Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:4][C:5]([O:8][C:9]2[C:14]3[N:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:3]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:4][C:5]([O:8][C:9]3[C:14]4[N:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:17][C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:6][CH:7]=2)=[CH:35][CH:34]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)c(Br)cn3)cccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)c(-c4ccc(F)cc4)cn3)cccc2s1
Temperature: 160 °C

Procedure:
To a mixture of N-{4-[5-bromo-4-(4-trifluoromethyl-phenyl)-pyridin-2-yloxy]-benzothiazol-2-yl}-acetamide, (Example 145(b)), (51 mg, 0.1 mmol) and 4-fluorophenylboronic acid (18 mg, 0.13 mmol, Aldrich) in dioxane (1 mL) was added Pd(PPh3)4 (6 mg, 0.005 mmol, Aldrich) and aqueous Na2CO3 (16 mg in 0.2 mL of water). The reaction mixture was heated in microwave synthesizer at 160° C. for 30 min. Purification by silica gel chromatography (EtOAc/hexanes) gave the title compound as a white solid. MS (ESI, pos. ion) m/z: 524 (M+1). Mp: 112.3–130.1° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH:8]=1)(=O)=O.C(N(CC)CC)C.CN(C)C=O.[CH2:29]([O:36][C:37]1[N:38]=[N:39][C:40]([C:51]#[CH:52])=[CH:41][C:42]=1[O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:29]([O:36][C:37]1[N:38]=[N:39][C:40]([C:51]#[C:52][C:7]2[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH:8]=2)=[CH:41][C:42]=1[O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC1CC=C(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
A microwave reaction vial was charged with 4-methoxycyclohex-1-enyl trifluoromethanesulfonate (1069 mg, 4.11 mmol), copper(I) iodide (16.83 mg, 0.09 mmol), tetrakis(triphenylphosphine)palladium(0) (54.6 mg, 0.05 mmol), triethylamine (1432 μl, 10.27 mmol) and dry N,N-dimethylformamide (6849 μl). The reaction was evacuated and purged with nitrogen and a solution of 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5; 650 mg, 2.06 mmol) in dry tetrahydrofuran (3 ml) was added before the whole was then stirred in the microwave at 70° C. for 1 hour. Upon cooling, the resulting mixture was partitioned between ethyl acetate and water and the organic extracts were washed with water and brine, dried (MgSO4), filtered and concentrated to afford a brown oil. This was purified by chromatography on silica eluting with 0-75% ethyl acetate in petrol to give 3,4-bis(benzyloxy)-6-[(4-methoxycyclohex-1-en-1-yl)ethynyl]pyridazine (Intermediate 20) as a brown oil (860 mg, 85%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[C:7]1=O)[CH2:13]2.[H][H]>[Pd].C(O)(=O)C>[CH:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH:7]1[NH:1][CH2:2][C:3]([OH:5])=[O:4])[CH2:13]2
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: [H][H]
Reactant: NCC(=O)O
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)CNC1C2CC3CC(C2)CC1C3
Temperature: 100 °C
Reaction time: 120 h

