Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].C([O-])([O-])=O.[K+].[K+].Br[C:18]1[S:19][CH:20]=[CH:21][N:22]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][C:18]1[S:19][CH:20]=[CH:21][N:22]=1
Reactant: Brc1nccs1
Reactant: COc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2nccs2)c(Cl)c1
Temperature: 150 °C
Yield: 80.8 %

Procedure:
To a suspension of 2-chloro-4-methoxyphenol (10 g, 63 mmol) and K2CO3 (9.7 g, 69.4 mmol) in N,N-dimethyl formamide (120 mL) was added 2-bromothiazole (11.4 g, 69.4 mmol). The suspension was heated at 150° C. for 4 hours, cooled to ambient temperature, and poured into water (1000 mL). The mixture was extracted with ether (2×300 mL) and the combined ether layers were dried (MgSO4), filtered and concentrated. The resulting black oil was purified by flash chromatography on silica gel eluting with a solvent gradient from 10% to 25% ethyl acetate in hexanes to provide 12.3 g of the title compound (81%) as a light yellow liquid. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.81 (s, 3H) 7.01 (dd, J=9.01, 3.13 Hz, 1H) 7.18-7.21 (m, 1H) 7.23 (t, J=3.13 Hz, 2H) 7.47 (d, J=9.19 Hz, 1H); MS (ESI) m/z 241.9 (M+H)+.
Reaction SMILES: [CH2:1]([OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:24](O)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:24]([O:23][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCCCCCO
Product: CCCCCCCCCCCCCCCCCCCCCCOC(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 106.5 gms. (0.326 moles) of behenyl alcohol, 43.5 gms. (0.343 moles) of benzoic acid and 225 mgms. stannous oxalate was heated to 230° C. under nitrogen. The reaction was held at 230° C. for two hours, and the distillate collected. It was then cooled to 100° C. The acidity was 10.0 mg KOH/gm. The ester was then given a treatment for 30 minutes at 85° C. with 50 gms. deionized water, 2 gms. sodium carbonate, 2 gms. sodium chloride, and 1 gm. hydrogen peroxide. It was then allowed to stand and the lower aqueous layer drained off. The top layer was washed with 50 gms. water at 80°-85° C. and then separated. The solid was then vacuum stripped at 100°-105° C. to remove residual moisture. The final product was a solid benzoate ester having the following formula: ##STR14##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][N:11]=[C:12](Br)[C:13]([CH3:16])([CH3:15])[CH3:14].[CH3:18][NH:19][C:20]#[N:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:13]([C:12]1[N:21]=[C:20]([NH:19][CH3:18])[N:10]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=2[Cl:9])[N:11]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(Br)=NNc1c(Cl)cc(Cl)cc1Cl
Reactant: CNC#N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CNc1nc(C(C)(C)C)nn1-c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
3.6 g (0.01 mol) of 2,2-dimethylpropionyl bromide 2,4,6-trichlorophenylhydrazone and 0.6 g (0.01 mol) of N-methylcyanamide were added to 50 ml of toluene. Then, 1.1 g (0.011 mol) of triethylamine was dropwise added under stirring at room temperature. After the dropwise addition, stirring was continued at the same temperature for further 1 hour. After washing the reaction mixture with water, the toluene layer was dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 2.8 g (yield: 85%) of 3-(tert-butyl)-5-(N-methylamino)-1-(2,4,6-trichlorophenyl)-1H-1,2,4-triazole as power having a melting point of from 165° to 166° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:14].O.NN.Cl>C(O)C>[NH2:3][CH:12]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:14]
Reactant: CC(C)CC(C(O)c1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)CC(N)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
(1RS,2SR)2-(1,3-Dioxo-2-azaindan-2-yl)-4-methyl-1-phenylpentan-1-ol (80.0 g, 247 mmol) was dissolved with heating (50° C.) in ethanol (800 ml), followed by addition of a mixture of 85% hydrazine hydrate (19.0 ml) in ethanol (200 ml). The resulting mixture was heated under reflux for 3 hours. After ice-cooling, 4N-HCl (700 ml) was added. The mixture was stirred at room temperature for 30 minutes. Insoluble matter was removed by filtration through celite and then washed with 4N-hydrochloric acid (140 ml). The washing was added to the filtrate and the solution was condensed under reduced pressure to remove the ethanol. A 6N-NaOH solution (570 ml) was added with ice-cooling and the mixture was extracted three times with chloroform. After being dried over sodium sulfate, the organic layer was evaporated to obtain 43.2 g of the title compound as white crystals (yield: 91%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=O.C([SiH](CC)CC)C.O>FC(F)(F)C(O)=O>[Cl:1][CH2:2][CH2:3][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2
Reactant: O=C1Cc2cc(C(=O)CCl)ccc2N1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1Cc2cc(CCCl)ccc2N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
5-Chloroacetyl-2-oxindole(4.18 g) in 30 mL of trifluoroacetic acid in an ice bath was treated with 4.65 g of triethylsilane and stirred at room temperature for 3 hours. The mixture was poured into 150 mL of water and the precipitate collected by vacuum filtration, washed with 50 mL of water and dried to give 2.53 g (65% yield) of 5-(2-chloroethyl)-2-oxindole as a reddish-brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][C:5]2([CH3:13])[CH3:12].CS(O)(=O)=O.[N-:19]=[N+]=[N-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:19][CH2:6][C:5]2([CH3:13])[CH3:12]
Reactant: CC1(C)CC(=O)c2ccc(Br)cc21
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CNC(=O)c2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 41.8 %

