Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:25])[C@:5]1([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])C.[Li+].[OH-].C1COCC1.CO>O>[C:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][CH2:9][C@@:5]1([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1)[C:4]([OH:25])=[O:3])=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: CCOC(=O)[C@]1(Cc2ccc(Br)cc2)CCCN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@]1(Cc1ccc(Br)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 108 %

Procedure:
A mixture of N-(tert-butoxycarbonyl)-2-(4-bromobenzyl)proline ethyl ester (3.00 g), LiOH (10 mmol), THF (25 mL), MeOH (10 mL) and H2O (5 mL) was stirred at room temperature overnight. The mixture was then heated at 74° C. overnight. The mixture was concentrated in vacuo, and water was added. The mixture was washed with Et2O and the aqueous layer was made acidic with the addition of 1N H2SO4. The aqueous layer was extracted with EtOAc. The EtOAc layer was washed with brine, dried over Na2SO4, and evaporated to give N-(tert-butoxycarbonyl)-2-(4-bromobenzyl)proline (3.02 g). MS (m/z) 284 (MH+-t-Boc); mp: 143.9° C.
Reaction SMILES: [CH3:1][CH2:2][OH:3].[F:4][C:5]([F:12])([F:11])[C:6]([F:10])=[C:7]([F:9])[F:8]>>[F:8][C:7]([F:9])([CH:6]([F:10])[C:5]([F:12])([F:11])[F:4])[CH:2]([OH:3])[CH3:1]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: CCO
Product: CC(O)C(F)(F)C(F)C(F)(F)F
Reaction time: 16 h
Yield: 95.6 %

Procedure:
A quantity of 3,3,4,5,5,5-hexafluoropentan-2-ol was prepared by combining absolute ethanol 200 proof (100 g, 2.17 moles, AAPER Alcohol and Chemical Co.) with t-amyl peroxy-2-ethylhexanoate (5 g, 0.021 moles) (available as Luperox 575 from Arkema, Oakville, Ontario, Canada) in a 600 mL Parr pressure reactor. The reactor was heated to 75 C and hexafluoropropene (120 g, 0.8 moles) (MDA Manufacturing Inc., Decatur, Ala.) was added at a constant rate. The reactor was allowed to stir at this temperature for 16 h. The crude reaction material was distilled using a ten plate Oldershaw column to afford 150 g of 3,3,4,5,5,5-hexafluoropentan-2-ol (b.p.=121° C.).
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:10][CH:11]2[CH:14]([N:15]=1)[C:13](=[O:16])[NH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:20])[CH:18]=[O:19]>C1C=CC=CC=1>[CH2:22]([O:21][C:17]([CH:18]([N:12]1[CH:11]2[CH:14]([N:15]=[C:9]([CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[S:10]2)[C:13]1=[O:16])[OH:19])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1NC2SC(COc3ccccc3)=NC12
Reactant: O=CC(=O)OCc1ccccc1
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)C(O)N1C(=O)C2N=C(COc3ccccc3)SC21
Temperature: 25 °C
Yield: 514.1 %

