Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH:13](=[N:20][O:21][CH2:22][CH2:23][OH:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O[C:26]1[CH:58]=[CH:57][C:29]([CH2:30][CH:31]2[S:35][C:34](=[O:36])[N:33]([C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]2=[O:56])=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:13](=[N:20][O:21][CH2:22][CH2:23][O:24][C:26]1[CH:58]=[CH:57][C:29]([CH2:30][CH:31]2[S:35][C:34](=[O:36])[N:33]([C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]2=[O:56])=[CH:28][CH:27]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCON=Cc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1SC(Cc2ccc(OCCON=Cc3ccccc3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.3 %

Procedure:
A solution of 450 mg of diethyl azodicarboxylate in 4 ml of tetrahydrofuran was added dropwise at room temperature to a solution of 383 mg of 2-(benzylideneaminooxy)ethanol (prepared as described in Preparation 1), 1.00 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione and 629 mg of triphenylphosphine in 10 ml of tetrahydrofuran, and the resulting mixture was stirred at room temperature for 16 hours. At the end of this time, the reaction product was purified by column chromatography through silica gel, using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.53 g of the title compound as a gum.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20](Br)[CH:21]=2)[N:16]=1.[Cl-].[NH4+]>CCCCC.C1COCC1.[Cl-].[Zn+2].[Cl-]>[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)[CH:21]=2)[N:16]=1
Reactant: Brc1cccnc1
Reactant: COc1ccc2cc(Br)ccc2n1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc2cc(-c3cccnc3)ccc2n1
Temperature: 25 °C

Procedure:
t-Butyl lithium (7.7 cm3 of a 2.6M solution in pentane) was added dropwise over 5 minutes to a stirred solution of 3-bromopyridine (1.44 cm3) in THF (25 cm3) at -100° under nitrogen. After stirring for 10 minutes a solution of anhydrous zinc chloride (2.05 g) in THF (20 cm3) was added slowly and the mixture was allowed to warm to room temperature over 1 hour. A solution of 2-methoxy-6-bromoquinoline (2.38 g) and tetrakis-(triphenylphosphine)palladium(O) (0.08 g) in THF (10 cm3) was added and the mixture was heated under reflux for 9 hours. Ammonium chloride solution (20 cm3) was then added, the mixture was concentrated in vacuo, and the aqueous phase extracted with chloroform (3×50 cm3). The dried (MgSO4) extracts were evaporated in vacuo to give a solid which was chromatographed on silica (Merck "MK. 60.9385") eluting with ethyl acetate:hexane, 1:1, to afford a residue which was recrystallised from petroleum ether (b.p. 60°-80°)-ether to afford 2-methoxy-6-(3-pyridyl)quinoline, m.p. 89°-91°, (0.35 g).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[BH4-].[Na+].Cl.S(Cl)(Cl)=O.[Cl-].[C-:29]#[N:30].[Na+]>O.C(O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[CH2:4][C:29]#[N:30]
Reactant: [C-]#N
Reactant: O=Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: N#CCc1ccc(Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of the compound from Example 25, (20.9 g., 0.067 mole) in 125 ml. of absolute ethanol was added 0.79 g. (0.021 mole) of NaBH4. The mixture was stirred for 20 minutes at room temperature. The reaction mixture was diluted by careful addition of water and was then acidified with dilute HCl. The ethanol was evaporated under reduced pressure and the aqueous residue was extracted with methylene chloride. The organic solution was washed with brine, dried over Na2SO4 and evaporated to provide 20 g. of benzylic alcohol. This alcohol (20 g., 0.064 mole) was dissolved in 150 ml. of chloroform and 18.7 ml. of thionyl chloride was added. After the solution had been stirred for 5 hours at room temperature, the solvent was evaporated to give 21.1 g. of benzylic chloride. NMR (CDCl3): 4.70 (2H, s, ArCH2Cl). This chloride (21.1 g., 0.064 mole) was dissolved in 150 ml. of 95% ethanol and a solution of NaCN (3.74 g., 0.076 mole) in 25 ml. of water was added. The mixture was refluxed for 8 hours. The ethanol was evaporated and the aqueous residue was extracted with methylene chloride. The organic extract was washed with brine, dried over Na2SO4 and evaporated. The crude product was quickly passed through a short silica gel column using methylene chloride as the solvent. The desired product (16.6 g.) was obtained as a yellow solid. NMR (CDCl3): 3.93 (2H, s, ArCH2CN); IR (CHCl3) 2250 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].Cl.[NH2:12][OH:13].CC(C)([O-])C.[K+].O>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[NH:12][OH:13])=[CH:4][C:3]=1[CH3:10]
Reactant: NO
Reactant: Cc1cc(C#N)ccc1Br
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=N)NO)ccc1Br
Reaction time: 0.5 h
Yield: 309.2 %

