Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C.O>ClCCl.CN(C)C1C=CN=CC=1>[S:21]([O:11][CH2:10][C@@H:9]1[CH2:12][CH2:13][CH2:14][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
A solution of N-Boc-L-prolinol (51.2 g, 254 mmol) in dichloromethane (250 mL) was cooled to 0° C., and thereto were added p-toluenesulfonylchloride (53.4 g, 280 mmol), triethylamine (30.9 g, 42.6 mL, 305 mmol), and 4-dimethylaminopyridine (5.00 g, 40.9 mmol). After stirring overnight at room temperature, to the mixture was added water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified with silica gel column (hexane/ethyl acetate=70/30 to 30/70) to give the title compound (89.7 g, 250 mmol, 99%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([CH2:7][C:8]2[O:12][N:11]=[C:10]([C:13]([O-:15])=O)[N:9]=2)=[CH:5][CH:4]=1.Cl.[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1.[OH-].[Na+].O.CN(C=O)C>[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH2:32][NH:33][C:13]([C:10]1[N:9]=[C:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:17][CH:16]=2)[O:12][N:11]=1)=[O:15]
Reactant: O=C([O-])c1noc(Cc2ccc(C(F)(F)F)cc2)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(Cc2ccc(C(F)(F)F)cc2)n1
Yield: 21.3 %

Procedure:
This compound was prepared according to method F with 5-(4-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxylate (0.104 g; 0.346 mmol) in THF (1 mL) and sodium hydroxide in water (2M, 1 mL) and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.080 g; 0.346 mmol), HATU (0.131 g; 0.346 mmol), N,N diisopropylethylamine (0.149 mL; 0.865 mmol), in DMF (4 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) and preparative HPLC method 2 to yield 0.033 g (21%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(4-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH:9]2[CH2:11][O:10]2)=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:18]=1[OH:30].C1(C)C=CC=CC=1>C(N(C(C)C)C(C)C)C>[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:18]=1[O:30][CH2:11][CH:9]([OH:10])[CH2:8][O:7][C:6]1[CH:12]=[CH:13][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: FC(F)(F)c1ccc(OCC2CO2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: OC(COc1ccc(C(F)(F)F)cc1)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl

Procedure:
8 g of 2-(4-trifluoromethyl-phenoxymethyl)-oxirane and 3.8 g of 2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenol are stirred in 80 ml of N-ethyl-diisopropylamine and 50 ml of toluene for 14 days at 100° C. The reaction mixture is concentrated, and the residue is taken up in ethyl acetate and washed with hydrochloric acid and water. After concentration of the organic phase and purification over silica gel, 1-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-3-(4-trifluoromethyl-phenoxy)-propan-2-ol is obtained. 1H-NMR (CDCl3) 300 MHz: 2.81 (d, 1H), 4.15-4.48 (m, 5H), 4.59 (d, 2H), 6.11 (t, 1H), 6.86 (s, 2H), 7.01 (d, 2H), 7.58 (d, 2H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[N+:23]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:21])([F:22])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1N

Procedure:
The title compound was prepared from (2-nitro-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example C7) (7.45 g, 19.75 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a light orange solid (6.75 g, 99%).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[C:17]#[C:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([C:43]#[N:44])=[N:41][CH:42]=2)O1>>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([C:2]([C:37]4[CH:38]=[CH:39][C:40]([C:43]#[N:44])=[N:41][CH:42]=4)=[C:3]([C:17]#[C:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:12][CH2:13]1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: Brc1c(C#Cc2ccc3ccccc3n2)nc2c(N3CCOCC3)ccnn12
Product: N#Cc1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1

Procedure:
Compound 18b (0.15 g, 0.35 mmol) was subjected to Suzuki coupling conditions with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile as described in Example 38, Step A to obtain compound 39a as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C22H19N2O: 458.2 (M+H). Found: 458.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18]CC)=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]3[CH2:40][CH2:39][N:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]3)=[CH:31][C:30]=2[N:45]2[CH:49]=[CH:48][C:47]([CH3:50])=[N:46]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1.[Li+].[OH-]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:21][CH2:22]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]3[CH2:40][CH2:39][N:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]3)=[CH:31][C:30]=2[N:45]2[CH:49]=[CH:48][C:47]([CH3:50])=[N:46]2)[C:25]([F:27])([F:28])[F:26])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(C5CCN(S(C)(=O)=O)CC5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccn(-c2cc(C3CCN(S(C)(=O)=O)CC3)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1