Procedure:
Into a 500 ml. flask equipped with a Dean-Stark condenser filled with Molecular Sieves 3A (Trade Name, manufactured by Nakarai Chemicals Ltd.) were charged with 3-phenoxymethyl-6-oxo-2-thia-4,7-diazabicyclo[3,2,0]hept-3-ene (995 mg.), benzyl glyoxylate (6.2 g.) and benzene (80 ml.). The mixture was heated under reflux for 3.5 hours. After benzene (40 ml.) was distilled off, the resultant solution was cooled to room temperature, and 25% aqueous solution of sodium bisulfite (150 ml.) was added thereto. The mixture was stirred for half an hour, and the precipitate was filtered off and washed with benzene. The organic layer was separated and washed twice with water (50 ml.) and twice with an aqueous solution of sodium chloride (150 ml.). Drying over magnesium sulfate and removal of the solvent gave an oil (8.7 g.) of 7-(benzyloxycarbonyl-1-hydroxymethyl)-3-phenoxymethyl-6-oxo-2-thia-4,7-diazabicyclo[3,2,0]hept-3-ene.
Reaction SMILES: CO[C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3([CH3:19])[O:18]CCO3)[CH:12]=2)[N:7]([CH2:20][CH3:21])[C:6]1=[O:22])=[O:4].[NH2:23][C:24]1[CH:25]=[C:26]([CH:37]=[CH:38][CH:39]=1)[C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1)=[O:28]>>[F:36][C:32]1[CH:31]=[C:30]([NH:29][C:27]([C:26]2[CH:25]=[C:24]([NH:23][C:3]([CH:5]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([C:14](=[O:18])[CH3:19])[CH:12]=4)[N:7]([CH2:20][CH3:21])[C:6]3=[O:22])=[O:4])[CH:39]=[CH:38][CH:37]=2)=[O:28])[CH:35]=[CH:34][CH:33]=1
Reactant: CCN1C(=O)C(C(=O)OC)c2cc(C3(C)OCCO3)ccc21
Reactant: Nc1cccc(C(=O)Nc2cccc(F)c2)c1
Product: CCN1C(=O)C(C(=O)Nc2cccc(C(=O)Nc3cccc(F)c3)c2)c2cc(C(C)=O)ccc21

Procedure:
Prepared as in Example 1 from 1-ethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid methyl ester and 3-amino-N-(3-fluoro-phenyl)-benzamide. 1H NMR (CDCl3) δ 1.25 (t, 3 H), 2.6 (s, 3 H), 3.85 (q, 2 H), 4.45 (s, 1 H), 6.85-8.05 (m, 11 H), 8.3 (s, 1 H), 9.65 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:26])[CH:3]=1.[CH3:27][C:28]1([CH3:34])[O:32][C:31](=[O:33])[NH:30][CH2:29]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:30]5[CH2:29][C:28]([CH3:34])([CH3:27])[O:32][C:31]5=[O:33])=[CH:3][C:4]=4[F:26])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: CC1(C)CNC(=O)O1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CC(C)(C)OC3=O)cc2F)CC1
Yield: 22.9 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-fluorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (480 mg) described in Preparation Example 86 and 5,5-dimethyloxazolidin-2-one (196 mg) described in Preparation Example 43, the title compound (119 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([C:8]23[CH2:13][CH:12]2[CH2:11][O:10][C:9]3=[O:14])[CH:7]=1.[NH3:16]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([C:8]2([C:9]([NH2:16])=[O:14])[CH2:13][CH:12]2[CH2:11][OH:10])[CH:7]=1
Reactant: N
Reactant: O=C1OCC2CC12c1cc(Br)ccc1F
Solvent: C1COCCO1
Product: NC(=O)C1(c2cc(Br)ccc2F)CC1CO
Temperature: 23 °C
Reaction time: 48 h

Procedure:
To a suspension of (1SR,5RS)-1-(5-bromo-2-fluoro-phenyl)-3-oxa-bicyclo[3.1.0]hexan-2-one (intermediate B5A) (4.6 g, 17 mmol) in dioxane (20 ml) at 23° C. was added ammonia (7 M in MeOH, 40 ml) and the mixture was stirred at 23° C. for 2 days (not complete). Evaporated all volatiles and directly subjected to silica gel chromatography with n-heptane/ethyl acetate to give recovered starting material (0.98 g, 21%) and the title compound as a white solid (3.5 g, 72%). MS (ISP): m/z=287.9 [(M+H)+] and 290.0 [(M+2+H)+].
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:3]=1.[CH2:21]([N:23]1[CH2:28][CH2:27][P:26]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[C:32]([O:37][CH3:38])[CH:31]=2)(=[O:29])[CH2:25][CH2:24]1)[CH3:22].Cl>COCCO.C(O)C>[CH2:21]([N:23]1[CH2:28][CH2:27][P:26]([C:30]2[CH:36]=[CH:35][C:33]([NH:34][C:2]3[N:7]=[N:6][CH:5]=[C:4]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:3]=3)=[C:32]([O:37][CH3:38])[CH:31]=2)(=[O:29])[CH2:25][CH2:24]1)[CH3:22]
Reactant: CCN1CCP(=O)(c2ccc(N)c(OC)c2)CC1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cnnc(Cl)c1
Agent: Cl
Solvent: CCO
Solvent: COCCO
Product: CCN1CCP(=O)(c2ccc(Nc3cc(Nc4ccccc4S(=O)(=O)C(C)C)cnn3)c(OC)c2)CC1