Procedure:
A solution of 4-bromo-3-methylbenzonitrile (20.0 g) in methanol (100 ml) was treated with hydroxylamine hydrochloride (4×2.08 g) and potassium t-butoxide (4×3.25 g) over 6 hours and the resulting mixture heated at reflux for 18 h. After cooling, the reaction mixture was poured into water (800 ml), the suspension stirred for 30 min, and the white solid filtered off and dried in vacuo to give the title compound (21.2 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:22]1[CH:23]=[CH:24][C:25]([F:29])=[C:26]([CH3:28])[CH:27]=1>>[F:29][C:25]1[CH:24]=[CH:23][C:22]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][C:2]([CH3:20])([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)=[CH:27][C:26]=1[CH3:28]
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Reactant: Cc1cc(Br)ccc1F
Product: Cc1cc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)ccc1F
Yield: 60.4 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (311 mg, 1.0 mmol) synthesized in Reference example 61 and 5-bromo-2-fluorotoluene (0.191 mL, 1.5 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 231 mg (yield 60%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][CH:23](C(OC)=O)[C:24]([O:26][CH3:27])=[O:25])[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(Cc1coc(-c2ccc(OC)c(OCc3ccccc3)c2)n1)C(=O)OC
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CCc1coc(-c2ccc(OC)c(OCc3ccccc3)c2)n1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
A 26.52 g quantity of the dimethyl 2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]malonate obtained in Reference Example 47 was suspended in 53 ml of dimethyl sulfoxide, and 2.62 g of lithium chloride and 1.12 ml of purified water were added. The mixture was stirred at 130° C. for 4 hours. After the reaction mixture was allowed to cool, water was added and extraction with ethyl acetate was performed. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give 16 g of white powdery methyl 3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]propionate.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:39][C:38]([NH2:40])=[N:37][C:36]=1[CH3:41])(=[O:34])=[O:33])([CH3:30])[CH3:29]>>[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:39][C:38]([NH:40][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])=[N:37][C:36]=1[CH3:41])(=[O:34])=[O:33])([CH3:30])[CH3:29]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(C)(C)CO
Product: Cc1nc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to general procedure II. Yellow solid. MS (ISP) 603.0 [(M−H)−]; mp 268° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:7]=1[Cl:8].O.[NH2:17][NH2:18]>C(O)C(C)C>[Cl:8][C:7]1[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:5][N:4]=[N:3][C:2]=1[NH:17][NH2:18]
Reactant: NN
Reactant: Clc1ccc(-c2cnnc(Cl)c2Cl)cc1
Solvent: O
Solvent: CC(C)CO
Product: NNc1nncc(-c2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.8 %