Procedure:
5-bromo-3,3-dimethyl-2,3-dihydro-1H-inden-1-one (1.6 g, 6.7 mmol) was dissolved in DCM (12 mL) and cooled to 0° C. Then MeSO3H (1.83 ml, 28.1 mmol) was added, followed by the portion-wise addition of NaN3 (653 mg, 10.1 mmol) over ˜10 min, while maintaining the internal reaction temperature below 5° C. The reaction was allowed to warm to room temperature and was stirred 3 h under nitrogen. At completion, the reaction was cooled to 0° C. and quenched with 8 M aq. NaOH. After stirring 30 minutes at room temperature, the quenched reaction was partitioned between DCM (50 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with DCM (2×30 mL). The combined organics were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. 6-bromo-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (711 mg, 40% yield) was isolated as a white solid after purification by flash chromatography over silica gel (eluting in 50-100% EtOAc/hexane). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.02 (br. s., 1H), 7.77 (d, J=8.0 Hz, 1H), 7.46-7.64 (m, 2H), 3.16 (d, J=3.0 Hz, 2H), 1.27 (s, 6H); MS (EI) m/z=255.1 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=O.[NH2:16][OH:17].Cl.CCN(CC)CC>CCO>[F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[N:16][OH:17]
Reactant: NO
Reactant: O=C(c1cccc([N+](=O)[O-])c1)C(F)(F)F
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(C(=NO)C(F)(F)F)c1
Yield: 79.5 %

Procedure:
A mixture of 2,2,2-trifluoro-1-(3-nitro-phenyl)ethanone (4 g), NH2OH.HCl (5.037 g), and Et3N (20.44 g) in EtOH (80 mL) was refluxed for 4 days. After concentration, the residue was extracted with CH2Cl2. The organic layer was washed with water and dried over MgSO4. The crude product was purified by silica gel flash chromatography (30% ethyl acetate in hexanes) to give the title compound (3.4 g) as a solid.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:12]O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:12])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1c(O)cccc1F
Reactant: CO
Product: COc1cccc(F)c1[N+](=O)[O-]

Procedure:
This compound was synthesized according to the procedure of Example 76, Step 5, using 3-fluoro-2-nitrophenol [Combi-Blocks, OR-7136] and methanol as the starting materials.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][NH:31][C:32](=[O:34])[CH3:33].[H-].[Na+]>O1CCCC1>[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][N:31]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:32](=[O:34])[CH3:33]
Reactant: CC(=O)NCc1ccccn1
Reactant: CCCCCCCCCCCCCCOc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccccc1CN(Cc1ccccn1)C(C)=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 33.7 %

