Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:13]([OH:15])=[O:14].[Cl:16][C:17]1[C:18]([N:23]2[C:27]([C:28](O)=O)=[CH:26][C:25](C(F)(F)F)=[N:24]2)=[N:19][CH:20]=[CH:21][CH:22]=1.N1C=CC=CC=1.CS(Cl)(=O)=[O:43]>C1COCC1>[Cl:16][C:17]1[C:18]([N:23]2[C:27]([C:28]3[O:14][C:13](=[O:15])[C:3]4[C:4]5[C:9](=[N:8][CH:7]=[CH:6][CH:5]=5)[CH:10]=[C:11]([CH3:12])[C:2]=4[N:1]=3)=[CH:26][C:25]([OH:43])=[N:24]2)=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc2ncccc2c(C(=O)O)c1N
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cc2ncccc2c2c(=O)oc(-c3cc(O)nn3-c3ncccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
To a suspension of 282 mg (1.39 mmol) of 6-amino-7-methyl-quinoline-5-carboxylic acid in 11 mL of anhydrous THF is added 407 mg (1.39 mmol) of 2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid followed by 560 μL (7.0 mmol) of pyridine. The mixture is stirred at ambient temperature during 30 minutes. Then the suspension is cooled to 0° C. and 430 μL (5.5 mmol) of methanesulfonyl chloride are added dropwise. The mixture is stirred at ambient temperature for 48 hours. Then the solvent is evaporated and the residue is sequentially triturated and filtrated with ethyl acetate and with a minimum of cold water. Purification of the residue by flash chromatography (SiO2, heptane/ethyl acetate 1:2) affords 286 mg (45%) of the product as a yellowish solid; LC/MS:468/460 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(=O)=O.[CH3:8][C:9]([CH3:11])=O.[C:12]([N:20]1[CH2:27][C@H:26](Cl)[CH2:25][C@H:21]1[C:22]([OH:24])=[O:23])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.S1C=[CH:32][CH:31]=[CH:30]1>>[C:12]([N:20]1[CH2:27][C@H:26]([C:9]2[CH:11]=[CH:32][CH:31]=[CH:30][CH:8]=2)[CH2:25][C@H:21]1[C:22]([OH:24])=[O:23])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccsc1
Reactant: O=C(O)[C@@H]1C[C@@H](Cl)CN1C(=O)c1ccccc1
Reactant: CC(C)=O
Agent: O=C=O
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)[C@@H]1C[C@@H](c2ccccc2)CN1C(=O)c1ccccc1

Procedure:
A dry, 3-necked 21 Morton flask (equipped with overhead stirrer, nitrogen inlet, and temperature probe) was charged with anhydrous aluminum chloride (124.23 g, 0.93 mole) followed by thiophene free benzene (810 ml). While stirring, the flask was cooled (dry ice-acetone) to an internal temperature of 6° C. Part C compound (powdered) was added (81 g, 0.26 mole) in portions. A rise in internal temperature to 7° C. was noted after the addition of ca. half the solid. The addition was briefly interrupted until the internal temperature returned to 6° C. and was then continued. The resulting heterogeneous mixture was vigorously stirred for 4 hours at 7°-8° C. and 1.5 hours at 8°-10° C. During this time the reaction became almost totally homogeneous and TLC indicated the conversion of Part C compound to a mixture of the title compound and (trans)-1-benzoyl-4-chloro- L-proline. The reaction was cooled to 7° C., and the mixture was hydrolyzed by the slow addition of 3N HCl (990 ml) such that the internal temperature did not rise above 30° C. The hydrolyzed mixture was treated with brine (180 ml), seeded with crystals of title compound, stirred at room temperature for 45 minutes and then held at room temperature overnight. The mixture was filtered through a coarse frit and the solid remaining in the reaction vessel was transferred to the funnel using 1N HCl (390 ml). The crude product was washed with water (4×500 ml). The last filtrate gave a weakly positive test for chloride (ethanolic silver nitrate). After drying on the filter for ca. 20 minutes the product weighed 122 g (159 mole %). The product was dried in vacuo to a weight of 98 g. The crude product was suspended in 240 ml of n-butyl acetate and heated to boiling. When the product dissolved, a second lower layer (presumably residual water) was evident. Boiling was continued until this layer disappeared. Sodium sulfate was added, boiling was continued an additional 5 minutes, and the mixture was filtered through celite (pre-washed with n-butyl acetate). The celite was washed with hot n-butyl acetate (2×ca. 50 ml). The filtrate volume was reduced to 240 ml, cooled, was seeded with crystals of title compound and stirred gently at ambient temperature overnight. The crystals were filtered and washed with n-butyl acetate (1×50 ml) and hexane (1×50 ml). The product was dried under high vacuum at 40° C. to a constant weight of 57.37 g (75.1 mole %; corrected for starting material and product HI). HPLC HI (λ218) of 99.03.
