Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH:18]([CH3:20])[CH3:19])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[K+].[K+].[C:27]1([C:33]2[N:34]=[N:35][NH:36][N:37]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC#N>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH:2]([N:35]3[N:36]=[N:37][C:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:34]3)[CH:18]([CH3:20])[CH3:19])[CH2:6][CH2:7]2)=[CH:12][CH:13]=1
Reactant: c1ccc(-c2nn[nH]n2)cc1
Reactant: CC(C)C(Br)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)C(C(=O)N1CCC(c2ccc(Cl)cc2)CC1)n1nnc(-c2ccccc2)n1
Temperature: 170 °C
Yield: 21.2 %

Procedure:
A mixture of 2-bromo-1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methylbutan-1-one (40 mg, 0.11 mmol), K2CO3 (50 mg, 0.36 mmol) and 5-phenyl-2H-tetrazole (15 mg, 0.1 mmol) in CH3CN (1 mL) was heated at 170° C. for 30 min in a microwave reactor. After this time, the reaction was filtered through a plug of celite, diluted with MeOH and purified directly by preparative HPLC to give 1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-2-(5-phenyl-2H-tetrazol-2-yl)butan-1-one (9 mg, 21%) as a solid. MS found: 424 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16](=[O:37])[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:19][C:18]=1[NH:30][CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.Cl[C:43]([O:45][CH2:46][CH3:47])=[O:44]>O1CCCC1.O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[N:10]=[C:9]2[NH:15][C:16]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:19][C:18]=1[NH:30][CH:31]1[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1)=[O:37]
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCN(C)CC3)cc2NC2CCOCC2)c2cc(Cc3cc(F)cc(F)c3)ccc21
Reaction time: 1 h
Yield: 62.2 %

Procedure:
To a solution of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide (200 mg, 0.356 mmol) in anhydrous tetrahydrofurane (9 mL) maintained at −50° C. under nitrogen atmosphere a 1M solution of LiHMSD in anhydrous tetrahydrofurane (0.374 mL) was added. After stirring at that temperature for 5 minutes ethyl chloroformate (0.036 mL, 0.374 mmol) was added. After 1 hour at −50° C. the reaction was completed. Reaction mixture was diluted with water/EtOAc, washed with brine, dried over sodium sulphate and evaporated to dryness. The crude was purified by flash chromatography on silica gel eluting with DCM/ethanol 100:5, affording 140 mg (62% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:12]=1[C:13]#N.C1C[O:23]CC1>>[NH2:10][C:11]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:12]=1[C:13]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:23]
Reactant: C1CCOC1
Reactant: N#Cc1cc(Cl)ccc1N
Reactant: Fc1ccc([Mg]Br)cc1
Product: Nc1ccc(Cl)cc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a 0° C. solution of 1.0M 4-fluorophenylmagnesium bromide in THF (196.6 mL, 196.6 mmol) was added a THF solution (100 mL) of 2-amino-5-chlorobenzonitrile (10.0 gm, 65.5 mmol) over 0.5 h. The ice bath was removed and the reaction stirred at ambient temperature for 17 h. The brown solution was cooled in an ice bath, treated with a drop wise addition of aqueous 1N HCl (300 mL) and extracted with ether (2×250 mL). The combined organic extracts were washed with aqueous 1N HCl (100 mL), water (2×150 ml), saturated aqueous sodium bicarbonate (150 ml), brine (100 mL), dried over MgSO4, filtered, concentrated in vacuo to 30 mL and diluted with 60 mL hexane. The resulting precipitate was filtered to give (2-amino-5-chlorophenyl)(4-fluorophenyl)methanone as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH:13]=[CH:14][CH2:15][OH:16].O[C:18]1[CH:32]=[CH:31][C:21]([O:22][C:23]([CH3:30])([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:19]=1>>[CH3:30][C:23]([O:22][C:21]1[CH:20]=[CH:19][C:18]([O:16][CH2:15][CH:14]=[CH:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:32][CH:31]=1)([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Reactant: Cc1oc(-c2ccccc2)nc1C=CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(OCC=Cc2nc(-c3ccccc3)oc2C)cc1