Procedure:
3,4-Dichloro-5-(4-chlorophenyl)-pyridazine (6.0 g, 23.1 mmol) was suspended in isobutanol (150 mL) at 0° C. and hydrazine monohydrate (11.1 g) was added dropwise over 10 min. The reaction mixture was slowly warmed up to RT and stirred for 24 h. The mixture was cooled in an ice/water bath for 15 min and filtered. The white solid thus obtained was washed with cold isopropanol and dried to give the title compound, 1-[4-chloro-5-(4-chloro-phenyl)-pyridazin-3-yl]-hydrazine, (5.0 g) as a white solid. HPLC: 1.65 min.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C@@H:16]([OH:26])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[Cl-].[CH2:34]([NH+:41]1[CH2:45][CH2:44][CH2:43][CH:42]1[CH2:46]Cl)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[CH2:34]([N:41]1[CH2:45][CH2:44][CH2:43][CH:42]1[CH2:46][O:26][C@H:16]1[CH2:15][N:14]2[C:13]3[CH:12]=[C:11]([C:27]([O:29][CH3:30])=[O:28])[CH:10]=[CH:9][C:8]=3[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:21]2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: ClCC1CCC[NH+]1Cc1ccccc1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](O)COc1ccccc1-3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](OCC1CCCN1Cc1ccccc1)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Methyl (7S)-14-cyclohexyl-7-hydroxy-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (prepared as described in International patent application WO2006/046030) in toluene (0.17 M) was treated with 30% NaOH (aq) (10 eq) and tetrabutylammonium bromide (0.25 eq). The solution was stirred at RT for 30 min, then 1-benzyl-2-(chloromethyl)pyrrolidinium chloride (2.5 eq) was added to the solution and the resulting mixture was stirred at 60° C. over night. Toluene was eliminated in vacuo; the residue was taken up in EtOAc and washed with 1 N HCl (aq), brine, before being dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by FC (PE/EtOAc 50:50+1% NEt3) to afford the product (80%). (ES+) m/z 579 (M+H)+
Reaction SMILES: [C:1]([C:4](CC(O)=S)=[S:5])(=[O:3])[NH2:2].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[NH2:15]>C(O)C.O>[C:1]([C:4]([NH:15][C:14]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:12]([O:11][CH3:10])[CH:13]=1)=[S:5])(=[O:3])[NH2:2]
Reactant: COc1ccc(N)cc1OC
Reactant: NC(=O)C(=S)CC(O)=S
Solvent: CCO
Solvent: O
Product: COc1ccc(NC(=S)C(N)=O)cc1OC
Reaction time: 2 h

Procedure:
The solution of carbamoyl-thiocarbonyl thioacetic acid prepared above was added to a solution of 3,4-dimethoxy-aniline (20 g) in ethanol (100 ml) and water (100 ml). The mixture was allowed to stand in a sealed vessel for 2 hr. The ethanol was evaporated under reduced pressure until crystallisation occurred. The product was collected by filtration, washed with cold ethanol, and dried to give N-(carbamoyl-thiocarbonyl-)-3,4-dimethoxyaniline (14.13 g); m.p. 149°-151° C.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1C(N)=O.[C:13]1(=[O:20])[CH2:18][CH2:17][CH2:16][C:15](=O)[CH2:14]1.[C:21]1([NH:27][NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.NN>O.C(O)C>[C:21]1([NH:27][N:28]=[C:18]2[C:13](=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCCC(=O)C1
Reactant: NNc1ccccc1
Agent: NC(=O)c1cc2ccccc2[nH]1
Agent: NN
Solvent: O
Solvent: CCO
Product: O=C1CCCCC1=NNc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83386.8 %

Procedure:
The title compound was prepared by a modification of published procedures (M. S. Berridge et al., Nucl. Med. Biol. 19 (5) 563-569 (1992); Brueckner R. et al., EP 1 424 337 A1 (2004)). To a stirred suspension of cyclohexane-1,3-dione (10 g, 0.089 mol) in water (64 mL) under nitrogen was added via dropping funnel 10-15 drops of a solution of phenylhydrazine (8.8 mL, 0.089 mmol) in water (124 mL). The mixture was stirred for 15 minutes at room temperature and then the remainder of the phenylhydrazine solution was added dropwise over a 4 hour period. Ethanol (21 mL) was added to facilitate stirring after about 30 mL of the hydrazine solution had been added. Stirring was continued for an additional 30 minutes. The orange solid was collected by filtration, washed with water and a small amount of 3:1 (v/v) water-ethanol, and dried in vacuo overnight to provide the title compound (15.01 g, 83.3%). MS (ES): [M+H]+ @m/z 203.1
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[N:3]=1.[NH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1.CC(O)C.Cl>O>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([C:4]2[N:3]=[C:2]([NH:21][C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=3)[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: N#Cc1ccc(N)cc1
Reactant: COc1ccc(-c2cc3nccn3c(Cl)n2)cc1OC
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(-c2cc3nccn3c(Nc3ccc(C#N)cc3)n2)cc1OC
Temperature: 87.5 °C
Reaction time: 8 h

