Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([S:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])=[N:2]1>N.CO.[Ni]>[NH:1]1[CH:5]=[N:4][C:3]([S:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:13][NH2:14])[CH:15]=[CH:16][CH:17]=2)=[N:2]1
Reactant: N#Cc1cccc(OCCSc2nc[nH]n2)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cccc(OCCSc2nc[nH]n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
A solution of 3-{[2-(1H-1,2,4-triazol-3-ylthio)ethyl]oxy}benzonitrile obtained in Reference Example 2 (9.00 g, 36.5 mmol) and Raney-nickel (5.00 g) in 5N ammonia/methanol (300 mL) was stirred at room temperature overnight under hydrogen atmosphere (1 atm). The catalyst was filtered off, and the filtrate was concentrate. The obtained residue was crystallized from toluene to give the title compound as a pale-blue powder (6.45 g, 71%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:13](O)[CH2:14][OH:15].C(O)(=O)C(O)=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[O:15]1[C:2]2([CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)[O:1][CH2:13][CH2:14]1
Reactant: OCCO
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC2(CC1)OCCO2
Yield: 99 %

Procedure:
Ethyl 4-oxocyclohexanecarboxylate (5.00 g, 29.4 mmol) was dissolved in toluene (200 mL), and ethylene glycol (15 mL) and oxalic acid (500 mg) were added thereto, followed by stirring under heating and reflux for 5 hours. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=8:2) to afford ethyl 1,4-dioxaspiro[4,5]decane-8-carboxylate (6.28 g, 99%).
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Na].[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[CH:17]2.[H-].[Na+]>CN(C)C=O.ClCCl>[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])[CH:18]=[CH:17]2
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triisopropylsilyl chloride (6.87 g) was added to the sodium salt prepared from 5bromoindole (6.35 g) and sodium hydride (1.71 g, 50% suspension in oil) in dimethylformamide (32 ml) and the mixture was stirred at room temperature for 2 hours then poured into ice water (150 ml). The crude intermediate obtained by evaporation of the dichloromethane extract was column chromatographed (silica gel, 40°-60° C. petroleum ether) to give 5-bromo-1-triisopropylsilylindole isolated as an oil.
Reaction SMILES: CC(O)=O.C([N:12]1[CH2:19][CH:18]2[CH:14]([CH2:15][N:16]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=3)[CH2:17]2)[CH2:13]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:27][C:22]1[CH:23]=[C:24]([CH3:26])[N:25]=[C:20]([N:16]2[CH2:17][CH:18]3[CH:14]([CH2:13][NH:12][CH2:19]3)[CH2:15]2)[N:21]=1
Reactant: Cc1cc(C)nc(N2CC3CN(Cc4ccccc4)CC3C2)n1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 127.1 %

Procedure:
HOAc. To a 4 L high pressure autoclave equipped with mechanical stirring, temperature probe, heating jacket, and gas inlet were added 5% Pd/C (66.9 g, Johnson Matthey 5R338, 56.8% H2O, 3.45 mol %) and a solution of 2-benzyl-5-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (160 g, 519 mmol) and acetic acid (30 mL, 519 mmol) in ethanol (3.2 L). The mixture was stirred at 50° C. under 50 psi of H2(g) for 4 h. The catalyst was removed and the resulting solution was then concentrated under reduced pressure to provide the desired product as a white solid (144 g, quantitative yield) as the HOAc salt. MS (ESI): mass calcd. for C12H18N4, 218.15; m/z found 219 [M+H]+. 1H-NMR (CDCl3, 400 MHz): 6.30 (s, 1H), 3.79-3.59 (m, 4H), 3.39 (m, 2H), 3.09-2.88 (m, 4H), 2.29 (s, 6H), 1.93 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[C:4]2[C:13]3[C:12](=[CH:14][CH:15]=1)[S:11](=[O:17])(=[O:16])[CH:10]([CH3:18])[NH:9][C:8]=3[CH:7]=[CH:6][CH:5]=2.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[C:4]2[C:13]3[C:12](=[CH:14][CH:15]=1)[S:11](=[O:17])(=[O:16])[CH:10]([CH3:18])[NH:9][C:8]=3[CH:7]=[CH:6][CH:5]=2
Reactant: COc1ccc2c3c(cccc13)NC(C)S2(=O)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1Nc2cccc3c(O)ccc(c23)S1(=O)=O
Temperature: -78 °C
Reaction time: 24 h