Procedure:
To a solution of 6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridazin-4-amine (prepared in Example 73: 0.02 mmol) and 4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline (0.7 mmol) in 1 mL of 2-Methoxy ethanol, is added 1 mL of 2.5M HCl in Ethanol. The reaction mixture is heated in a sealed tube at 140 degree until formation of the desired compound. The reaction mixture is filtered through a syringe filter and can be purified by Prep-HPLC.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:2]1.[OH:25][CH2:26][CH2:27][NH2:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[OH:25][CH2:26][CH2:27][NH:28][C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:13]2[C:12]([CH3:24])=[CH:11][CH:10]=[C:9]([NH:8][C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)=[O:7])[CH:14]=2)=[CH:20][CH:19]=1)=[O:23]
Reactant: NCCO
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)NCCO)cc1
Yield: 92.1 %

Procedure:
5′-(3-Furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylic acid (30 mg, 0.093 mmol), 2-hydroxyethylamine (5.7 mg, 0.093 mmol), HATU (35.5 mg, 0.093 mmol), HOBT (12.6 mg, 0.093 mmol) and DIPEA (48 μl, 0.28 mmol) in DMF (2 ml) were stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (150 ml), washed with water (2×30 ml) and dried (magnesium sulphate). The solvent was evaporated under vacuum and the residue chromatographed on a silica flash column eluting with DCM/methanol/triethylamine (96:2:2). Concentration of the product fractions under vacuum gave N-(4′-{[(2-hydroxyethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-3-furamide (31.2 mg, 92%). NMR; δH [2H6]—DMSO 9.91,(1H, s), 8.49,(1H, t), 8.35,(1H, s), 7.92,(2H, d), 7.78,(1H, t), 7.67,(1H, dd), 7.59,(1H, d), 7.43,(2H, d), 7.27,(1H, d), 6.97,(1H, m), 4.73,(1H, t), 3.52,(2H, q), 3.35,(2H, m), 2.19,(3H, s). LCMS: retention time 2.72 min, MH+365.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]3[CH:15]=2)=[CH:4][CH:3]=1.[NH:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH2:20][C:19]1=[O:27].CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[K+].[K+]>[Cu]I>[N:8]1[C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([N:18]3[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[CH2:20][C:19]3=[O:27])=[CH:3][CH:4]=2)=[CH:15][N:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=12
Reactant: Brc1ccc(Oc2cn3ccccc3n2)cc1
Reactant: O=C1Cc2cccnc2N1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Product: O=C1Cc2cccnc2N1c1ccc(Oc2cn3ccccc3n2)cc1
Temperature: 180 °C
Yield: 17.2 %