Reaction SMILES: [Li+].[OH-:2].CO[C:5](=O)[CH2:6][CH2:7][CH2:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20]C)[O:11][N:10]=1.Cl.[O:24]1[CH2:29]COCC1>O>[OH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12]1[O:11][N:10]=[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:29]([OH:24])=[O:2])[CH:13]=1
Reactant: C1COCCO1
Reactant: COC(=O)CCCc1cc(-c2ccccc2OC)on1
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: O
Product: O=C(O)CCCCc1cc(-c2ccccc2O)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Add a solution of LiOH (1.04 g, 43.6 mmol) in water (15 mL) to a rapidly stirred solution of 4-[5-(2-methoxy-phenyl)-isoxazol-3-yl]-butyric acid methyl ester (2.28 g, 8.7 mmol) in dioxane (120 mL), stir at room temperature overnight After 1 hour, acidify to pH 1 with 5N HCl solution and concentrate to remove the majority of the dioxane. Add water to residue and place in refrigerator overnight Filter out solids, wash with water, dry in a 50° C. vacuum oven for 6 hours to afford the title compound (3.11 g, 87%). MS (IS) 262 (M+1)+.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:21])[CH2:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15]([N:20]=1)=[N:16][CH:17]=[CH:18][N:19]=2)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C>CCO.O=[Pt]=O.O>[CH2:1]([O:5][C:6](=[O:21])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[NH:19][CH2:18][CH2:17][NH:16][C:15]=2[N:20]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)CCC#Cc1ccc2nccnc2n1
Agent: O=[Pt]=O
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CCCCOC(=O)CCCCc1ccc2c(n1)NCCN2
Reaction time: 4 h

Procedure:
A mixture of 5-5 (0.83 g, 2.93 mmol), triethylamine (0.222 g, 2.20 mmol), and PtO2.H2O (0.083 g) in EtOH (15 mL) was stirred under a hydrogen balloon for four hours. The reaction was filtered through Celite and concentrated to yield a dark brown oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][F:18])=[CH:11][CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[S:20]([NH2:30])(=[O:29])([C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)=[O:21]>C(O)(C)C.C(O)(C(F)(F)F)=O>[NH2:30][S:20]([C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][F:18])=[CH:11][CH:10]=3)[C:5]([F:19])=[CH:4][N:3]=2)=[CH:26][CH:27]=1)(=[O:21])=[O:29]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: FCCCc1ccc(Nc2nc(Cl)ncc2F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: NS(=O)(=O)c1ccc(Nc2ncc(F)c(Nc3ccc(CCCF)cc3)n2)cc1
Temperature: 100 °C

Procedure:
2-Chloro-5-fluoro-N4-[4-(3-fluoropropyl)phenyl]-4-pyrimidineamine (100 mg) and sulfanilamide (100 mg) were suspended in isopropanol (1 mL) and TFA (5 drops). The solution was heated at 100° C. overnight. The solution was evaporated and purified by flash column chromatography (2.0 M NH3/MeOH in dichloromethane=1-3%) and recrystallized from ethyl acetate to give N2-(4-aminosulfonylphenyl)-5-fluoro-N4-[4-(3-fluoropropyl)phenyl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 1.89-2.02 (m, 2H), 2.67 (t, J=8.1 Hz, 2H), 4.38 (t, J=5.7 Hz, 1H), 4.53 (t, J=5.7 Hz, 1H), 7.11 (br, 2H), 7.19 (d, J=8.1 Hz, 2H), 7.60 (d, J=8.7 Hz, 2H), 7.65 (d, J=8.1 Hz, 2H), 7.80 (d, J=8.7 Hz, 2H), 8.12 (d, J=3.9 Hz, 1H), 9.38 (br, 1H), 9.57 (br, 1H); 19F NMR (282 MHz, DMSO-d6): δ −201.79; LCMS: purity: 91.96%; MS (m/e): 420.74 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([O:20][CH3:21])([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1)[CH:4]([OH:6])[CH3:5].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:29][S:30]([O:6][CH:4]([CH3:5])[C:3]([O:20][CH3:21])([O:2][CH3:1])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:8]=1)(=[O:32])=[O:31]
