Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([C:19]([F:22])([F:21])[F:20])=[N:17][N:18]=3)[N:15]=2)[CH2:7]1)(=O)=O.[F:23][C:24]1[CH:25]=[C:26](O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.CC#N>[F:23][C:24]1[CH:29]=[C:28]([CH:27]=[CH:26][CH:25]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([C:19]([F:22])([F:21])[F:20])=[N:17][N:18]=3)[N:15]=2)[CH2:7]1
Reactant: Oc1cccc(F)c1
Reactant: CS(=O)(=O)OC1CN(c2ccc3nnc(C(F)(F)F)n3n2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: Fc1cccc(OC2CN(c3ccc4nnc(C(F)(F)F)n4n3)C2)c1

Procedure:
A stirred partial solution of 6-[3-(methanesulfonyloxy)azetidin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (169 mg, 0.5 mmol), 3-fluorophenol (112 mg, 1.5 mmol) and potassium carbonate (207 mg, 1.5 mmol) in DMF (3 mL) was heated at 100° C. for 24 hours. The reaction mixture was filtered and the product was isolated by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 6-[3-(3-fluorophenoxy)azetidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (58 mg, 33%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](O)=[O:6].Cl.[CH3:13][NH:14][O:15][CH3:16].CCN(CC)CC>S(Cl)(Cl)=O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([N:14]([O:15][CH3:16])[CH3:13])=[O:6]
Reactant: O=C(O)c1cc(F)cc(Br)c1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A solution of 3-bromo-5-fluorobenzoic acid (commercially available) (10.0 g, 45.7 mmol) in thionyl chloride (80 mL) was heated at reflux for 2 hours. Thionyl chloride was removed under reduced pressure and the residue was added to solution of N,O-dimethylhydroxylamine hydrochloride (5.32 g, 54.8 mmol) and Et3N (10.1 g, 0.1 mol) in DCM (300 mL) dropwise at 0° C. After the reaction mixture was stirred at r.t. overnight, it was washed with water (3×100 mL), brine, dried over anhydrous Na2SO4 and concentrated. The colorless oil was used in next step without further purification (11.0 g, yield: 95%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14])#[CH:2].[CH2:16]([O:18][C:19](=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][C:22]=1[F:28])[CH3:17].O1CCCC1.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:16]([O:18][C:19](=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]#[C:1][C:3]2[CH:12]=[CH:11][C:10]3[C:9](=[O:13])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=3[CH:4]=2)=[CH:23][C:22]=1[F:28])[CH3:17]
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Reactant: CCOC(=O)Cc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1F

Procedure:
Following general procedure F and using 6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalene-1-one (Intermediate 13, 0.298 g, 1.43 mmol), 2-fluoro-4-iodo phenyl acetic acid ethyl ester (Reagent C, 0.44 g, 1.43 mmol), triethyl amine (Intermediate 13, 3 mL), anhydrous tetrahydrofuran (7 mL), copper(I)iodide (0.04 g, 0.2 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.15 g, 0.213 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 14-16% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.43 g, 77%).
Reaction SMILES: [CH2:1]([NH2:17])[CH2:2][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][CH3:16].[C:18]1(=[O:23])[O:22][CH2:21][CH2:20][CH2:19]1>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1>[CH2:1]([NH:17][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][OH:23])[CH2:2][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][CH3:16]
Reactant: O=C1CCCO1
Reactant: CCCCCCCCCCCCCCCCN
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNC(=O)CCCO
Yield: 797.2 %

Procedure:
A mixture of 59.45 g of hexadecylamine, 10.60 g of gamma butyrolactone, 200 ml of toluene, and 20 mg of zinc chloride was refluxed under nitrogen for three days. Upon cooling, the reaction mixture formed a precipitate which was recrystallized twice from toluene to yield 321.5 g (78.12%) of N-hexadecyl-4-hydroxybutyramide, m.p. 89.5°-90°
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:16]([O:21][CH2:22][CH3:23])(=[O:20])[C:17]([CH3:19])=O>C(O)C>[CH2:14]([O:13][C:11]([C:3]1[NH:2][C:10]2[C:5]([C:4]=1[C:17](=[CH2:19])[C:16]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:12])[CH3:15]
Reactant: CCOC(=O)C(C)=O
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: Cl
Solvent: CCO
Product: C=C(C(=O)OCC)c1c(C(=O)OCC)[nH]c2ccccc12