Procedure:
Synthesized from 3-(5-methyl-2-phenyloxazol-4-yl)-prop-2-en-1-ol and ethyl 2-(4-hydroxyphenoxy)-2-methylpropanoate (American Home Products, U.S. Pat. No. 3,795,691) via an analogous procedure to that reported for Example 2, Step A: 1H NMR (300 MHz, CDCl3) δ 7.95-7.99 (m, 2H), 7.36-7.43 (m, 3H), 6.80 (s, 4H), 6.61 (dt, 1H), 6.49 (d, 1H), 4.62 (d, 2H), 4.18 (q, 2H), 2.37 (s, 3H), 1.49 (s, 6H), 1.23 (t, 3H); MS (EI): 422 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]1[CH2:14][CH2:13][CH2:12]1.[H-].[Na+].I[CH2:18][CH3:19]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:18][CH3:19])[N:6]=[C:5]2[CH:11]1[CH2:14][CH2:13][CH2:12]1
Reactant: CCI
Reactant: Brc1ccc2[nH]nc(C3CCC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1nc(C2CCC2)c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
The 5-bromo-3-cyclobutyl-1H-indazole intermediate (1.501 g, 5.97 mmol) was dissolved in anhydrous DMF (25 mL), cooled to 0° C. and treated with a 60% dispersion of sodium hydride in mineral oil (330 mg, 8.26 mmol). The cold bath was removed and the reaction mixture was stirred at room temperature for 2 h after which time iodoethane (1.034 g, 6.62 mmol) was added and the reaction mixture was stirred 8 h. The reaction mixture was then cooled and quenched by addition of a saturated aqueous solution of NH4Cl (10 mL) then extracted with EtOAc (20 mL). The organic extract was dried over MgSO4, filtered, and evaporated to an oil, which was purified by silica gel flash chromatography with a 0-10% EtOAc/hexanes gradient to afford titled compound as a light yellow oil (1.14 g, 68%). 1H NMR (DMSO-d6) 7.90 (s, 1H), 7.58 (d, J=8.5, 1H), 7.44 (d, J=8.5, 1H), 4.35 (q, J=7.2, 2H), 3.85 (pent, J=7.6, 1H), 2.35-2.31 (m, 4H), 2.31-2.02 (m, 1H), 1.99 (m, 1H), 1.35 (t, J=7.6, 3H). LC/MS (Method B) 4.27 min, [M+1]+ 279/281.
Reaction SMILES: [OH-].[K+].[OH:3][CH:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:5]#[C:6][C:7]([O:9]CC)=[O:8]>C(O)C>[OH:3][CH:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:5]#[C:6][C:7]([OH:9])=[O:8]
Reactant: CCCCCCCCCC(O)C#CC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCC(O)C#CC(=O)O
Temperature: 25 °C
Reaction time: 9 h

Procedure:
A solution of potassium hydroxide (885 mg, 15.8 mmol) in 95% ethanol (35 ml) was added to ethyl 4-hydroxytridec-2-ynoate (2.68 g, 10.5 mmol) in the same solvent (5 ml) at 0°. After stirring at room temperature for 9 hours, most of the solvent was removed and water (20 ml) was added. The mixture was extracted thoroughly with dichloromethane (discarded), acidified to pH 1 with dilute hydrochloric acid and extracted with ethyl acetate. Evaporation of the dried (magnesium sulphate) ethyl acetate extracts gave an off-white solid, which on recrystallization from petroleum ether (at -78°) gave the title acid as colorless prisms: mp 65°-6°.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][N:11]=2)[N:3]=1.C(Cl)(=O)C([Cl:21])=O>CN(C)C=O.ClCCl>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([Cl:21])=[O:8])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][N:11]=2)[N:3]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ncc(Cl)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(Br)nn1-c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a 100 mL flask, 3-bromo-1-(3,5-dichloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid (0.4 g, 1.2 mmol), dichloromethane (10 mL) and oxalyl dichloride (0.31 g, 2.4 mmol) were added. After five drops of N,N-dimethyl formamide was added, a large number of gas was released. After being stirred for 8 hours at room temperature, the reaction mixture was evaporated to dryness at reduced pressure. Then toluene (100 mL) was added, and the reaction mixture was concentrated again under vacuum to give the product (0.42 g) as green solid in 100% yield.