Reactant: COC(OC)(c1cccc(Oc2ccccc2)c1)C(C)O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(OC)(c1cccc(Oc2ccccc2)c1)C(C)OS(C)(=O)=O

Procedure:
The oil, 1,1-dimethoxy-1-(3-phenoxyphenyl)propan-2-ol, from Example 26 and 11.3 g of triethylamine are dissolved in 65 ml of toluene. Then the solution is cooled to 10°-12° C. and 9.7 g of methanesulfonyl chloride in 35 ml of toluene is added over 30 minutes. After the addition is completed, the mixture is poured into 100 ml of saturated sodium bicarbonate solution, and 100 ml of toluene is added. The organic layer is separated, dried over magnesium sulfate and evaporated to yield 23.25 g of 1,1-dimethoxy-1-(3-phenoxyphenyl)prop-2-yl methanesulfonate, as an oil.
Reaction SMILES: Cl.[N:2]1([C:7](N)=[NH:8])C=CC=N1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:19]([C:20]3[N:25]=[C:24]([NH:26][C@H:27]4[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]4)[C:23]([F:33])=[CH:22][N:21]=3)=[CH:18][N:17]([S:34]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[C:14]2=[N:15][CH:16]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]2[C:19]([C:20]3[N:25]=[C:24]([NH:26][C@H:27]4[CH2:32][CH2:31][CH2:30][N:29]([C:7](=[NH:2])[NH2:8])[CH2:28]4)[C:23]([F:33])=[CH:22][N:21]=3)=[CH:18][N:17]([S:34]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[C:14]2=[N:15][CH:16]=1
Reactant: N=C(N)n1cccn1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCNC4)n3)c3cc(Cl)cnc32)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCN(C(=N)N)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of pyrazole-1-carboxamidine hydrochloride (0.12 g, 0.80 mmol) and 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-N-[(3S)-3-piperidyl]pyrimidin-4-amine, 1c, (0.40 g, 0.80 mmol) in DMF (0.9 mL) was added iPr2NEt (0.14 mL, 0.80 mmol). The reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted into water, filtered, washed with additional water, then ether. The filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography using 5-20% MeOH/CH2Cl2 gradient (product elutes with 20% MeOH) to afford 190 mg of the desired product.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][C:13]1[S:14][C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:16]([CH3:20])[N+:17]=1[CH2:18][CH3:19].[Cl:26][C:27]([Cl:38])([Cl:37])[C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>>[Cl:26][C:27]([Cl:37])([Cl:38])[C:28]1[CH:36]=[CH:35][C:31]([C:32]([CH:12]=[C:13]2[N:17]([CH2:18][CH3:19])[C:16]([CH3:20])=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[S:14]2)=[O:33])=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1sc(C)[n+](CC)c1C
Reactant: O=C(Cl)c1ccc(C(Cl)(Cl)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCOC(=O)C1=C(C)N(CC)C(=CC(=O)c2ccc(C(Cl)(Cl)Cl)cc2)S1

Procedure:
Analogous to Preparation Example 1 B, the 2,4-dimethyl-3-ethyl-5-ethoxycarbonyl-thiazolium p-toluene-sulfonate is reacted with p-trichloromethylbenzoyl chloride to give 2-(p-trichloromethyl-benzoylmethylene)-3-ethyl-4-methyl-5-ethoxycarbonylthiazoline.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](O)=[O:46])([CH3:44])[CH3:43])=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=1)(=O)C.[NH:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.OCCN1CCNCC1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45]([N:52]4[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]4)=[O:46])([CH3:44])[CH3:43])=[CH:35][CH:36]=3)=[C:28]([CH:49]([CH3:50])[CH3:51])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C1CNCCN1