Procedure:
Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1-(methylsulfonyl)piperidin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.[CH3:13][S-:14].[Na+].Cl>CN(C)C=O>[Cl:12][C:4]1[CH:3]=[C:2]([S:14][CH3:13])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: C[S-]
Reactant: COC(=O)c1ccc(Br)cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC)cc1Cl
Reaction time: 2 h
Yield: 76.9 %

Procedure:
To a solution of methyl 4-bromo-2-chlorobenzoate (1.25 g) in N,N-dimethylformamide (10 ml) was added sodium thiomethoxide (459 mg) under ice-cooling and the mixture was stirred for 2 hr. To the reaction mixture was added 1N hydrochloric acid and the resulting product was extracted 3 times with diethyl ether. The organic layers were combined, washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was applied to silica gel column chromatography (hexane/ethyl acetate=10/1) to give methyl 2-chloro-4-(methylthio)benzoate (835 mg) as a colorless oil.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1
Reactant: O=c1ccoc2ccccc12
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCOc2ccccc21
Reaction time: 48 h
Yield: 65.3 %

Procedure:
According to the general procedure, a solution of chromone (45 mg, 0.31 mmol), Hünig's base (540 μL) and rac-32 (9.8 mg, 0.0062 mmol, 2.0 mol %) in PhMe (3 mL) was pressurized with H2 to 100 bar and stirred for 48 h. Filtration of the reaction mixture and evaporation of the solvent gave the crude product, which was purified by column chromatography (30% EtOAc in hexane, silica gel) to give 48 (30 mg, 66%) as a colorless oil. 1H NMR35 (300 MHz, CDCl3): δ 7.90 (dd, 1H J=7.8, 1.5 Hz), 7.50-7.45 (m, 1H), 7.05-6.96 (m, 2H), 4.54 (t, 2H, J=6.6 Hz), 2.82 (t, 2H, J=6.3 Hz); 13C NMR (75.5 MHz, CDCl3): δ 192.0, 162.0, 136.1, 127.3, 121.5, 118.0, 67.1, 37.9.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N1C=CC=CC=1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].C(=O)(O)[O-].[Na+]>ClCCl>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][C:14](=[O:15])[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1nccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)Oc1ccccc1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a stirred mixture of 2-aminothiazole (2 g, 20 mmol), pyridine (10 mL), and anhydrous dichloromethane (20 mL) was added phenyl chloroformate (3 mL, 24 mmol) under argon at 0° C. The mixture was stirred at the same temperature for 5 min and at rt overnight before saturated aqueous sodium bicarbonate solution (30 mL) was added slowly. After mixed with heptanes (30 mL), the mixture was stirred for 30 min. The solid was filtered, washed with water (3×3 mL) and then diethylether (3×3 mL), and dried to give phenyl thiazol-2-ylcarbamate (3.4 g, 15 mmol, 75% yield) as an off-white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([CH:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])O)=[N:7][CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>S(Cl)(Cl)=O.CN(C)C=O>[CH2:1]([O:4][C:5]1[C:6]([CH:11]([S:28][C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)[C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:7][CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cccnc1C(O)c1cc(F)ccc1F
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: C=CCOc1cccnc1C(Sc1ccc(Cl)cc1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.7 %