Procedure:
A 600 ml stainless steel Parr reactor, equipped with a stirrer, two inlets, one with a tubing reaching nearly to the bottom of the reactor, and an outlet was used. Into the open reactor there were charged 100 grams of glycine (Aldrich, 99+%), 206.7 grams of 2-adamantanone (Aldrich, 99%), 10 grams of palladium (5%) on charcoal, and 300 grams of glacial acetic acid. The reactor was closed and dry nitrogen was passed through said one inlet into the reaction mixture to replace the air in the reaction mixture and in the reactor. The nitrogen was turned off and the reactor was pressurized with hydrogen through the other inlet. Under a hydrogen pressure of 725 psig (5100 kPa), the reaction mixture was heated to 100° C. and stirred at this temperature for 5 days. After cooling down to room temperature, the excess hydrogen was vented from the reactor and the reactor was opened. The mixture was filtered by suction to remove the solid Pd/C catalyst. The filtrate was evaporated to remove the acetic acid and water. The crude product was washed with ether and recrystallized from a dilute aqueous solution. A pure product was obtained after two recrystallization. Elemental analysis:Calculated for C12H1 7NO2 :C:68.67; H:9.15; N:6.69. Found C:68.85; H:9.12; N:6.75. M.P.:255.4 C (by DSC at 10 C/min. under He).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.C(N(CC)CC)C.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[Cl-].[Na+]>CN1CCCC1=O.O>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([Cl:12])=[N:4][N:3]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nnc(Cl)c2ccccc12
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2nnc(Cl)c3ccccc23)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of 2.09 g (10.5 mmol) of commercially available 1,4-dichlorophthalazine in 20 ml of N-methylpyrrolidone were added 7.32 ml (52.5 mmol) of triethylamine and 2.35 g (12.6 mmnol) of N-tert-butoxycarbonylpiperazine, followed by heating at 70° C. with stirring in an atmosphere of argon for 2 hours. The reaction mixture was allowed to cool to room temperature and then poured into water, and sodium chloride was added thereto. The precipitated crystals were collected by filtration, washed with water, and dried, followed by purification by silica gel chromatography to give 2.77 g (76%) of 4-(4-chloro-1-phthalazinyl)-1-piperazinecarboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][N:13]([C:16]([C@H:18]([NH:28][C:29](=[O:41])[C:30]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])([CH3:32])[CH3:31])[CH2:19][O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:17])[CH2:12][CH2:11]3)[CH2:9][NH:8][C:5]2=[CH:6][CH:7]=1.CN1CCOCC1.[CH3:49][S:50](Cl)(=[O:52])=[O:51]>ClCCl>[CH3:49][S:50]([N:8]1[C:5]2[C:4](=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:10]2([CH2:11][CH2:12][N:13]([C:16]([C@H:18]([NH:28][C:29](=[O:41])[C:30]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])([CH3:32])[CH3:31])[CH2:19][O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:17])[CH2:14][CH2:15]2)[CH2:9]1)(=[O:52])=[O:51]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCC2(CC1)CNc1ccc(F)cc12
Reactant: CS(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCC2(CC1)CN(S(C)(=O)=O)c1ccc(F)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.134 g the intermediate from Step B in 5 mL of dichloromethane was added 0.080 mL of N-methylmorpholine, and 0.022 mL of methanesulfonylchloride and stirred at 0° C. for 30 min. The reaction mixture was diluted with an additional 5 mL of dichloromethane and washed with 5 mL of saturated sodium bicarbonate solution, brine (5 mL), dried over MgSO4 and concentrated. Flash chromatography of the residue over 20 g of silica gel gave 0.101 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:17]=O)=[CH:5][C:6]2[C:12]3=[N:13][N:14]=[N:15][N:11]3[CH2:10][CH2:9][CH2:8][C:7]=2[CH:16]=1.[NH2:19][C@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:21]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(OC(N1CCC[C@H](NCC2C=C3C(CCC4N3N=NN=4)=CC=2OC)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:29]([O:28][C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:20]([NH:19][CH2:17][C:4]2[C:3]([O:2][CH3:1])=[CH:16][C:7]3[CH2:8][CH2:9][CH2:10][N:11]4[N:15]=[N:14][N:13]=[C:12]4[C:6]=3[CH:5]=2)[C@@H:21]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COc1cc2c(cc1C=O)-c1nnnn1CCC2
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Agent: COc1cc2c(cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1)-n1nnnc1CC2
Product: COc1cc2c(cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1)-c1nnnn1CCC2

Procedure:
This compound was prepared from Compound 10 and Compound 5 in the same manner of Compound 7.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[C:4]([F:13])[CH:3]=1.IC1C=C(O)C=CC=1.[CH:22]1([C:27]([OH:44])([C:38]#[C:39][Si](C)(C)C)[CH2:28][C:29]2[O:34][C:33]([CH3:36])([CH3:35])[O:32][C:31](=[O:37])[CH:30]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([C:27]([OH:44])([CH2:28][C:29]2[O:34][C:33]([CH3:35])([CH3:36])[O:32][C:31](=[O:37])[CH:30]=2)[C:38]#[C:39][C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]#[N:12])[CH2:10][CH2:9]3)=[C:4]([F:13])[CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: N#CC1(c2ccc(Br)cc2F)CC1
Reactant: CC1(C)OC(=O)C=C(CC(O)(C#C[Si](C)(C)C)C2CCCC2)O1
Agent: Oc1cccc(I)c1
Product: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C3(C#N)CC3)c(F)c2)C2CCCC2)O1