Agent: OCCN1CCNCC1
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(C)C(=O)N2CCNCC2)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 48 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethyl-carbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and piperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethyl-carbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(2-hydroxyethyl)piperazine, respectively.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)=[CH:11][NH:10]2)[CH:4]=1.Cl.[F:21][C:22]1([F:26])[CH2:25][NH:24][CH2:23]1.C(N(C(C)C)C(C)C)C>O1CCCC1>[F:21][C:22]1([F:26])[CH2:25][N:24]([C:3]2[N:8]=[CH:7][N:6]=[C:5]([N:9]3[C:13](=[O:14])[C:12]([N:15]4[CH:19]=[CH:18][N:17]=[N:16]4)=[CH:11][NH:10]3)[CH:4]=2)[CH2:23]1
Reactant: O=c1c(-n2ccnn2)c[nH]n1-c1cc(Cl)ncn1
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=c1c(-n2ccnn2)c[nH]n1-c1cc(N2CC(F)(F)C2)ncn1

Procedure:
100 mg (0.3 mmol) of the compound from Example 12A, 52 mg (0.4 mmol) of 3,3-difluoroazetidine hydrochloride and 174 μl (130 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are initially charged in 2 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 30 min. After concentration under reduced pressure, the residue is taken up in acetonitrile/water and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 36 mg (34% of theory)
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:14]3[N:15]=[CH:16][N:17]=[C:13]3[C:12]([NH:18][C:19]3[CH:34]=[CH:33][C:22]([C:23]([NH:25][CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:24])=[CH:21][CH:20]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.Cl.N1C=CC=CC=1>O>[O:2]=[C:3]1[CH:8]=[C:7]([C:9]2[N:14]3[N:15]=[CH:16][N:17]=[C:13]3[C:12]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:25][CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:24])=[CH:33][CH:34]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][NH:4]1
Reactant: COc1cc(-c2ccc(Nc3ccc(C(=O)NCc4cccnc4)cc3)c3ncnn23)ccn1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(NCc1cccnc1)c1ccc(Nc2ccc(-c3cc[nH]c(=O)c3)n3ncnc23)cc1
Yield: 62.8 %

Procedure:
4-[5-(2-Methoxy-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino]-N-pyridin-3-ylmethyl-benzamide (46 mg, 51 μmol) is treated in a sealed tube with pyridine hydrochloride (153 mg, 1.32 mmol) and one drop of water at 150° C. for two hours. The reaction mixture is evaporated and the residue purified by flash chromatography (silica gel, dichloromethane/7N NH3 in methanol 96:4 then 85:15) affording the title compound (14 mg) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][Cl:15].[OH-].[K+]>CO>[Cl:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: ClCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)c1ccc(OCCCCl)cc1
Temperature: 25 °C
Yield: 68 %

Procedure:
To a mixture of p-hydroxyacetophenone (50.7 g, 0.37 mol) and 1-bromo-3-chloropropane (160 ml, 1.5 mol) in methanol (250 ml) was added portionwise potassium hydroxide (63 g, 1.12 mol). The mixture was stirred at reflux for 24 hours, cooled to room temperature, filtered through Celite and evaporated in vacuo. The residual semi-solid was diluted with diethyl ether (500 ml) and washed with H2O (2×300 ml). The ether solution was dried over MgSO4, filtered and evaporated in vacuo to give p-chloropropoxy acetophenone as a liquid in 68% yield (53.38 g). 1H NMR (CDCl3): δ7.98-7.89 (d, J=8.9 Hz, 2H), 7.02-6.92 (d, J=8.9 Hz, 2H), 4.16 (t, J=5.9 Hz, 2H), 3.75 (t, J=6.4 Hz, 2H), 2.52 (s, 3H), 2.34-2.16 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[C:19](=[O:20])[O:18][CH:17]3O)[N:4]=1.[CH:23]([Mg]Cl)=[CH2:24].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[C:19](=[O:20])[O:18][CH:17]3[CH:23]=[CH2:24])[N:4]=1