Procedure:
The 3-allyloxy-2-[(2,5-difluorophenyl)-hydroxymethyl]pyridine (370 mg, 1.33 mmol) obtained in Referential Example 10 was dissolved in thionyl chloride (2.0 ml). To the resulting solution was added a catalytic amount of dimethylformamide. The resulting mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. Dioxane was added to the residue, followed by further concentration. The residue thus obtained was dissolved in dimethylformamide (10 ml). To the resulting solution were added 4-chlorobenzenethiol (217 mg, 1.5 mmol) and potassium carbonate (828 mg, 6.0 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 50° C. for 1 hour. After the reaction mixture was cooled to room temperature, diethyl ether (50 ml) was added thereto. The resulting mixture was washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (hexane:ethyl acetate=10:1) to give the title compound (256 mg, 68%) as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14](Br)[CH:13]=2)[O:9][N:8]=1.[N:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([C:24]3[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=3)[CH:15]=[C:16]([C:18]#[N:19])[CH:17]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(Br)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: OB(O)c1ccncc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: N#Cc1cc(-c2ccncc2)cc(-c2nc(-c3ccccn3)no2)c1
Yield: 8.8 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-bromo-5-cyanophenyl)-1,2,4-oxadiazole (70 mg, 0.21 mmol), 4-pyridylboronic acid (53 mg, 0.43 mmol), and tetrakis(triphenylphosphine) palladium(O) (Pd(PPh3)4, 25 mg, 0.021 mmol) in a solution of ethylene glycol dimethyl ether (3 mL) and 2M sodium carbonate (3 mL) was headed in a sealed vial at 100° C. for 1 hour with vigorous stirring. The reaction was cooled and diluted with chloroform. The organic solution was washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography of the residue using a gradient of 50% ethyl acetate in hexane to 100% ethyl acetate followed by trituration with 5% ethyl acetate in diethyl ether afforded 6 mg (9%) of 3-(2-pyridyl)-5-(3-cyano-5-(4-pyridyl)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3): δ −8.88 (d, 1H), 8.78 (m, 3H), 8.64 (s, 1H), 8.26 (d, 1H), 8.15 (s, 1H), 7.93 (t, 1H), 7.61 (m, 2H), 7.52 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22]Br)[CH:7]=1)[CH3:2].[CH3:25][CH:26]([SH:28])[CH3:27].[H-].[Na+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22][S:28][CH:26]([CH3:27])[CH3:25])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CBr)c1
Reactant: CC(C)S
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CSC(C)C)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
[3-(4-Bromo-2-bromomethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (0.4 g, 0.87 mmol) and 2-propanethiol (0.08 g, 1.0 mmol) were combined in 1,4-dioxane (20 mL). Sodium hydride (60% in mineral oil; 0.04 g, 1.0 mmol) was added, and the reaction was stirred at room temperature for 20 minutes. The mixture was worked up to give the title compound.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][C:33]1[C:34]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:42][CH:41]=2)=[N:35][CH:36]=[C:37]([OH:39])[CH:38]=1.[CH2:55](O)[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]>O1CCCC1>[F:32][C:33]1[C:34]([C:40]2[CH:41]=[CH:42][C:43]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:44][CH:45]=2)=[N:35][CH:36]=[C:37]([O:39][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH:38]=1
Reactant: CCCCCCCCOc1ccc(-c2ncc(O)cc2F)cc1
Reactant: CCCCCCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ncc(OCCCCCCCC)cc2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
2.00 g (11.5 mmol) of diethyl azodicarboxylate are added dropwise at 0° C. to 3.00 g (11.5 mmol) of triphenylphosphine in 50 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 30 minutes. 2.42 g (7.7 mmol) of 3-fluoro-5-hydroxy-2-(4-octyloxyphenyl)pyridine and 1.00 g (7.7 mmol) of 1-octanol are subsequently added. After a reaction time of 18 hours at room temperature, the solvent is removed by distillation and the residue is purified by chromatography (silica gel/hexane: ethyl acetate 95:5). Recrystallization from acetonitrile gives 1.38 g of 3-fluoro-5-octyloxy-2-(4-octyloxyphenyl)pyridine. ##STR18## The compound has the phase sequence: X 51.3 (42.5) SA 50 N 69 I.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[Cl:13][C:14]1[C:21]([Cl:22])=[C:20]([O:23][CH3:24])[CH:19]=[CH:18][C:15]=1[CH:16]=[O:17].O>C1COCC1>[Cl:13][C:14]1[C:21]([Cl:22])=[C:20]([O:23][CH3:24])[CH:19]=[CH:18][C:15]=1[CH:16]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[OH:17]
Reactant: Brc1ccccn1
Reactant: COc1ccc(C=O)c(Cl)c1Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccccn2)c(Cl)c1Cl
Temperature: -65 °C