Procedure:
An ethanol solution saturated with gaseous hydrochloric acid containing 39.1 g (207 mmol) of ethyl 1H-indole-2-carboxylate and 45.3 ml (410 umol) of ethyl pyruvate is brought to approximately 60° C. for 3 h. The mixture is concentrated under reduced pressure and the residue is taken up in diethyl ether. The organic phase is washed with water and dried over sodium sulphate. The solvent is evaporated under reduced pressure and the residue is crystallized from cyclohexane. 45.4 g (158 mmol) of solid product are obtained, which product is used as is in the following stage.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].ClC1C(Cl)=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.CN(C)[CH:22]=[O:23]>O>[CH2:4]1[N:3]2[C:6]3[C:7]([O:23][CH2:22][CH:1]2[CH2:2][CH2:5]1)=[N:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1[N:17]=3
Reactant: CN(C)C=O
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: CCN(CC)CC
Solvent: O
Product: c1ccc2nc3c(nc2c1)OCC1CCCN31
Reaction time: 48 h

Procedure:
A mixture of 4.93 ml. of L-2-pyrrolidinomethanol, 20 ml. of triethylamine, 10.0 g. of 2,3-dichloroquinoxaline and 100 ml. of dimethylformamide is heated on a steam bath for 48 hours. A 200 ml. portion of water is added and the mixture is stored in a freezer for 48 hours. The solid is recovered by filtration, dissolved in dichloromethane, passed through Magnesol® and concentrated. The residue is dissolved in 15 ml. of ethyl acetate, stored in a freezer for several days, concentrated to a crystalline residue and washed with ether. These crystals are recrystallized from 5 ml. of ethanol, giving the desired product as yellow crystals, m.p. 121°-123° C., [α]D25 +114° (methanol).
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:19]([F:22])([F:21])[F:20])[CH:11]=[C:12]([C:15]#[C:16][CH2:17][NH2:18])[CH:13]=2)[C:8]([OH:33])([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[C:7]1=[O:34])[CH3:2].C([N:39]=[C:40]=[O:41])C.[CH2:42](N(CC)CC)[CH3:43]>C1COCC1>[CH2:35]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:19]([F:20])([F:22])[F:21])[CH:11]=[C:12]([C:15]#[C:16][CH2:17][N:18]([CH2:42][CH3:43])[C:40]([NH2:39])=[O:41])[CH:13]=2)[C:8]([OH:33])([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[C:7]1=[O:34])[CH3:36]
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c1cc(C#CCN)cc2C(F)(F)F
Reactant: CCN(CC)CC
Reactant: CCN=C=O
Solvent: C1CCOC1
Product: CCN(CC)CCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c1cc(C#CCN(CC)C(N)=O)cc2C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.1 %