Procedure:
0.6 g of 7-methoxy-2-methyl-2,3-dihydronaphtho[1,8-de][1,3]thiazine-1,1-dioxide is dissolved in 23 mL dichloromethane and the solution is cooled to −78° C. 2.3 mL of boron tribromide (1 molar solution in dichloromethane) is added dropwise. Then the mixture is stirred for 24 hours at ambient temperature. After evaporation in vacuo, the residue is purified by chromatography. Yield: 0.36 g; m.p.: 245° C.–246° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1.[Al+3].[Cl-].[Cl-].[Cl-]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][C:4]=1[O:9][CH3:10]
Reactant: COc1ccccc1OC
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: COc1ccc(C(=O)CCC(=O)O)cc1OC
Reaction time: 24 h
Yield: 50 %

Procedure:
11.4 g (0.09 mol) of 1,2-dimethoxybenzene are mixed with 3 g (0.03 mol) of succinic anhydride, and then, under stirring, the semisolid mass is added with 7.8 g (0.06 mol) of AlCl3 under a light nitrogen flow. After 24 hours at room temperature under a nitrogen atmosphere, 300 ml of ethyl ether are added. A precipitate is formed which is filtered and treated by cooling with 100 ml of HCl 6N, extracting several times with CH2Cl2 and washing with water. The organic solution, anhydrified with anhydrous sodium sulphate, is concentrated to dryness, obtaining a yellow solid which is crystallised by n-hexane/EtOAc giving 3 g of product. Yield 50%.
Reaction SMILES: [O:1](C(O)C)C1C=CC=CC=1.[CH:11]1[CH:16]=[C:15]2[C:17]([NH:19][S:20][C:14]2=[CH:13][CH:12]=1)=O>>[S:20]1(=[O:1])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:16][C:15]=2[CH:17]=[N:19]1
Reactant: CC(O)Oc1ccccc1
Reactant: O=c1[nH]sc2ccccc12
Product: O=S1N=Cc2ccccc21
Reaction time: 1 h

Procedure:
50% of 20% strength carbendasulf solution from Example 9 was combined with 10% of Proxel press paste (BIT) and 40% of phenoxyethanol and stirred for about 1 hour, giving a clear deep red solution.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].[Br:14]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>ClC(Cl)(Cl)Cl>[Br:14][CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[C:10]([O:12][CH3:13])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccccc1OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccccc1OC
Reaction time: 2 h

Procedure:
A mixture of 14.6 g (81.2 mmol) of methyl (2-methoxyphenyl)acetate, 15.2 g (85.3 mmol) of N-bromosuccinimide and a catalytic amount of AIBN in tetrachloromethane (180 ml) was heated under reflux with stirring for 2 h. The cooled reaction solution was filtered, and the solvent was removed in vacuo. Yield: 21.6 g (100%) of yellow oil
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:6]=1[C:7]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][C:16]([C:20](=[O:25])N(OC)C)=[C:15]2[N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:8]>O1CCCC1>[C:20]([C:16]1[CH:17]=[N:18][C:19]2[C:14]([C:15]=1[N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][C:7](=[O:8])[C:6]1[C:32]([Cl:36])=[CH:33][CH:34]=[CH:35][C:5]=1[Cl:4])(=[O:25])[CH3:1]
Reactant: CON(C)C(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1N1CCOCC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1N1CCOCC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a 0.9M solution of methylmagnesium bromide in tetrahydrofuran (1.3 ml) was added dropwise a solution of 8-(2,6-dichlorobenzoylamino)-3-(N-methoxy-N-methylcarbamoyl)-4-morpholinoquinoline (107 mg) in dry tetrahydrofuran (1 ml) with cooling in an ice bath. The mixture was stirred at the same temperature for 1 hour, at ambient temperature for 1 hour, at 50° C. for 2 hours. The mixture was partitioned between ethyl acetate and saturated ammonium chloride aqueous solution. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel. The obtained oil was crystallized from ethanol to give 3-acetyl-8-(2,6-dichlorobenzoylamino)-4-morpholinoquinoline (19 mg) as a white crystal.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH:31]1([NH2:35])[CH2:34][CH2:33][CH2:32]1>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[C:15]2[O:14][CH:13]([CH2:12][NH:35][CH:31]3[CH2:34][CH2:33][CH2:32]3)[CH2:17][C:16]=2[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4c(C)cccc4C)c3O2)cc1
Reactant: NC1CCC1
Product: Cc1cccc(C)c1-c1cc(Cl)cc2c1OC(CNC1CCC1)C2