Reactant: C=C[Mg]Cl
Reactant: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3O)n1
Agent: Cl
Solvent: C1CCOC1
Product: C=CC1OC(=O)c2c(Oc3nc(OC)cc(OC)n3)cccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.6 g of 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-hydroxy-phthalide (see Example 84) are placed in 60 ml of absolute tetrahydrofuran at -45° C., and the solution is treated within 10 minutes with 18 ml of a 2M solution of vinylmagnesium chloride solution in tetrahydrofuran. The reaction solution is then stirred for approximately 16 hours at room temperature, a further 6 ml of vinyl-magnesium chloride solution are added and the reaction solution is heated at reflux temperature for a further hour. When it has cooled, the reaction solution is acidified with 1N hydrochloric acid and freed of tetrahydrofuran in a rotary evaporator. The aqueous phase is then extracted with tert-butyl methyl ether, and the organic phase is washed and concentrated by evaporation under reduced pressure. Silica gel chromatography using ethyl acetate/n-hexane (2:3) as eluant yields pure 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-vinyl-phthalide, m.p. 94°-97° C.
Reaction SMILES: [CH2:1]([N:3]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[N:4]1)[CH3:2].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:6]=[N:7][N:3]([CH2:1][CH3:2])[N:4]=2)=[CH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCn1nnc(-c2ccc(C)cc2)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCn1nnc(-c2ccc(CBr)cc2)n1
Reaction time: 1.5 h
Yield: 103.7 %

Procedure:
A solution of 18.8 grams (0.100 mole) of 2-ethyl-5-(4-methylphenyl)-1,2,3,4-tetraazole in 156 mL of carbon tetrachloride was stirred, and 19.6 grams (0.110 mole) of N-bromosuccinimide, followed by 0.24 gram (0.001 mole) of benzoyl peroxide were added. Upon completion of addition, the reaction mixture was heated to reflux where it stirred for 90 minutes. After this time the reaction mixture was cooled and filtered. The filtrate was concentrated under reduced pressure, yielding 27.7 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:13][CH2:14][CH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([NH2:25])[C:17]=1[F:26])(=[O:12])[CH3:11].[F:27][C:28]([F:43])([C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([F:42])=[CH:34][CH:33]=1)[C:29](Cl)=[O:30].FC(F)(C1C2C(=CC=CC=2)C(F)=CC=1)C(O)=O.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[C:10]([O:13][CH2:14][CH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([NH:25][C:29](=[O:30])[C:28]([F:43])([F:27])[C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]([F:42])=[CH:34][CH:33]=2)[C:17]=1[F:26])(=[O:12])[CH3:11]
Reactant: O=C(Cl)C(F)(F)c1ccc(F)c2ccccc12
Reactant: CC(=O)OCCc1c([N+](=O)[O-])ccc(N)c1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)C(F)(F)c1ccc(F)c2ccccc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCCc1c([N+](=O)[O-])ccc(NC(=O)C(F)(F)c2ccc(F)c3ccccc23)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of DIEA (7.8 mL) and 2-(3-amino-2-fluoro-6-nitrophenyl)ethyl acetate (4.6 g, 19 mmol), prepared as in step 8 of Example 1, in DCM (60 mL) was added 2,2-difluoro-2-(4-fluoronaphthyl)acetyl chloride (prepared by refluxing 2,2-difluoro-2-(4-fluoronaphthyl)acetic acid, as prepared in the