Procedure:
To the suspension of 5-chloro-7-(3,4-dimethoxyphenyl)imidazo[1,2-c]pyrimidine (57.94 mg, 0.2 mmol) and 4-aminobenzonitrile (35.44 mg, 0.3 mmol) in the mixture of 2.5 ml 2-propanol and 1.5 ml H2O was added conc.HCl. Then the mixture was stirred at 85 to 90° C. overnight, and cooled to room temperature. The produced solid was collected by filtration and purified by preparative TLC to give the desired product of 4-[7-(3,4-dimethoxy-phenyl)-imidazo[1,2-c]pyrimidin-5-ylamino]-benzonitrile. (38 mg, 51.2%).
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[O:11][CH2:12][CH2:13][C:3]=12.[OH:14][C@@:15]1([CH3:30])[C@@H:20]([CH3:21])[CH2:19][NH:18][CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>CCO>[OH:14][C@@:15]1([CH3:30])[C@@H:20]([CH3:21])[CH2:19][N:18]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[O:11][CH2:12][CH2:13][C:3]=23)[CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: O=[N+]([O-])c1cnc2c(c1I)CCO2
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@@]1(C)O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2c([N+](=O)[O-])cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@]1(C)O
Temperature: 110 °C
Reaction time: 12 h
Yield: 69.4 %

Procedure:
To a vial containing 4-iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine (76 mg, 0.26 mmol) and tert-butyl [(3R,4S,5S)-4-hydroxy-4,5-dimethylpiperidin-3-yl]carbamate (60 mg, 0.24 mmol), EtOH was added (2.0 mL), followed by DIPEA (114 mg, 0.883 mmol). The mixture was stirred at 110° C. for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a yellow foamy solid (68 mg, 69%). LCMS calc. for C19H29N4O6 (M+H)+: m/z=409.2. found 409.0.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1>O1CCCC1.C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[N:1][N:2]2[CH:6]=[N:5][CH:4]=[N:3]2)=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Nn1cncn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1ccc(C=Nn2cncn2)cc1
Yield: 68.3 %

Procedure:
A solution of 42.3 g (0.377 mol) of 75% pure 1-amino-1H-1,2,4-triazole, 40.0 mL (0.372 mol) of 4-fluorobenzaldehyde and 2.0 g of p-toluenesulfonic acid in 600 mL of tetrahydrofuran was stirred at room temperature for 21/2 days. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous Na2CO3, water and brine and dried (MgSO4). Removal of solvent gave a white solid which was recrystallized from n-butylchloride to afford 48.3 g (67%) of desired product as white needles; mp 118°-120° C. Concentration of the filtrate and recrystallization of the residue afforded 12.8 g (18%) more of product; mp 118°-120° C.
Reaction SMILES: [Br:1]NC(=O)CCC(N)=O.[N+:10]([C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[CH:15][CH:14]=1)([O-:12])=[O:11]>O1CCCC1>[Br:1][C:17]1[C:16]2[C:20](=[CH:21][C:13]([N+:10]([O-:12])=[O:11])=[CH:14][CH:15]=2)[NH:19][CH:18]=1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: NC(=O)CCC(=O)NBr
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(Br)c[nH]c2c1
Reaction time: 18 h
Yield: 86 %