Procedure:
The title compound was prepared (0.027 g, 21%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and cyclobutylamine (0.49 g, 6.77 mmol). mp 203-205° C.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccncc1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Product: O=C(Nc1ccncc1)c1cc(N(CC2CC2)C2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclohexyhcyclopropylmethyl)amino]pyrimidine-4-carboxylic acid (Intermediate 13) and 4-aminopyridine (Tyger), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.C(N(CC)CC)C.Cl[Si:35]([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl>[CH3:13][C:9]1([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=3)[CH:5]=[CH:4][C:3]=2[CH:2]([O:1][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH2:11][CH2:10]1
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3O[Si](C)(C)C)cc1
Temperature: 25 °C

Procedure:
To a solution of 0.23 g (0.54 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 9) in 4 ml of dry CH2Cl2 was added 0.06 ml of triethylamine (0.81 mmol). The solution was flushed with nitrogen and then 0.12 g (0.81 mmol) of chlorotrimethylsilane was slowly added by syringe. The mixture was stirred at room temperature (flushed with nitrogen) for 30 minutes, concentrated in vacuo to an oil and purified by flash chromatography (silica, 10% EtOAc-hexane) to yield the title compound as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]=[N:17][C:18]([C:31](=[O:33])[NH2:32])=[C:19]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[N:20]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:31]([C:18]1[N:17]=[N:16][C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10]2)=[N:20][C:19]=1[NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:27])=[CH:29][CH:30]=1)(=[O:33])[NH2:32]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2nnc(C(N)=O)c(Nc3ccc(C(=O)O)cc3)n2)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2nnc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Reaction time: 0.08 h

Procedure:
Compound 5 (90 mg, 0.20 mmol) was mixed with morpholine (53 μL, 0.60 mmol) in DMF (5 mL). To the mixture were added DIEA (105 μL, 0.60 mmol) and PyBOP (312 mg, 0.60 mmol). The mixture was stirred for 5 min, diluted with 100 mL EtOAc, washed with brine ×2, dried, and concentrated in vacuo. The residue was subjected to flash column chromatography with 50 to 100% EtOAc in hexane to isolate (R)-tert-butyl 1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-ylcarbamate in quantitative yield. (R)-tert-butyl 1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-ylcarbamate was treated with DCM (10 mL) and TFA (3 mL) for 1 h at RT. The mixture was concentrated in vacuo to dryness. The residue was subjected to reverse phase prep HPLC to isolate the (R)-3-(3-aminopiperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide (6) as HCl salt. MS found for C20H26N8O3 as (M+H)+ 427.1, (M−H)− 425.2. UV: λ=270 nm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH2:19][NH:18][C:17](=[O:20])[CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N>CN(C=O)C.O1CCOCC1.[Cu]I.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH2:19][N:18]([C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[C:25]#[N:26])[C:17](=[O:20])[CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(c2cccc(OCc3ccccc3)c2)CN1
Reactant: N#Cc1cccc(Br)c1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cccc(N2CC(c3cccc(OCc4ccccc4)c3)CC2=O)c1
Temperature: 100 °C
Yield: 55.1 %

Procedure:
A mixture of 4-(3-benzyloxyphenyl)-pyrrolidin-2-one (1.8 g, 6.7 mmol), 3-bromobenzonitrile (1.83 g, 1.5 eq) and potassium phosphate (2.6 g, 1.8 eq) was created in a dry flask with a stir bar under N2. This mixture was dissolved in 10 mL DMF and 10 mL dioxane. To this solution was added 60 μL of 1,2-trans-cyclohexanediamine and CuI (100 mg). The solution was stirred and heated at 100° C. under N2 for 20 h, and then cooled down to r.t. EtOAc (100 mL) was added and the mixture was filtered, washed with NH4Cl solution, water and brine. The solution was also dried over MgSO4 and concentrated under a reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc:Hexane=1:3) to give 1.36 g of the desired product. Yield: 55%.
Reaction SMILES: [CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]([O:21]CC)=[O:20])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1N=NN(C(C2C=CC=CC=2)C(OCC)=O)N=1)CCCCCCCCC>>[CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH:18]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:19]([OH:21])=[O:20])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1nnn(C(C(=O)OCC)c2ccccc2)n1
Agent: CCCCCCCCCCc1nnn(C(C(=O)OCC)c2ccccc2)n1
Product: CCCCCCCCCCCCc1nnn(C(C(=O)O)c2ccccc2)n1