Reaction SMILES: [C:1](OC(C)COC)(=O)C.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.O=C=NC1CC(C)(C)[CH2:57][C:52]([CH3:62])([CH2:53][N:54]=[C:55]=O)[CH2:51]1.[C:63]([O:66][CH2:67][CH2:68][CH2:69]C)(=[O:65])[CH3:64]>C(OCC)(=O)C.C(O)(=O)C>[CH3:1][C:68]1([CH3:69])[CH2:55][N:54]2[C:63]([CH3:64])([O:65][CH2:51][C:52]([CH3:62])([CH3:57])[CH2:53]2)[O:66][CH2:67]1
Reactant: CCCCOC(C)=O
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Reactant: COCC(C)OC(C)=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC1(C)COC2(C)OCC(C)(C)CN2C1
Reaction time: 0.5 h

Procedure:
In a glass jar 8.48 grams of 3,3,6,6,8a-pentamethyl-tetrahydro-1,8-dioxa-4a-aza-napthalenes (as prepared in Example 1) was combined with 2.84 grams of propylene glycol monomethylether acetate, 0.92 grams of a 2% dibutyl tin dilaurate solution in ethyl acetate, and 0.11 grams of a BYK 306 and 0.04 grams of Byk 361. To this was added 68.66 grams of a solution of 32.93 grams of Desmodur® XP 2410 (hexamethylene diisocyaante trimer available from Bayer), 31.38 grams of Desmodur® Z4470BA (isophorone diisocyanate trimer available from Bayer) and 4.35 grams n-butyl acetate. This mixture was stirred and then 0.36 grams of acetic acid was added and the mixture and stirred. The mixture was drawndown to give coatings of ˜4 mils in thickness. The coating was baked at 140° F. for 30 minutes. At one day the coating had a Fischercope hardness of 90 N/mm2 and a swell ratio of 1.70. At 30 days the coating had a Fischercope hardness of 158 N/mm2, a Tg (at the midpoint) of 59° C. and a gel fraction of 96%.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1)=[CH2:2].S(Cl)([Cl:14])=O>CN(C)C=O.C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:14])=[O:8])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C=Cc1ccc(C(=O)Cl)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
While 16.6 g of p-vinylbenzoic acid (manufactured by Wako Pure Chemical Industries, Ltd.), 80 ml of toluene, two drops of N,N-dimethylformamide were stirred at room temperature, 9.7 ml of thionyl chloride (manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto, which was heated and stirred at 60° C. for 2 hours. The inside of the reaction system was cooled to 40° C., toluene and an excessive amount of thionyl chloride were removed under reduced pressure, and p-vinyl benzoic acid chloride was obtained. While 22.5 g of 2-aminoanthraquinone (manufactured by Tokyo Chemical Industry Co., Ltd.) and 110 ml of pyridine were stirred on ice, p-vinyl benzoic acid chloride was slowly added dropwise thereto. After stirring the mixture on ice for 30 minutes, the temperature was increased to 60° C. and the mixture was heat while stirring for 3 hours. Thereafter, the mixture was cooled to room temperature and water was added thereto. The resulting coarse crystals were filtrated and washed with water and methanol, and then 500 ml of methanol was added to the collected coarse crystals, and then heated while stirring at 60° C. Thereafter, the resultant crystals were separated by filtration, washed with methanol and dried. Thus, 20.1 g of M-19 was obtained (yield: 70%).
