O)O)[CH:13]=1>>[Cl:11][C:8]1[N:9]=[CH:10][C:5]2[S:4][CH:3]=[C:2]([C:14]3[CH:13]=[N:12][C:21]4[C:16]([CH:15]=3)=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:6]=2[N:7]=1
Reactant: Clc1ncc2scc(Br)c2n1
Reactant: OB(O)c1cnc2ccccc2c1
Product: Clc1ncc2scc(-c3cnc4ccccc4c3)c2n1
Yield: 58 %

Procedure:
2-Chloro-7-(quinolin-3-yl)thieno[3,2-d]pyrimidine (140 mg, 58% yield) was prepared in the same manner as Step 6 of Example 1 using 7-bromo-2-chlorothieno[3,2-d]pyrimidine (200 mg, 0.81 mmol) and quinolin-3-ylboronic acid (140 mg, 0.81 mmol).