Procedure:
When in the general procedure of Example 79 an appropriate amount of ethyl (±)-5-dodecyl-α-phenyl-2H-tetrazole-2-acetate was substituted for ethyl (±)-5-decyl-α-phenyl-2H-tetrazole-2-acetate, the title compound was obtained, mp 76°-78° C.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[N:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:19])([F:18])[F:17])[C:5]=1[CH2:20][OH:21])([CH3:3])[CH3:2].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]([C:4]1[N:8]=[N:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:17])([F:19])[F:18])[C:5]=1[CH2:20][O:21][C:23]1[N:28]=[C:27]([CH3:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][CH:24]=1)([CH3:3])[CH3:2]
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)c1nnn(-c2ccccc2OC(F)(F)F)c1CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: Cc1ccccc1
Product: Cc1nc(OCc2c(C(C)C)nnn2-c2ccccc2OC(F)(F)F)ccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 95.7 %

Procedure:
To an ambient temperature solution of [5-isopropyl-3-(2-trifluoromethoxy-phenyl)-3H-[1,2,3]triazol-4-yl]-methanol (2.0 g, 6.64 mmol) in degassed toluene (22 mL) are added 6-chloro-2-methyl-3-nitro-pyridine (1.15 g, 6.64 mmol), cesium carbonate (3.25 g, 9.96 mmol), 2-(di-t-butylphosphino)-1,1′-binapthyl (332 mg, 0.833 mmol, 12.5 mol %), and palladium (II) acetate (150 mg, 0.666 mmol, 10 mol %). The reaction mixture is heated to 70° C. overnight. The reaction is filtered through a pad of diatomaceous earth. The filtrate is concentrated and the residue is chromatographed (SiO2 120 g, 0% to 20% EtOAc/Hexane to yield 6-[5-Isopropyl-3-(2-trifluoromethoxy-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-3-nitro-pyridine (2.78 g, 96%). 1H NMR (400 MHz, CDCl3) δ 8.23 (d, 1H, J=8.8 Hz), 7.61-7.53 (m, 2H), 7.48-7.42 (m, 2H), 6.51 (d, 1H, J=8.8 Hz), 5.42 (s, 2H), 3.26 (sept, 1H, J=7.0 Hz), 2.71 (s, 3H), 1.43 (d, 6H, J=7.0 Hz).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]1[C:11]([Cl:12])=[C:10]([C:13]2[O:17][N:16]=[C:15]([CH2:18][OH:19])[C:14]=2[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2Cl)=[O:21])[N:9]=[N:8]1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>CCOC(C)=O>[F:36][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:31]=1)[CH2:6][N:7]1[C:11]([Cl:12])=[C:10]([C:13]2[O:17][N:16]=[C:15]([CH2:18][OH:19])[C:14]=2[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[O:21])[N:9]=[N:8]1
Reactant: C1COCCN1
Reactant: O=C(c1ccccc1Cl)c1c(CO)noc1-c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1Cl
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1N1CCOCC1)c1c(CO)noc1-c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1Cl
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Dissolve {5-[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-3-hydroxymethyl-isoxazol-4-yl}-(2-chloro-phenyl)-methanone (0.10 g, 018 mmol) in morpholine (1.0 mL) and stir at 80° C. for 20 hours. Dilute the solution with EtOAc (25 mL) and wash with 1N HCl (20 mL), water (20 mL), and saturated NaHCO3 (20 mL) then dry, filter, and concentrate. Purify the crude material by flash chromatography to give the title compound: MS (IS) 615.9 (M+1), MS (ES−) 613.9 (M−1): 1HNMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.74 (s, 2H), 7.45 (dd, 1H, J=1.4, 7.5), 6.93 (dt, 1H, J=1.5, 7.4), 6.83 (dt, 1H, J=1.0, 7.4), 6.40 (m, 1H), 5.42 (s, 2H), 4.85 (d, 2H, J=7.3), 3.80 (t, 1H, J=7.3), 3.44 (m, 4H), 2.64 (m, 4H).
Reaction SMILES: [CH:1]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:9][CH2:10][C:11](O)=[O:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[SH:9][CH2:10][C:11]([O:8][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:12]
Reactant: OC1CCCCCC1
Reactant: O=C(O)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(CS)OC1CCCCCC1

Procedure:
Into a 100 ml reaction flask equipped with stirrer, thermometer, reflux condenser and heating mantle are placed 28.5 grams of cycloheptanol; 9.2 grams of mercaptoacetic acid and 0.5 grams of paratoluene sulfonic acid. The reaction mass is heated to reflux and refluxed for a period of 10 hours. At the end of the 10 hour period, the reaction mass is washed with one 25 ml volume of water followed by drying over anhydrous sodium sulfate. The reaction mass is then distilled in a micro distillation apparatus yielding the compound having the structure ##STR115##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[O:16][C:15]3[CH:21]=[CH:22][N:23]=[CH:24][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[O:8]C.B(Br)(Br)Br>>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][C:17]([CH3:19])([CH3:20])[O:16][C:15]3[CH:21]=[CH:22][N:23]=[CH:24][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[OH:8]
Reactant: COc1c(Br)cc(C(=O)N2CC(C)(C)Oc3ccncc32)cc1Br
Agent: BrB(Br)Br
Product: CC1(C)CN(C(=O)c2cc(Br)c(O)c(Br)c2)c2cnccc2O1
Yield: 49.8 %