Procedure:
Ethyl 2-chloroimidazo[1,2-a]pyridine-3-carboxylate (2.00 g) was added to a solution of p-bromophenol (1.617 g) and NaH (0.427 g) in DMF(dry) (10 ml) at 100° C. The mixture was stirred at 100° C. under a dry atmosphere overnight. The reaction mixture was diluted with MeOH, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-30% EtOAc in hexane) to give ethyl 2-(4-bromophenoxy)imidazo[1,2-a]pyridine-3-carboxylate (1.5 g) as a colorless solid and 2-(4-bromophenoxy)imidazo[1,2-a]pyridine (530 mg) as a colorless solid. The mixture of 2-(4-bromophenoxy)imidazo[1,2-a]pyridine (410 mg), 1,3-dihydro-2H-pyrrolo[2,3-b]pyridine-2-one (164 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (174 mg), copper(I) iodide (116 mg), K2CO3 (338 mg) and THF(dry) (5 mL) was heated at 180° C. for 3 h under microwave irradiation. The solid was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound (72 mg) as an orange solid (mixture with 1,3-dihydro-2H-pyrrolo[2,3-b]pyridine-2-one, ca. 20% purity).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[N:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][C:25]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:26])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)N1CCOCC1

Procedure:
The title compound was prepared from 4-(4-trifluoromethyl-phenoxy)-phenol and morpholine-4-carbonyl chloride. The crude product was purified by preparative HPLC (74%, white crystals). HPLC-MS m/z=368.1 (M+1), Rt: 4.85 min.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH2:14][CH:15]([NH2:17])[CH3:16].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Br:31]Br>ClCCl>[ClH:1].[Br:31][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH3:2])=[C:5]([CH2:14][CH:15]([NH2:17])[CH3:16])[CH:6]=1
Reactant: COc1c(CC(C)N)ccc2ccccc12
Reactant: BrBr
Agent: Cl
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1c(CC(C)N)cc(Br)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the product from Example 4 (1.2 g, 4.78 mmol) and TEA (0.97 g, 9.56 mmol) in dichloromethane (100 ml) at 0° C. was added trifluoroacetic anhydride (1.2 g, 5.74 mmol). The reaction mixture was stirred at 0° C. for 1 h and evaporated to a residue, which was filtered through silica (ethyl acetate/hexane: 2/8). The fractions containing the protected amine were combined and concentrated to a residue that was dissolved in acetic acid (5 mL) and cooled to 0° C. Bromine (0.91 g, 5.74 mmol) was added and the reaction mixture stirred at this temperature for 30 min. The solid that formed was collected by filtration and dissolved in a mixture of methanol in water (1:1, 20 mL). To this solution was added 1 N aqueous sodium hydroxide (3 mL) and the mixture was stirred at room temperature overnight. Volatiles were evaporated and the desired compound was extracted with dichloromethane and transformed to hydrochloride salt, which was recrystallized from methanol-diethyl ether. Analysis. Calcd. for C14H16BrNO.HCl.0.2 CH3OH: C, 65.39; H, 7.21; N, 5.56. Found: C, 65.16; H, 7.07; N, 5.42.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)=[N:22][CH:23]=3)=[C:14]([F:37])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]>C(Cl)Cl.FC(F)(F)C(O)=O>[F:37][C:14]1[CH:13]=[C:12]([N:8]2[CH2:7][C@H:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[O:10][C:9]2=[O:11])[CH:17]=[CH:16][C:15]=1[C:18]1[CH:23]=[N:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)c(F)c2)C(=O)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(N4CCNCC4)nc3)c(F)c2)C(=O)O1
Yield: 97.5 %