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][CH:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:7]([OH:9])=[O:8].[CH3:23]O>>[OH:5][CH:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:7]([O:9][CH3:23])=[O:8]
Reactant: CCCCCCCCCCCCCC(O)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCCCC(O)C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To methanol (10 ml), cooled in an ice-brine bath, was added thionyl chloride (0.87 ml) dropwise. After stirring at 0° C. for 10 minutes, 2-hydroxypentadecanoic acid (1.54 g) was added. The mixture was stirred at room temperature for 3 hours, and concentrated under vacuum. The residue was dissolved in ethyl acetate (60 ml), and washed with water (40 ml×2), saturated aqueous sodium bicarbonate (30 ml), and brine (30 ml). The organic phase was dried, concentrated to dryness, and triturated in diisopropyl ether to give methyl 2-hydroxypentadecanoate (0.77 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15](O)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ncc2c(n1)CCN(c1cccc(C(=O)Nc3ccccc3)c1)C2
Temperature: 60 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (54 mg, 0.20 mmol), aniline (0.027 mL, 0.30 mmol), and N,N-diisopropylethylamine (0.174 mL, 1.0 mmol) in 1.5 mL DMF at room temperature was added HBTU (83 mg, 0.22 mmol). After 1 hour at room temperature, the reaction was briefly warmed to approx. 60° C. and then continued at room temperature. At 2 hours the reaction was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was triturated with EtOAc to give the title compound as an off-white solid (52 mg, 75%). 1H NMR (DMSO-d6) δ: 10.15 (s, 1H), 8.13 (s, 1H), 7.74-7.79 (m, 2H), 7.49-7.52 (m, 1H), 7.31-7.41 (m, 4H), 7.22 (dt, J=7.5, 2.3 Hz, 1H), 7.06-7.13 (m, 1H), 6.41 (s, 2H), 4.29 (s, 2H), 3.65 (t, J=6.0 Hz, 2H), 2.77 (t, J=5.9 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[S:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=1.O.[Cl-].[NH4+].ClCCl>C(O)C.[Fe]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:11]2[S:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[C:2]([F:1])[CH:7]=1
Reactant: O=C1CSC(c2ccc([N+](=O)[O-])cc2F)=NN1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: Nc1ccc(C2=NNC(=O)CS2)c(F)c1
Temperature: 90 °C
Yield: 91.6 %

Procedure:
2-(2-Fluoro-4-nitrophenyl)-4H-[1,3,4]thiadiazin-5-one (Step 4, 0.964 g, 0.00378 mol) is heated in ethanol (20 ml) until dissolved. Water (10 ml) and ammonium chloride (2.02 g, 0.0378 mol) are added and the mixture heated to 90° C. Iron powder (0.84 g, 0.0151 mol) is added portionwise and the mixture stirred and heated for 30 minutes. The reaction is cooled and dichloromethane (100 ml) added. The mixture is filtered and the organic layer separated, washed with saline, dried (MgSO4) and evaporated to give the title compound as a yellow solid (0.78 g, 92%), [M+H]+=226.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27]([O:29]C)=[O:28].O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27]([OH:29])=[O:28]
Reactant: COC(=O)Cc1ccccc1OCc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(COc2ccccc2CC(=O)O)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a mixture of methyl 2-[2-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate (0.50 g), tetrahydrofuran (2 mL) and methanol (2 mL) was added a 1N aqueous sodium hydroxide solution (2.0 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid (2 mL) and water were added to acidify the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated: to give crystals (0.41 g, 87%) of 2-[2-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from methyl acetate-hexane gave colorless prism crystals. melting point: 117-118° C.
Reaction SMILES: B(O)O.Br[C:5]1[N:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][CH:6]=1.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O>>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:5]1[N:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][CH:6]=1
Reactant: OB(O)c1ccco1
Reactant: O=Cc1cccc(Br)n1
Agent: OBO
Product: O=Cc1cccc(-c2ccco2)n1

Procedure:
6-(furan-2-yl)picolinaldehyde was prepared using the general boronic acid coupling procedure for 6-bromopicolinaldehyde and furan-2-ylboronic acid (60 mg, 93.2 mg theoretical, 64.4%). LC-MS m/z 174.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=O.N1CCCCC1.C(O)(=O)[CH2:20][C:21]([OH:23])=[O:22].Cl>N1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1/[CH:5]=[CH:20]/[C:21]([OH:23])=[O:22]
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccc(OC)c(/C=C/C(=O)O)c1
Temperature: 85 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