preceding step, with oxalyl chloride) (7.8 g, 30 mmol) in DCM (40 mL). The mixture was stirred at room temperature for 1 hour. Additional DCM (100 mL) was added, and the resulting mixture was washed with 10% citric acid (3×40 mL) and brine, and dried over Na2SO4. After evaporating the solvent, the residue was purified by flash column chromatography eluting with DCM to give the title compound (5.3 g, 61%) as a yellow oil. 1H-NMR (400 MHz, CDCl3) δ 8.45 (m, 2H), 8.21 (d, J=7.0 Hz, 2H), 7.87 (s, 1H), 7.85 (t, J=4.1 Hz, 1H), 7.66 (m, 2H), 7.22 (t, J=8.3 Hz, 1H), 4.34 (t, J=6.4 Hz, 2H), 3.36 (t, J=6.4 Hz, 2H), 2.00 (s, 3H).
Reaction SMILES: [C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[S:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1>O1CCCC1>[CH3:3][C:2]1([C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH2:4][CH:12]2[S:11][CH:15]1[CH:14]=[CH:13]2
Reactant: C=C(C)C(=O)OC(C)(C)C
Reactant: c1ccsc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(C)CC2C=CC1S2
Temperature: 700 °C
Reaction time: 24 h

Procedure:
In tetrahydrofuran solvent (500 g), tert-butyl methacrylate (1.2 mole) of Chemical Formula 3d below and thiophene (1.0 mole) are dissolved, and the solution is introduced into a 2-liter flask. After stirring at 700° C., 10 atm for 24 hours, the solvent and excess amount of tert-butyl methacrylate are removed by using a rotary evaporator. The residue is distilled in vacuo to obtain pure 1,1-dimethylethyl 2-methyl-7-thiabicyclo[2.2.1]hept-5-ene-2-carboxylate of Chemical Formula 125 (yield: 50%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#N)[CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:21]1[O:23][C@H:22]1[CH2:24]Cl.[OH2:26]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@:8]23[CH2:9][C@H:24]2[CH2:22][O:23][C:21]3=[O:26])[CH:5]=[CH:6][CH:7]=1
Reactant: O
Reactant: ClC[C@H]1CO1
Reactant: N#CCc1cccc(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1OC[C@@H]2C[C@]12c1cccc(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Fluoro phenyl acetonitrile (70 g) was dissolved in THF (500 ml), and NaHMDS (1000 ml, 1.06 M) was then added dropwise to the solution under cooling in an ice-salt bath. The obtained mixture was stirred for 1 hour, and R-(−)-epichlorohydrin (40.6 ml) was then added dropwise to the reaction solution (approximately 10 minutes, internal temperature<10° C.). The obtained mixture was stirred for 2 hours (wherein the internal temperature was maintained around 0° C.), and it was then stirred at room temperature for 14 hours. Thereafter, the reaction solution was cooled on ice, and a small amount of water was added dropwise thereto. The reaction solution was concentrated under reduced pressure, and thereafter, ethanol (700 ml) and a 1 N potassium hydroxide aqueous solution (1000 ml) were added to the residue. The obtained mixture was heated to reflux for 5 hours. Thereafter, the temperature of the reaction solution was returned to room temperature, and 5 N hydrochloric acid (400 ml) was then added to the solution. The obtained mixture was stirred at 60° C. for 1 hour. Thereafter, the reaction solution was concentrated under reduced pressure, and ethyl acetate and water were added to the concentrate to carry out liquid separation. The organic layer was successively washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution. The resultant organic layer was dried over magnesium sulfate, and the solvent was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate), so as to obtain the title compound (84.9 g).