Procedure:
A solution of tert-butyl 4-[5-(4-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2-fluorophenyl)-2-pyridinyl]-1-piperazinecarboxylate (0.191 g, 0.372 mmol) in DCM (10 mL) and trifluoroacetic acid (10 mL) was stirred at room temperature for 3 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc and 1 M NaOH solution. The organic layer was dried and evaporated to give the titled compound (0.150 g, 98%) as a colourless foam. APCI MS m/z 414 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.22 (t, J=5.8 Hz, 1H), 7.72 (bdt, J=9.0, 2.1 Hz, 1H), 7.52-7.60 (m, 2H), 7.38 (dd, J=8.6, 2.1 Hz, 1H), 6.89 (d, J=9.0 Hz, 1H), 4.72-4.80 (m, 1H), 4.16 (t, J=9.0 Hz, 1H), 3.78 (dd, J=9.1, 6.7 Hz, 1H), 3.41-3.51 (m, 6H), 2.80-2.85 (m, 4H), 1.84 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(N(CC)CC)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][NH:8][C:6]1[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=[C:2]([C:24]#[C:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:7]=1
Reactant: CC(C)(C)CNc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C#Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)CNc1nc(C#Cc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
Dissolve (6-chloro-3-nitropyridin-2-yl)-(2,2-dimethylpropyl)amine (7.3 g, 30.0 mmol), phenylacetylene (5.0 mL, 45 mmol) and triphenylphosphine (1.5 mmol, 0.39 g) in triethylamine (10 mL/g) in an oven-dried round bottom flask is flushed with nitrogen and evacuated three times. Add Pd(OAc)2 (0.10 g, 0.45 mmol) and the nitrogen flush/evacuation cycle is repeated (3×). Heat at 70-80° C. with stirring under nitrogen for 1-3 h, then cool at RT for 2 h. Concentrate and partition between water (25 mL) and EtOAc (150 mL). Separate the organic layer and wash with water (4×25 mL), saturated aqueous NaCl (25 mL), dry with MgSO4, filter, and concentrate. Purify the crude solid by recrystallization from EtOAc/hexanes to give the title product as a bright orange solid (6.5 g, 21.2 mmol, 71%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:3]=1.[N+:16]([O-])([OH:18])=[O:17].C(=O)([O-])O.[Na+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([N+:16]([O-:18])=[O:17])[CH:9]=2)[CH:3]=1
Reactant: COc1ccc(-c2cc(C)ccn2)cc1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COc1ccc(-c2cc(C)ccn2)cc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-(4-methylpyridin-2-yl)anisole (1.38 g) in sulfuric acid (3 ml) was added fuming nitric acid (0.5 ml) dropwise at 0° C., and the mixture was stirred at 5° C. for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The separated organic layer was washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 100 g, 0-5% methanol in dichloromethane) to give 4-(4-methylpyridin-2-yl)-2-nitroanisole (378 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[CH:6]2.[H-].[Na+].CI.[C:28](O)(=O)C(O)=O>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([CH3:28])([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[CH:6]2
Reactant: O=C(O)C(=O)O
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc2cc(OC)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc2cc(OC)ccc2c1

Procedure:
A mixture of 31.6 g. of diethyl 6-methoxy-2-naphthylmalonate, 2.4 g. of sodium hydride, and 350 ml. of methanol is stirred for one hour; then 24 g. of methyliodide are added and the resulting mixture is refluxed for two hours. The cooled mixture is neutralized with aqueous oxalic acid. The product, diethyl 6-methoxy-2-naphthyl-α-methylmalonate, is isolated, hydrolyzed, and decarboxylated by the means of the above described processes to give 6-methoxy-2-naphthyl-α-methylacetic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19](=[O:20])[N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[N:38](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:37]=[N:36][N:35]=4)=[CH:24][CH:23]=3)[C:17]([CH2:58][CH2:59][CH2:60][CH3:61])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19](=[O:20])[N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:35][N:36]=[N:37][N:38]=4)=[CH:24][CH:23]=3)[C:17]([CH2:58][CH2:59][CH2:60][CH3:61])=[N:16]2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1nn(-c2ccc(OCc3ccccc3)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCCCc1nn(-c2ccc(OCc3ccccc3)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 8 h
Yield: 43 %

Procedure:
Deprotection of 2-[4-(benzyloxy)phenyl]-5-n-butyl-2,4-dihydro-4-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one in 75% aqueous acetic acid was accomplished by the procedure of Example 5, Step C, except that the mixture was kept at 60° C. overnight. After work-up, the residue was flash chromatographed over silica gel (10 mL for 0.05 mmole; gradient elution with 2-5-10% methanol in CH2Cl2) to give a 43% yield of the title compound as a glassy solid, homogeneous by TLC in 10% MeOH/CH2Cl2 ; mass spectrum (FAB) m/e 558 (M+1)+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[S:17]([C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:19])=[O:18]>C(Cl)Cl>[CH2:1]([NH:8][S:17]([C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 12.6 %