Procedure:
A mixture of 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-(3-amino-1-propynyl)-3-hydroxy-3-(2-naphthyl)oxindole (40 mg, 0.074 mmol), ethyl isocyanate (0.0065 mL, 0.0821 mmol), and triethylamine (0.025 mL, 0.0821 mmol) in THF (0.5 mL) was stirred for 4 h at room temperature and the reaction was quenched with sat. aqueous NaHCO3. The mixture was extracted with ethyl acetate and the extracts were dried over MgSO4 and concentrated. The residue was purified by column chromatography with 40:1 to 20:1 chloroform/methanol to give the title compound (20.6 mg). The hydrochloride of the title compound was obtained by treating with 4 N HCl in dioxane followed by concentration to dryness.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:15]3[C:11]([S:12][C:13]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=4)=[N:14]3)=[N:10][C:9]=2[CH3:25])=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(N(C(C)C)C(C)C)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:37]1[CH2:38][CH2:39][N:34]([CH2:33][CH2:32][O:22][C:19]2[CH:20]=[CH:21][C:16]([C:13]3[S:12][C:11]4=[N:10][C:9]([CH3:25])=[C:8]([C:5]5[CH:4]=[C:3]([C:26]([F:28])([F:27])[F:29])[C:2]([NH2:1])=[N:7][CH:6]=5)[N:15]4[N:14]=3)=[CH:17][C:18]=2[O:23][CH3:24])[CH2:35][CH2:36]1
Reactant: COc1cc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)c(C)nc3s2)ccc1O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)c(C)nc3s2)ccc1OCCN1CCOCC1
Temperature: 105 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-(6-amino-5-(trifluoromethyl)pyridin-3-yl) -6-methylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-methoxyphenol (0.042 g, 0.1 mmol, 1 eq) in dry DMF (1 mL), 4-(2-chloroethyl)morpholine hydrochloride (0.024 g, 0.13 mmol, 1.25 eq), iPr2EtN (0.021 mL, 0.13 mmol, 1.3 eq) and K2CO3 (0.018 g, 0.13 mmol, 1.25 eq) were added. The mixture was stirred at 105° C. for 1 h and cooled to RT. The solvent was evaporated, and the dry residue was taken up in DCM, washed with water (2×1 mL), dried (MgSO4), filtered and concentrated to dryness. Purification by reversed-phase chromatography (RP-C18, ACN/water) using a pre-packed cartridge and, subsequently, preparative HPLC gave the desired product. HPLC-MS: (5-100% B in 8 min, 0.6 mL/min): tR=3.3 min, [M+H]+ m/z 534.1; 1H NMR (300 MHz, CDCl3) δ/ppm 8.44 (d, J=1.7, 1H), 7.98 (d, J=1.8, 1H), 7.49 (d, J=0.8, 1H), 7.41 (d, J=2.0, 1H), 7.31 (d, J=2.1, 1H), 5.07 (s, 2H), 4.01-3.89 (m, 6H), 3.69-3.59 (m, 4H), 3.47 (s, 3H), 2.62-2.51 (m, 3H), 2.38 (dd, J=9.0, 2.7, 7H).
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.[CH2:11]([O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([N:30](CC)CC)C>>[CH2:11]([O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:30])=[O:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc(OCc2ccccc2)cc1

Procedure:
A solution of 3R-carboxylate-6-nitro-2H-3,4-dihydro-[2-1b]imidazopyran (Example 21, 1 eq.), triethylamine (1 eq.), diphenylphosphoryl azide (1 eq.) in toluene is heated at 80° C. for 4 h, cooled and t-butanol is added. The reaction is warmed to 70° C. for an additional 1 h. Workup in the standard fashion gives the Boc amine. Deprotection of the Boc group (trifluoroacetic acid:dichloromethane, 1:1) and addition of 4-benzyloxybenzoyl chloride and triethylamine gives the 4-benzyloxybenzamide of 3R-amino-6-nitro-2H-3,4-dihydro-[2-1b]imidazopyran.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:15])([CH3:14])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(N(CC)CC)C.[F:23][C:24]([F:41])([F:40])[C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH2:32][CH2:33][N:34]([C:37](Cl)=[O:38])[CH2:35][CH:36]=2)=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:40][C:24]([F:23])([F:41])[C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH2:36][CH2:35][N:34]([C:37]([O:13][CH2:12][C@@:11]([OH:15])([CH3:14])[CH2:10][N:3]3[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]3[Cl:1])=[O:38])[CH2:33][CH:32]=2)=[CH:29][CH:30]=1
Reactant: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Reactant: O=C(Cl)N1CC=C(c2ccc(C(F)(F)F)cc2)CC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[C@](O)(COC(=O)N1CC=C(c2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 100 °C
Reaction time: 16 h
Yield: 31.6 %

Procedure:
(R)-2-Chloro-1-(2,3-dihydroxy-2-methyl)-propyl-4-nitroimidazole prepared in Example 10 (0.74 g, 3.11 mmol) and triethylamine (1.74 ml, 12.42 mmol) were added to a suspension of 4-(4-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine-1-carbonylchloride (0.60 g, 2.07 mmol) in toluene (36 ml) followed by stirring at 100° C. for 16 hours. The mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-(4-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine-1-carboxylate (0.32 g, yield 31%) as a light yellow oil.
Reaction SMILES: [Br-].[NH2:2][C:3]1[C:8]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:7]([C:29]([F:32])([F:31])[F:30])[C:6]([C:33]#[N:34])=[CH:5][CH:4]=1.[F:35][C:36]([F:42])([F:41])[CH2:37][C:38](O)=O.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.CCN(C(C)C)C(C)C>C1COCC1>[F:35][C:36]([F:42])([F:41])[CH2:37][C:38]1[NH:2][C:3]2[C:8]([CH:9]=1)=[C:7]([C:29]([F:30])([F:31])[F:32])[C:6]([C:33]#[N:34])=[CH:5][CH:4]=2
Reactant: N#Cc1ccc(N)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1C(F)(F)F
Reactant: O=C(O)CC(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc2[nH]c(CC(F)(F)F)cc2c1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.3 %