Procedure:
The desired product was prepared analogously to example F(7), Step 5, substituting 1-(4-bromo-2-fluoro-phenyl)-cyclopropanecarbonitrile (0.96 g, 4.0 mmol), from Step 2 above in place of 3-iodophenol, and 6-(2-cyclopentyl-2-hydroxy-but-3-ynyl)-2,2-dimethyl-[1,3]dioxin-4-one (1.06 g, 4.0 mmol; from Step 4 above) in place of 6-but-3-ynyl-3-chloro-6-cyclopentyl-dihydro-pyran-2,4-dione. Yield: 1.241 g, 73%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH2:16][CH2:17][CH3:18])[N:12]=[N:11]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH2:16][CH2:17][CH3:18])[N:12]=[N:11]1
Reactant: CS(=O)(=O)Cl
Reactant: CCCn1nnn(-c2cc(O)c(Cl)cc2Cl)c1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCn1nnn(-c2cc(OS(C)(=O)=O)c(Cl)cc2Cl)c1=O
Temperature: 25 °C

Procedure:
A stirred solution of 0 5 g (0.0017 mole) of 1-(2,4-dichloro-5-hydroxyphenyl)-1,4-dihydro-4-propyl-5H-tetrazol-5-one (Example 10, Step A) and 0.26 g (0.0026 mole) of triethylamine in 30 mL of methylene chloride was cooled to 0° C. Methanesulfonyl chloride (0.22 g, 0.0019 mole) was added slowly to the reaction mixture. After complete addition, the mixture was allowed to warm to room temperature and was stirred for several days. The mixture was poured into ice water and extracted with diethyl ether. The ether extract was dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated under reduced pressure to leave a residue. The residue was purified by column chromatography on silica gel to yield 0.33 g of 1-(2,4-dichloro-5-methylsulfonyloxyphenyl)-1,4-dihydro-4-propyl-5H-tetrazol-5-one was a solid, mp 64°-65° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:18]4[C:19]([F:26])=[N:20]C(C=C)=CC=4)=[C:13]([C:14]([F:17])([F:16])[F:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.C[N+]1([O-])CC[O:31][CH2:30]C1.[O:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:18]4[CH:36]=[CH:37][C:38]([CH:39]([OH:35])[CH2:30][OH:31])=[N:20][C:19]=4[F:26])=[C:13]([C:14]([F:17])([F:16])[F:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)c(F)n1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Solvent: CCOC(C)=O
Product: OCC(O)c1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)c(F)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1-(Cyclopropylmethyl)-5-(6-ethenyl-2-fluoropyridin-3-yl)-4-(trifluoromethyl)-1H-benzotriazole (77 mg, 0.21 mmol) was dissolved in tetrahydrofuran (1.4 mL) and treated with osmium tetraoxide (270 uL, 0.043 mmol, 0.2 equiv) and N-methylmorpholine N-oxide (25 mg, 0.21 mmol, 1 equiv). After stirring at ambient temperature for 1.5 hours, the mixture was diluted with ethyl acetate (40 mL) and washed with sodium bicarbonate (2×30 mL, aqueous saturated). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]([O:7]CC)=O)[CH3:2].[CH3:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[CH2:17][Mg]Cl.[Cl-].[NH4+]>C1COCC1>[CH2:11]([O:10][CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:7])[CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:16]([CH3:17])[CH:15]=1)[CH3:12]
Reactant: Cc1cccc(C[Mg]Cl)c1
Reactant: CCOC(=O)C(OCC)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(OCC)C(=O)Cc1cccc(C)c1
Temperature: -78 °C

Procedure:
Under an argon atmosphere, to a solution of ethyl diethoxyacetate (1.80 mL, 10.1 mmol) in THF (20 mL) was added slowly a THF solution of (72) prepared above at −78° C. After stirring at −78° C. for an hour, to this was added 20% aqueous solution of ammonium chloride (10 mL) and the product was extracted with ethyl acetate (×3). The organic layer was sequentially washed with water (×1) and saturated brine (×1), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=9/1) to give 1,1-diethoxy-3-(3-methylphenyl)propan-2-one (73) as a colorless oily substance (1.38 g, 5.84 mmol, 58.0%).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:25]1([CH3:34])[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH3:34][C:25]1[CH:30]=[CH:29][C:28]([C:31]([O:15][CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:17][CH:16]=3)[CH2:14][CH2:13]2)=[O:32])=[CH:27][CH:26]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccc(CN2CCC(O)CC2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccc([N+](=O)[O-])cc3)CC2)cc1
Yield: 82.9 %