Procedure:
29.3 g of 2-bromopyridine in 150 ml of dry THF is added to 75 ml of 2.6M n-butyllithium that was chilled to -65° C. 2,3-dichloro-4-methoxybenzaldehyde (38.0 g) is then added in 300 ml of THF and the reaction mixture allowed to come to room temperature. It is poured into H2O and the crystalline product filtered off, washed with ether and dried to give α-(2,3-dichloro-4-methoxyphenyl)-2-pyridinemethanol, mp 174°-176° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23]CC2C=CC=CC=2)[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12])[CH2:5][CH3:6].C1COCC1>[Pd].CO>[OH:23][C:21]1[CH:20]=[C:10]([CH:9]=[C:8]([O:7][C@H:4]([CH2:3][O:2][CH3:1])[CH2:5][CH3:6])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12]
Reactant: CC[C@@H](COC)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@@H](COC)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reaction time: 6 h
Yield: 102.5 %

Procedure:
To a solution of 3-({(1S)-1-[(methyloxy)methyl]propyl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide (4.6 g, 11 mmol) in 1:1 THF:methanol (100 mL) was added 10% w/w palladium on carbon (450 mg) and the resulting mixture was stirred under an atmosphere of hydrogen for 6 hours. The atmosphere was replaced with argon and the mixture was filtered and evaporated to afford the title compound as a white solid (3.6 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:20])=[CH:14][C:15](=[O:19])[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(C)C=CC(S([N:37]=[N+:38]=[N-])(=O)=O)=CC=1>C1COCC1>[N+:37](=[C:14]1[C:13](=[O:20])[C:12]2[C:17](=[CH:18][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[O:16][C:15]1=[O:19])=[N-:38]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: O=c1cc(O)c2ccc(OCc3ccccc3)cc2o1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: [N-]=[N+]=C1C(=O)Oc2cc(OCc3ccccc3)ccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
A solution of 7-benzyloxy -4-hydroxy coumarin (2.5 g, 9.3 mmol; prepared in accordance with Example 5) in anhydrous THF (40 mL) was mixed with triethylamine (0.9 g, 9 mmol) taken in a 100 mL 3-neck round-bottom flask under an atmosphere of N2. A solution of p-toluenesulfonyl azide (2.8 g, 14 mmol) in dry THF (20 mL) was added dropwise through an addition funnel. The mixture was stirred at room temperature for 3 hrs. The color of the solution turned orange. The solvent was rotary evaporated and the product was taken in CH2Cl2 and washed with water (3 times). Petroleum ether (twice the volume) was added to the solution and the solid precipitate was filtered with a flit and dried at 45° C. The product was recrystallized using CH2Cl2 ; yield 90%. The product was characterized by NMR: 13C NMR (100 MHz, CD2 Cl2): 173.3, 165.4, 158.7, 156.0, 136.0, 129.1, 128.8, 128.0, 127.6, 113.9, 113.0, 103.0, 75.7, 71.2; DSC--m. pt. 191° C. followed by decomposition; IR (KBr): 2182, 2154, 1717, 1647, 1605 cm-1 ; MS(APCI): (M+H), 295 (base peak).
Reaction SMILES: [N+](=[CH2:3])=[N-].[C:4]([C:12]1[CH:13]=[C:14]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:16][CH:17]=1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)Cl>[C:4]([C:12]1[CH:13]=[C:14]([CH2:18][C:19]([O:21][CH3:3])=[O:20])[CH:15]=[CH:16][CH:17]=1)(=[O:11])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)Cc1cccc(C(=O)c2ccccc2)c1
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: COC(=O)Cc1cccc(C(=O)c2ccccc2)c1
Reaction time: 0.25 h