Procedure:
By the same method as in Example 6, (3,5-dibromo-4-methoxy-phenyl)-(2,2-dimethyl-2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone (70 mg, 0.15 mmol) was reacted with 1M solution of boron tribromide (0.9 ml, excess amount) to obtain the target compound 9, (3,5-dibromo-4-hydroxy-phenyl)-(2,2-dimethyl-2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone (33 mg, 49%).
Reaction SMILES: C(OC(=O)CN1C2C=CC=CC=2NC[C@H](NC(OC(C)(C)C)=O)C1=O)C1C=CC=CC=1.O=C1N(CC(O)=O)C2C=CC=CC=2N(C(=O)C)CC1NC(=O)C1C=CC=CC=1.[O:60]=[C:61]1[N:67]([CH2:68][C:69]([NH:71][C@H:72]2[CH2:76][C:75](=[O:77])[O:74][CH:73]2[O:78][CH2:79][C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)=[O:70])[C:66]2[CH:86]=[CH:87][CH:88]=[CH:89][C:65]=2[N:64]([C:90](=[O:94])[CH2:91][O:92]C)[CH2:63][C@@H:62]1[NH:95][C:96](=[O:106])[C:97]1[CH:102]=[C:101]([Cl:103])[C:100]([OH:104])=[C:99]([Cl:105])[CH:98]=1>>[O:60]=[C:61]1[N:67]([CH2:68][C:69]([NH:71][C@H:72]2[CH2:76][C:75](=[O:77])[O:74][CH:73]2[O:78][CH2:79][C:80]2[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=2)=[O:70])[C:66]2[CH:86]=[CH:87][CH:88]=[CH:89][C:65]=2[N:64]([C:90](=[O:94])[CH2:91][OH:92])[CH2:63][C@@H:62]1[NH:95][C:96](=[O:106])[C:97]1[CH:98]=[C:99]([Cl:105])[C:100]([OH:104])=[C:101]([Cl:103])[CH:102]=1
Reactant: COCC(=O)N1C[C@H](NC(=O)c2cc(Cl)c(O)c(Cl)c2)C(=O)N(CC(=O)N[C@H]2CC(=O)OC2OCc2ccccc2)c2ccccc21
Agent: CC(=O)N1CC(NC(=O)c2ccccc2)C(=O)N(CC(=O)O)c2ccccc21
Agent: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Product: O=C(CN1C(=O)[C@@H](NC(=O)c2cc(Cl)c(O)c(Cl)c2)CN(C(=O)CO)c2ccccc21)N[C@H]1CC(=O)OC1OCc1ccccc1

Procedure:
was synthesized from 600b via methods used to prepare 661 from 600b, excluding steps used to make 604d from 603d, using instead the method to prepare 688a from 678a to afford 854 mg of 692a, 1H NMR (CD3OD) δ2.45(d, 1H), 2.6(m, 1H), 2.7(m, 1H), 3.0(m, 1H), 3.5-3.7(m, 4H), 4.0(q, 2H), 4.45(m,3H), 4.55(m, 4H), 5.35(s, 1H), 5.6(d, 1H), 7.2-7.5(m, 9H), 7.85(s, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][CH:8]=[O:9])[CH:4]=[C:3]1[C:10]([OH:12])=O.S(Cl)([Cl:15])=O>C1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][CH:8]=[O:9])[CH:4]=[C:3]1[C:10]([Cl:15])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: Cn1cc(NC=O)cc1C(=O)O
Solvent: c1ccccc1
Product: Cn1cc(NC=O)cc1C(=O)Cl

Procedure:
A suspension of 1-methyl-4-formylamino-2-pyrrolecarboxylic acid (V) in benzene is heated at 80° C. in presence of an excess of thionyl chloride until a solution is obtained. The reaction is then stopped. By repeatedly evaporating from benzene at reduced pressure and temperature, there is obtained the crude chloride (II) which is stocked and used without further purification following determination of the title (generally not below 60%) by conversion to an ester and quantitative analysis of the resulting ester derivative. IR: 1740 cm−1.