Procedure:
0.5 g (0.00212 mol) of 1-(4-nitro-benzyl)-piperidin-4-ol and 0.595 ml (0.00424 mol) of triethylamine were dissolved in 15 ml of toluene, treated with 0.561 ml (0.00424 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.623 g (83%) of 1-(4-nitro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as yellow crystals. MS: me/e=355 (C20H23N2 O4+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)[C:5]([F:14])=[CH:4][N:3]=1.[CH2:15]1[CH2:25][O:24][C:23]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=2[O:16]1>>[CH2:15]1[CH2:25][O:24][C:23]2[CH:22]=[CH:21][C:19]([NH:20][C:2]3[N:7]=[C:6]([NH:8][N:9]4[CH:13]=[CH:12][CH:11]=[CH:10]4)[C:5]([F:14])=[CH:4][N:3]=3)=[CH:18][C:17]=2[O:16]1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: Fc1cnc(Cl)nc1Nn1cccc1
Product: Fc1cnc(Nc2ccc3c(c2)OCCO3)nc1Nn1cccc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(1H-pyrrol-1-yl)-4-pyrimidineamine was reacted with 3,4-ethylenedioxyaniline to produce N2-(3,4-ethylenedioxyphenyl)-5-Fluoro-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 11.63 (s, 1H), 9.94 (s, 1H), 8.23 (d, 1H, J=4.7 Hz), 6.86 (m, 4H), 6.58 (d, 1H, J=8.8 Hz), 6.12 (t, 2H, J=2.3 Hz), 4.15 (s, 4H). LCMS: ret. time: 17.36 min.; purity: 96%; MS (m/e): 328 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([S:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[Cl:14].C([O-])(=[O:17])C.[K+].CS(C)=O>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[Cl:14][C:4]1[CH:5]=[CH:6][C:7]([S:9][C:10]([F:13])([F:12])[F:11])=[CH:8][C:3]=1[CH2:2][OH:17]
Reactant: FC(F)(F)Sc1ccc(Cl)c(CCl)c1
Reactant: CC(=O)[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: OCc1cc(SC(F)(F)F)ccc1Cl
Temperature: 60 °C
Reaction time: 5 h
Yield: 77.7 %

Procedure:
A mixture of 55.7 g of crude 2-chloromethyl-4-(trifluoromethylthio)chlorobenzene, 23 g of potassium acetate, 150 ml of dimethyl sulfoxide and 10 g of triethylbenzylammonium chloride is stirred for 5 hours at 60° C. It is decomposed by pouring into water, extracted with benzene and the benzene evaporated. The oily residue is dissolved in 200 ml of ethanol, 100 ml of water and 20 ml of hydrochloric acid are added and the mixture is stirred and refluxed for 7 hours. Ethanol is distilled off, the residue mixed with water and extracted with benzene. The oil obtained by evaporation of the dried extract, is distilled in vacuo. There are obtained 40.2 g crude 2-chloro-5-(trifluoromethylthio)benzyl alcohol boiling at 140°-150° C./2 kPa. According to the 1H-NMR spectrum the product contains approximately 80% of the named compound and the remainder is the position isomer. In this state the substance is suitable for further processing.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.O=[C:7]1[CH2:15][C@@H:14]2[C@@H:9]([CH2:10][CH:11]=[CH:12][CH2:13]2)[CH2:8]1.[H-].[Na+].[OH2:18]>>[CH2:2]([O:1][C:5]([CH:4]=[C:7]1[CH2:15][C@@H:14]2[C@@H:9]([CH2:10][CH:11]=[CH:12][CH2:13]2)[CH2:8]1)=[O:18])[CH3:3]
Reactant: C1CCOC1
Reactant: O=C1C[C@H]2CC=CC[C@H]2C1
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C=C1C[C@H]2CC=CC[C@H]2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A tetrahydrofuran solution (100 ml) of 8-oxo-cis-bicyclo[4,3,0]nona-3-ene (80g) was added to a tetrahydrofuran solution (1000 ml) of the ylide prepared with triethyl phosphonoacetate (160 g) and sodium hydride (60% mineral oil dispersion, 23.5 g). The mixture was stirred for 30 min. at room temperature and poured into water and then extracted with ethylacetate. The organic layer was washed with water, dried, concentrated under reduced pressure to give 8-ethoxycarbonylmethylene-cis-bicyclo[4,3,0]nona-3-ene.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:30]=[CH:29][C:19]([CH2:20][NH:21]C(=O)OC(C)(C)C)=[CH:18][CH:17]=2)=[C:4]([O:31]C)[CH:3]=1.BrB(Br)Br>>[ClH:1].[NH2:21][CH2:20][C:19]1[CH:18]=[CH:17][C:16]([C:5]2[C:6]3[C:7]4[CH:15]=[CH:14][S:13][C:8]=4[C:9](=[O:12])[NH:10][C:11]=3[C:2]([Cl:1])=[CH:3][C:4]=2[OH:31])=[CH:30][CH:29]=1
Reactant: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: BrB(Br)Br
Product: Cl
Product: NCc1ccc(-c2c(O)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1
Yield: 158.9 %