Procedure:
Add N-bromosuccinamide (NBS) to 6-nitroindole 1 (22.72 g, 140.12 mmol) dissolved in tetrahydrofuran (600 mL) and allow the resulting mixture to stir for 18 hours. Quench the reaction mixture with saturated aqueous sodium thiosulfate solution (600 mL), dilute with ethyl acetate (EtOAc) (600 mL), and separate the layers. Sequentially, wash the organic layer with saturated aqueous sodium bisulfate (100 mL), saturated aqueous sodium bicarbonate (100 mL), water (100 mL), and brine (100 mL). Dry the resulting organic layer over Na2SO4 and filter. Concentrate the filtrate to give a yellow solid. Recrystallize the solid from dichloromethane and hexane to give 29.21 g of the title compound (86%). LRMS (API ES+)=263.0 (M+Na).
Reaction SMILES: [Si]([O:8][C@H:9]1[C@@H:13]([O:14][Si](C(C)(C)C)(C)C)[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:23]2=[O:38])[O:11][CH:10]1[C@H:39]([OH:71])[C@@H:40]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[NH:41][CH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:63])[C@H:47]([CH2:59][CH:60]([CH3:62])[CH3:61])[NH:48][C:49](=[O:58])[O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[C@@H:13]([OH:14])[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[C:23]2=[O:38])[O:11][CH:10]1[C@H:39]([OH:71])[C@@H:40]([C:64]([O:66][C:67]([CH3:68])([CH3:70])[CH3:69])=[O:65])[NH:41][CH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:63])[C@H:47]([CH2:59][CH:60]([CH3:61])[CH3:62])[NH:48][C:49](=[O:58])[O:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@H](CC(C)C)NC(=O)OCc4ccccc4)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@H](CC(C)C)NC(=O)OCc4ccccc4)C(=O)OC(C)(C)C)[C@@H](O)[C@H]3O)c2=O)cc1
Yield: 71.1 %

Procedure:
By using an analogous procedure to that described for Example 44, tert-butyl (5S,12S)-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-isobutyl-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (100 mg, 0.097 mmol, obtained from Example 4) and tetrabutylammonium fluoride 0.292 ml, 0.292 mmol) were stirred in tetrahydrofuran (1 ml) under nitrogen for 2.5 hours at room temperature. The residue was chromatographed (flash column, silica gel, 6.5% methanol in methylene chloride) to provide tert-butyl (5S,12S)-12-[(R)-[(3S,4R,5R)-3,4-dihydroxy-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-isobutyl-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (55 mg, 71%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:18])[NH:16][CH3:17])=[CH:11][CH:10]=2)[C:6]([C:19]([O:21][CH3:22])=[O:20])=[CH:5][C:4]=1[N+:23]([O-])=O>[Pd].CO>[NH2:23][C:4]1[CH:5]=[C:6]([C:19]([O:21][CH3:22])=[O:20])[C:7]([C:9]2[CH:10]=[CH:11][C:12]([C:15](=[O:18])[NH:16][CH3:17])=[CH:13][CH:14]=2)=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: CNC(=O)c1ccc(-c2cc(OC)c([N+](=O)[O-])cc2C(=O)OC)cc1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1ccc(-c2cc(OC)c(N)cc2C(=O)OC)cc1

Procedure:
The mixture of methyl 5-methoxy-4′-(methylcarbamoyl)-4-nitrobiphenyl-2-carboxylate (Step 1, 275 mg, 0.75 mmol), Pd (10% wt on active carbon, 27 mg) and MeOH (20 mL) is evacuated to remove air and then the reaction is stirred under a hydrogen balloon until the starting material is consumed. Pd/C is filtered off and the filtrate is concentrated in vacuo to afford Methyl 4-amino-5-methoxy-4′-(methylcarbamoyl)biphenyl-2-carboxylate; ESMS m/z 315.1 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[CH:6][C:5]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[OH-].[Na+]>C(O)C.O>[Cl:26][C:21]1[CH:20]=[C:19]([C:13]2([C:15]([F:17])([F:16])[F:18])[O:12][N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:33])=[O:2])=[C:5]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:6]=3)[CH2:14]2)[CH:24]=[C:23]([Cl:25])[CH:22]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1-c1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
In a solution of 0.78 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-phenyl benzoic acid methyl ester in 15 ml of ethanol, a solution of 0.30 g of sodium hydroxide in 15 ml of water was added, and stirred at 60° C. for 3 hours. After the completion of the reaction, ethanol was distilled off under reduced pressure, adjusted to pH 1 to 2 with 12N hydrochloric acid, and then extracted with ethyl acetate (50 ml×1). The organic phase was washed with water, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 0.70 g of the aimed product as brown glass substance. The resulting product was used as such without purification for the next step.