Procedure:
1300 ml of a methylene chloride solution titrating 12.5 g/liter of diazomethane was added progressively at 10°-15°C to a solution of 50 g of m-benzoyl-phenyl acetic acid in 500 ml of methylene chloride and after stirring for 15 minutes, excess diazomethane was destroyed by the addition of acetic acid. The organic solution was washed with an aqueous saturated sodium bicarbonate solution and then with water and evaporated to dryness under reduced pressure to obtain 52.5 g of methyl m-benzoyl-phenyl-acetate which was used as is for the α-alkylation step.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[S:33])=[CH:27][CH:26]=1>>[F:23][C:24]([F:34])([F:35])[C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[CH:13][C:8]4[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=4[N:10]=3)[CH2:15][CH2:16]2)=[S:33])=[CH:29][CH:30]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Reactant: FC(F)(F)c1ccc(N=C=S)cc1
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4ccc(C(F)(F)F)cc4)CC3)nc21

Procedure:
Pipemidic acid (30 mg, 0.0989 mmol) and 4-trifluoromethylphenyl isothiocyanate (16.7 mg, 0.0824 mmol) were used. Purification on silica yielded compound 31 in Table 1, below (31 mg, 77%). 1H NMR (300 MHz, CDCl3) δ 9.34 (s, 1H), 8.69 (s, 1H), 7.65-7.57 (m, 2H), 7.51 (s, 1H), 7.37-7.31 (m, 2H), 4.34 (q, J=6.80 Hz, 2H), 4.27-3.97 (m, 8H), 1.49 (t, J=7.25, 7.25 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][C@@H:4]([C:9](=[O:31])[NH:10][C@H:11]1[CH2:28][C:27]2=[CH:29][N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=32)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:30])[CH2:5][C:6]([OH:8])=[O:7]>C(O)(=O)C>[CH3:1][CH:2]([CH3:32])[CH2:3][C@@H:4]([C:9](=[O:31])[NH:10][C@H:11]1[CH2:28][CH:27]2[CH2:29][N:20]([CH:21]3[CH:26]2[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:30])[CH2:5][C:6]([OH:8])=[O:7]
Reactant: CC(C)C[C@H](CC(=O)O)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Solvent: CC(=O)O
Product: CC(C)C[C@H](CC(=O)O)C(=O)N[C@H]1CC2CN(CCCCCCNC1=O)C1CCCCC21

Procedure:
(3R,10S)-5-Methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid (200 mg, 0.45 mmol) was dissolved in 10 mL of glacial acetic acid and was hydrogenated at 100 psi H2 pressure in the presence of Pt2O (60 mg) in a Parr reactor at room temperature for 15 hrs. Argon gas was bubbled into the reaction mixture for 15 mins. and the catalyst (Pt2 O) was filtered off (through a cone of celite). The clear filtrate was evaporated to dryness and further co-evaporated with toluene twice to give quantitative yield of (3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadecan-10-ylcarbamoyl)hexanoic acid as a white solid. MS: 448 (M-H)31 .
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH:10]=NCCC)[CH:7]=[CH:6][C:5]=1[NH:15][CH2:16][CH2:17][CH3:18])([O-:3])=[O:2].Cl.[OH2:20]>>[N+:1]([C:4]1[CH:9]=[C:8]([CH:7]=[CH:6][C:5]=1[NH:15][CH2:16][CH2:17][CH3:18])[CH:10]=[O:20])([O-:3])=[O:2]
Reactant: CCCN=Cc1ccc(NCCC)c([N+](=O)[O-])c1
Reactant: O
Agent: Cl
Product: CCCNc1ccc(C=O)cc1[N+](=O)[O-]

Procedure:
(a-2) A mixture of 53.7 parts of 2-nitro-N-propyl-4-[(propylimino)methyl]benzenamine, 360 parts of concentrated hydrochloric acid and 300 parts of water was stirred and refluxed for 30 minutes. The reaction mixture was cooled and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 20.4 parts of 3-nitro-4-(propylamino)benzaldehyde; mp. 73.6° C. (int. 2)