Procedure:
A mixture of {[6-amino-3-cyano-2-(trifluoromethyl)phenyl]methyl}(triphenyl)phosphonium bromide (0.50 g, 0.92 mmol), 3,3,3-trifluoropropanoic acid (0.175 g, 1.40 mmol), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (2.60 g, 4.10 mmol, 50% in EtOAc) and DIEA (0.65 mL, 3.70 mmol) in THF (25 mL) was stirred at ambient temperature for 6 h. The mixture was concentrated and then diluted with anhydrous DMF (15 mL) and stirred at 100° C. for 18 h. The reaction was poured into water (100 mL) and extracted with Et2O (2×60 mL). The combined organic portions were washed with sat'd NaHCO3 (50 mL) and brine (50 mL). Drying (MgSO4), filtration, and concentration was followed by purification (SiO2, 30% EtOAc in hexanes) to afford 2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.189 g, 70%) as a pale yellow solid:
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:13](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[C:6]([CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH3:13])[CH:7]=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C=O)cc(Br)c1O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1cc(C=O)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.7 %

Procedure:
The intermediate 3-bromo-4,5-dimethoxybenzaldehyde was prepared as follows: To a solution of 5-bromovanillin (2.00 g, 8.65 mmol) in acetone (50 mL) was added potassium carbonate (1.4 g, 10.38 mmol) and dimethylsulfate (1 mL, 10.38 mmol). The solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and the organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to afford 1.88 g of 3-bromo-4,5-dimethoxybenzaldehyde (89%).
Reaction SMILES: [CH3:1][C:2]([OH:10])([C:6]#[C:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][C:2]([O:10][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1)([C:6]#[C:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5]
Reactant: C#CCC(C)(O)C#CCC
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C#CCC(C)(C#CCC)OC1CCCCO1

Procedure:
4-Methyl-1,5-octadiyn-4(RS)-ol is reacted with dihydropyran in the presence of p-toluenesulfonic acid in dry benzene to provide 4-methyl-4(RS)-tetrahydropyran-2-yloxy-1,5-octadiyne which in turn is reacted with triethyl tin hydride to provide 4-methyl-4(RS)-tetrahydropyran-2-yloxy-oct-5-yn-trans-1-enyl triethyl tin, having the following structural formula: ##STR12##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:13][CH2:12][CH:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:27])=[CH:21][CH:20]=1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 75.8 %

Procedure:
Example 11 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.028 g) and (4-chlorophenyl)acetic acid (0.019 g) to give the title compound (0.033 g).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]([C:26]([OH:28])=[O:27])=[N:14][CH:15]=[C:16]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:17]=2)=[CH:7][CH:6]=1)=[O:4].CO.[CH3:32][Si](C=[N+]=[N-])(C)C.CO.ClCCl>C(#N)C>[CH3:29][N:2]([CH3:1])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]([C:26]([O:28][CH3:32])=[O:27])=[N:14][CH:15]=[C:16]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:17]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1ccc(Nc2cc(Cc3ccc(F)cc3)cnc2C(=O)O)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ncc(Cc2ccc(F)cc2)cc1Nc1ccc(C(=O)N(C)C)cc1
Yield: 49.5 %