2,5-Dimethoxybenzaldehyde (1.7 g) was dissolved in pyridine (10 ml). Piperidine (0.2 ml) and malonic acid (2.0 g) were added to the soluton. The solution was stirred for 1 hour at 85° C. and then for 3 hr. at 110° C. The solution was cooled. Water (80 ml) was added to the solution. Conc. hydrochloric acid was added to the solution until pH of the solution was down to about 2. The crystals were deposited. The crystals were separated from the solution by filtration, washed with water and dried to give the title compound (1.97 g) having the following physical data.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][C:27]=2[C:2]2[C:3]3[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][CH2:19]1
Reactant: COc1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(OC)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and 2-(2-cyclopropylmethoxy-5-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c7) the title compound is obtained as yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C@H:5]([CH:13]([CH3:15])[CH3:14])[N:6]=[C:7]([O:10][CH2:11][CH3:12])[CH2:8][N:9]=1)[CH3:2].C([Li])CCC.CSC.[C:24]1(=[O:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=[CH:25]1.N1C=CN=CC1>O1CCCC1>[CH2:11]([O:10][C:7]1[C@@H:8]([CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][C:24](=[O:31])[CH2:25]2)[N:9]=[C:4]([O:3][CH2:1][CH3:2])[C@H:5]([CH:13]([CH3:14])[CH3:15])[N:6]=1)[CH3:12]
Reactant: CCOC1=N[C@@H](C(C)C)C(OCC)=NC1
Reactant: O=C1C=CCCCC1
Agent: C1=CNCC=N1
Agent: [Li]CCCC
Solvent: CSC
Solvent: C1CCOC1
Product: CCOC1=N[C@H](C2CCCCC(=O)C2)C(OCC)=N[C@H]1C(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
A solution of (S)-3,6-diethoxy-2-isopropyl-2,5-dihydro-pyrazine (6.0 g, 28.3 mmol) in tetrahydrofuran (58 mL) is cooled to −78° C. n-butyllithium (1.6 M in hexane, 21.4 mL, 34.2 mmol) is added slowly via syringe, and the reaction is allowed to stir at −78° C. for 30 minutes. The reaction mixture is then transferred via canula to a solution of CuBr-Me2S (3.35 g, 16.3 mmol) in tetrahydrofuran:dimethylsulfide (90 mL, [2:1]) at −50° C. The reaction is warmed to −30° C. and stirred further for 30 minutes. The reaction is then cooled to −78° C. and cyclohept-2-eneone (5.23 mL, 46.9 mmol) is added dropwise over 10 minutes. The reaction is maintained at −78° C. until the disappearance of the dihydropyrazine is confirmed by TLC and quenched by the addition of a saturated aqueous solution of ammonium chloride at −78° C. The reaction is allowed to warm to ambient temperature, diluted with water, and extracted with diethyl ether. The organic extracts were washed with ammonium chloride, dilute ammonium hydroxide, water and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by column chromatography eluting with a gradient of hexane in ether (20-25%) to afford the title compound (6.52 g, 72% yield), slightly contaminated with cyclohept-2-enone. LCMS (m/z): 323.13 (M+1).
Reaction SMILES: [CH2:1]1[C@@H:5]([OH:6])[C@H:4](/[CH:7]=[CH:8]/[C:9]([F:19])([F:18])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:3]([CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C@H:2]1[OH:29].C([O-])([O-])=O.[K+].[K+].I[CH:37]([CH3:39])[CH3:38].O>CN(C=O)C.C(OCC)(=O)C>[CH3:38][CH:37]([O:27][C:26]([CH2:25][CH2:24][CH2:23]/[CH:22]=[CH:21]\[CH2:20][C@@H:3]1[C@@H:4](/[CH:7]=[CH:8]/[C:9]([F:18])([F:19])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:5]([OH:6])[CH2:1][C@@H:2]1[OH:29])=[O:28])[CH3:39]
Reactant: CC(C)I
Reactant: O=C(O)CCC/C=C\C[C@@H]1[C@@H](/C=C/C(F)(F)COc2ccccc2)[C@H](O)C[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/C(F)(F)COc2ccccc2)[C@H](O)C[C@@H]1O
Reaction time: 2 h

Procedure:
A sample of this product was hydrolyzed using methanol and 3N NaOH. After 2 h at 25° C., the mixture was acidified and extracted with ethyl acetate. After drying-concentration of the extracts, crude 11-protected Tafluprost acid was obtained. The crude 11-protected Tafluprost acid was esterified using K2CO3 and 2-iodopropane in DMF. After 2 h at 60° C., water and ethyl acetate were added and phase separated, the aqueous layer was extracted with ethyl acetate. After drying-concentration of the extracts, crude 11-protected Tafluprost was obtained. The crude 11-protected Tafluprost was deprotected using 3N HCl in THF and water. After 1 h at 25° C., saturated aqueous solution of sodium bicarbonate was added and phase separated, the aqueous layer was extracted with ethyl acetate. After drying-concentration of the extracts, crude Tafluprost was obtained. HPLC (Phenomenex Luna 5 μm silica) analysis of the crude product showed that 0.4% 5,6-trans isomer was found and HPLC (Chiralcel OD-H) analysis of the crude product showed that 0.1% enantiomer was found.