Procedure:
To a solution of benzylamine 42 (0.140 mL, 1.278 mmol) in DCM (2.557 mL) was added triethylamine (0.535 mL, 3.84 mmol) and methyl 2-(chlorosulfonyl)benzoate 41 (300 mg, 1.278 mmol) and the resulting colorless solution was stirred at rt for 20 h. The reaction mixture was partitioned between DCM and H2O. The organic layer was washed with 1M HCl, saturated NaHCO3, and brine, dried over MgSO4, filtered and concentrated. The crude mixture was purified by Biotage using EtOAc/Hex ((20:80 to 40:60); 25+S column) to afford compound 43 (49 mgs, 13% yield) as a colorless oil. LRMS (ESI): (calc.) 305.07 (found) 306.2 (MH)+
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)[CH2:13][CH2:14][CH3:15].[F-].[Cs+]>O1CCOCC1>[CH2:12]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=2)=[CH:18][CH:17]=1)[CH2:13][CH2:14][CH3:15]
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CCCCc1ccc(B(O)O)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: CCCCc1ccc(-c2ccc(N)c([N+](=O)[O-])c2)cc1
Temperature: 120 °C

Procedure:
A Smith Process Vial charged with 4-bromo-2-nitroaniline (205 mg, 0.945 mmol), 4-butyl phenyl boronic acid (336 mg, 1.89 mmol), cesium fluoride (430 mg, 2.83 mmol), bis(tri-t-butyl-phosphine)-palladium (24.1 mg, 0.0472 mmol), and dioxane (2 ml) is purged with Argon (g) for 5 minutes and then heated in a microwave to 120° C. for 15 minutes. The crude reaction is filtered through Celite using EtOAc as eluent. The filtrate is concentrated in vacuo and the crude product is purified with silica gel flash column chromatography (0-100% ethyl acetate in hexanes gradient) to afford 4′-butyl-3-nitro-biphenyl-4-ylamine: ESMS m/z 271.2 (M+H+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CCCCCC.[Br:17][C:18]1[C:19]([CH3:23])=[N:20][NH:21][CH:22]=1.N#N.Cl[C:27]([O:29][CH3:30])=[O:28].[NH4+].[Cl-]>>[CH3:30][O:29][C:27]([N:20]1[C:19]([CH3:23])=[C:18]([Br:17])[CH:22]=[N:21]1)=[O:28]
Reactant: COC(=O)Cl
Reactant: Cc1n[nH]cc1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N#N
Agent: [Cl-]
Solvent: CCCCCC
Product: COC(=O)n1ncc(Br)c1C
Temperature: 25 °C

Procedure:
Lithium bis(trimethylsilyl)amide in hexane (0.7 mL, 0.7 mmol, 1M) was added to a solution of 4-bromo-3-methyl-1H-pyrazole (100 mg, 0.62 mmol) under the N2 at −78° C., and the mixture was allowed to warm to room temperature for a period of 2 hrs. The mixture was cooled again to −78° C., methyl chloroformate (0.7 mmol, 0.054 mL) was added drop wise, stirring was continued at −78° C., and the reaction was allowed to warm to room temperature and stirred for overnight. The reaction mixture was treated with NH4Cl, extracted with ethyl acetate, and the combined organic layers were washed with brine and dried over Na2SO4. The solvent was evaporated and the crude product was chromatographed on an ISCO with 10% EtOAc/Heptane, got 128 mg white solid as a 1:1 mixture of the title compound 299a and 4-bromo-3-methyl-pyrazole-1-carboxylic acid methyl ester.