Procedure:
3-({4-[(dimethylamino)carbonyl]phenyl} amino)-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylic acid (79 mg, 0.201 mmol) was dissolved in a 9:1 acetonitrile:methanol solution (5 mL) and trimethylsilyldiazomethane (0.3 mL, 0.603 mmol) was added and the reaction was stirred at ambient temperature until complete by TLC (10% methanol/dichloromethane). The mixture was concentrated under reduced pressure, aqueous sodium bicarbonate was added, and the aqueous layer was extracted with chloroform. The combined organics were washed with brine and dried over sodium sulfate to yield methyl 3-({4-[(dimethylamino)carbonyl]phenyl}amino)-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (40.5 mg, 49% yield). 1H NMR (CDCl3) δ 9.49 (s, 1 H), 8.00 (s, 1 H), 7.34-7.36 (m, 3 H), 7.12-7.05 (m, 4 H), 6.97-6.94 (m, 2 H), 3.97 (s, 3 H), 3.87 (s, 2 H), 3.07 (br s, 3 H), 3.02 (br s, 3 H); MS m/z 408 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)=[CH:19][N:18]=2)=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:30][C:31]1C=C[C:34](S([O-])(=O)=O)=[CH:33][CH:32]=1.CN(C)C=[O:44]>>[CH2:3]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C@H:33]([CH3:34])[CH2:32][C@@H:31]([OH:44])[CH3:30])=[CH:27][CH:28]=3)=[CH:19][N:18]=2)=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCc1ccc(-c2ncc(-c3ccc(O)cc3)cn2)cc1
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCc1ccc(-c2ncc(-c3ccc(O[C@H](C)C[C@H](C)O)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.15 g of 55% sodium hydride was mixed with 3 ml of dimethylformamide. A solution of 1.00 g of 4-[2'-(4"-n-octylphenyl)-5-pyrimidinyl]phenol in 2 ml of dimethylformamide was added dropwise thereto under ice-cooling. After the completion of the addition, the obtained mixture was stirred at room temperature for one hour. Then, a solution of 0.79 g of monotosylate of (R,R)-2,4-pentadediol in 2 ml of dimethylformamide was added dropwise thereto and the mixture was stirred at 80° C. for 1.5 hour. After cooling, the reaction mixture was poured into 100 ml of ice-water and extracted with diethyl ether. After washing with water and desolvating, the residue was purified by silica gel column chromatography with the use of a mixture of ethyl acetate and n-hexane (3:7) as a developing solvent to thereby give 0.76 g of the title compound.
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH:7]1[CH2:11][CH:10]([N:12]2[CH:20]=[N:19][C:18]3[C:13]2=[N:14][C:15]([NH2:22])=[N:16][C:17]=3[Cl:21])[C:9](=[CH2:23])[CH:8]1[CH2:24][O:25][C:26]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.CO>[NH2:22][C:15]1[N:16]=[C:17]([Cl:21])[CH:18]2[CH:13]([N:14]=1)[N:12]([CH:10]1[CH2:11][CH:7]([OH:6])[CH:8]([CH2:24][O:25][C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:9]1=[CH2:23])[CH:20]=[N:19]2
Reactant: C=C1C(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1n1cnc2c(Cl)nc(N)nc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C1C(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C(O)CC1N1C=NC2C(Cl)=NC(N)=NC21
Temperature: 25 °C
Reaction time: 13 h
Yield: 71.9 %

Procedure:
The compound of formula (V) obtained in Example 1-7 (3.2 g, 4.12 mmol) was dissolved in anhydrous tetrahydrofuran (32 ml). To the resulting solution, 1 M tetrabutyl ammonium fluoride solution in tetrahydrofuran (8.24 mL, 8.24 mmol) was added and stirred at room temperature for 13 hrs. After completion of the reaction, the resulting mixture was quenched by adding distilled water (30 ml). The solution thus obtained was extracted with ethyl acetate (30 ml), dried over anhydrous sodium sulfate, filtered, and condensed. The resulting material was stirred in methanol (32 ml) to obtain the title compound (1.6 g, yield: 71.6%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)[CH3:6].[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.Cl>ClCCCl>[CH2:5]([C:7]1[CH:8]=[CH:9][C:10]([S:13][CH3:14])=[C:11]([CH:12]=1)[C:20]([C:19]1[CH:23]=[CH:24][C:16]([CH3:15])=[CH:17][CH:18]=1)=[O:21])[CH3:6]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCc1ccc(SC)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCc1ccc(SC)c(C(=O)c2ccc(C)cc2)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Aluminum chloride (10.8g) was added in portions to an ice-cooled, stirred solution of 4-(ethyl)thioanisole (12.3g) and 4-methylbenzoyl chloride (12.5g) in 1,2-dichloroethane (60 ml). The mixture was allowed to come to ambient temperature and was stirred overnight. It was then poured into a mixture of concentrated hydrochloric acid (about 100 ml) and ice (200 gm), which mixture was extracted with chloroform (3 × 100 ml), and the combined organic fractions were washed with 10% w/v aqueous sodium carbonate solution (2 × 100 ml) and water (100 ml), dried over magnesium sulphate and evaporated to leave the crude product as an oil. This oil was distilled twice to give the title compound as a clear oil (bp 152°-154° C./0.01 mm). The structure was confirmed by NMR.