Procedure:
Following General Procedure F, tert-butyl 4-(6-chloro-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)benzylcarbamate (15 mg, 0.032 mmol) was reacted with tribromoborane (1.0 M in methylene chloride, 1 mL, 1 mmol) to afford the desired product (10 mg, 80%) as a brown solid: 1H NMR (500 MHz, CD3OD) δ 7.64 (d, J=8.2 Hz, 2H), 7.59 (d, J=5.4 Hz, 1H), 7.43-7.38 (m, 2H), 7.30 (s, 1H), 6.08 (d, J=5.4 Hz, 1H), 4.27 (s, 2H); ESI MS m/z 357 [C18H13ClN2O2S+H]+; ESI MS m/z 357 [C18H13ClN2O2S+H]+; HPLC 98.4% (AUC), tR=8.62 min.
Reaction SMILES: C(O)C.[O-]CC.[Na+].[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:19]([O:22][CH:23]([CH3:30])[CH2:24]CS([O-])(=O)=O)[CH2:20][CH3:21]>O>[CH2:19]([O:22][CH:23]([CH3:30])[CH2:24][CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8]([O:16][CH2:17][CH3:18])=[O:15])[CH2:20][CH3:21]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCOC(C)CCS(=O)(=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCOC(C)CC(C(=O)OCC)C(=O)OCC
Yield: 65.8 %

Procedure:
Into 345 ml of ethanol, 43.4 g of 95%-sodium ethoxide was added, and under stirring, 114 g of diethyl malonate was added dropwise at 33°-36° C. in 55 min. After further 30 min. of stirring, 114 g of the above 2-propoxypropylmethane sulfonate was added at 34°-38° C. in 1 hour. The mixture was heated and refluxed at 80°-82° C. for 18 hours. After the completion, the product was poured in cold water and extracted with benzene, followed by washing with water, removed by distillation of benzene, and vacuum distillation to obtain 100 g of ethyl 4-propoxy-2-ethoxycarbonylvalerate (75°-115° C./5 mmHg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]2[CH2:33][CH2:32][N:31]([C:13]([C:9]3[CH:10]=[N:11][O:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[O:15])[CH2:30]2)=[CH:27][CH:28]=1
Reactant: Clc1ccc(C2CCNC2)cc1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: O=C(O)C(=O)O
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(c3ccc(Cl)cc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-(4-chlorophenyl)pyrrolidine oxalate (16.3 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (4.4 mg). Calcd for C21H19ClN2O2: 366.1135, found 366.1138.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.C([O:16][C:17]([C:19]1([CH2:26][CH2:27]OC)[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1)=O)C.[Cl-].C[Al+]C>C1(C)C=CC=CC=1>[OH:25][CH:22]1[CH2:23][CH2:24][C:19]2([C:17](=[O:16])[N:11]([C:8]3[CH:9]=[N:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:12])[F:13])=[CH:6][CH:7]=3)[CH2:27][CH2:26]2)[CH2:20][CH2:21]1
Reactant: Nc1ccc(OCC(F)(F)F)nc1
Reactant: CCOC(=O)C1(CCOC)CCC(O)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1N(c2ccc(OCC(F)(F)F)nc2)CCC12CCC(O)CC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6-(2,2,2-Trifluoro-ethoxy)-pyridin-3-ylamine (5.11 g, obtained in example 108, step 2) was added to a solution of 4-hydroxy-1-(2-methoxy-ethyl)-cyclohexanecarboxylic acid ethyl ester (5.10 g, obtained in example 2, step 3) in toluene (160 mL). The mixture was stirred for 10 minutes at RT. Then, dimethylaluminiumchloride (1M in hexane, 66.4 mL) was added dropwise over a period of 30 minutes. The reaction mixture was heated to reflux for 2 hours and then at 95° C. for 16 hours. The mixture was cooled, poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The title compound was obtained as an inseparable mixture of cis and trans diastereomeres as a brown oil (9.56 g, 100%). This mixture was used without further purification. MS (m/e): 345.1 [MH+].