Procedure:
The title compound is prepared by the procedure of Example 27 using 2.45 g of product from Example 22, 0.960 g of product from Example 12, 0.322 g of washed 50% sodium hydride and 30 ml of tetrahydrofuran. The reaction is stirred at 0° C. for 1 hour, room temperature for 18 hours; followed by heating at reflux temperature for 6 hours. The residue is purified by column chromatography (silica gel: 80% ethyl acetate/hexane) to give 0.976 g of the desired product as a yellow oil. The spectral data shows the presence of 2 rotomers.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.Br[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:21][C:22]([N:24]3[CH2:25][CH2:26][N:27]([C:30]4[N:31]=[CH:32][CH:33]=[CH:34][N:35]=4)[CH2:28][CH2:29]3)=[O:23])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)N1CCN(c2ncccn2)CC1
Reactant: Fc1ccc(-c2n[nH]c(-c3ccc(F)cc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCN(c2ncccn2)CC1
Yield: 69.1 %

Procedure:
100 mg 3,5-bis-(4-fluoro-phenyl)-1H-(1,2,4)triazole, 111 mg 2-bromo-1-(4-pyrimidin-2-yl-piperazin-1-yl)-ethanon and 237 mg potassiumcarbonat in 5 mL acetone was stirred 24 h at RT. The reaction was filtered and the filtrate was evaporated. The residue was crystallized with acetonitrile to yield 124 mg of the desired compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: c1cn[nH]c1
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-nitro-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-nitro-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([OH:3])=O.C(Cl)(=O)C.Cl.Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[C@@H:32]([N:36]1[CH2:39][C:38]3([CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[CH2:37]1)[CH2:31][CH2:30]2.C(N(CC)CC)C>>[CH3:14][C:11]1[CH:12]=[CH:13][C:5]([CH2:4][C:1](=[O:3])[N:42]2[CH2:43][CH2:44][C:38]3([CH2:37][N:36]([CH:32]4[C:33]5[C:29](=[CH:28][C:27]([C:22]6[N:21]=[CH:26][CH:25]=[CH:24][N:23]=6)=[CH:35][CH:34]=5)[CH2:30][CH2:31]4)[CH2:39]3)[CH2:40][CH2:41]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: c1cnc(-c2ccc3c(c2)CC[C@@H]3N2CC3(CCNCC3)C2)nc1
Reactant: Cc1ccc(CC(=O)O)c(C(=O)O)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: Cc1ccc(CC(=O)N2CCC3(CC2)CN(C2CCc4cc(-c5ncccn5)ccc42)C3)c(C(=O)O)c1
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 69 %

Procedure:
To 2-(carboxymethyl)-5-methylbenzoic acid (100 mg, 0.52 mmol, prepared according to the procedure described in Tetrahedron, 1975, 31(20), 2607-2619) in a microwave reaction vessel was added acetyl chloride (0.5 mL). The tube was sealed and irradiated (Biotage Inc., microwave) while stirring at 130° C. for 20 minutes. The reaction was cooled to room temperature and the excess acetyl chloride was removed in vacuo. Dichloromethane was added to azeotrope the excess acetyl chloride and the crude anhydride was dried under vacuum. The crude anhydride was dissolved in acetonitrile (2 mL) and 2-[(1S)-5-pyrimidin-2-yl-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane dihydrochloride (3-1e, 220 mg, 0.52 mmol) was added followed by triethylamine (0.16 mL, 2.06 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated and the desired product was purified using reverse phase chromatography (Biotage SNAP (15 g), water/CH3CN=95/5% to 50/50%) to afford (176 mg, 69%) 5-methyl-2-{2-oxo-2-[2-(5-pyrimidin-2-yl-indan-1-yl)-2,7-diaza-spiro[3.5]non-7-yl]ethyl}benzoic acid. MS (ES+) 497.6 (M+H)+. 1H NMR (CDCl3) δ 1.54-1.58 (m, 2H), 1.60-1.64 (m, 2H), 2.15-2.38 (m, 5H), 2.78-3.02 (m, 2H), 3.04-3.24 (m, 1H), 3.26-3.52 (m, 6H), 3.62-3.66 (m, 2H), 4.41-4.45 (m, 1H), 7.06-7.27 (m, 3H), 7.34-7.57 (m, 1H), 7.68 (s, 1H), 8.31 (s, 2H), 8.73-8.79 (m, 2H).
Reaction SMILES: O[Li].O.C([O:6][C:7](=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[O:14][N:13]=1)C.Cl>O.O1CCOCC1>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[O:14][N:13]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][C:7]([OH:25])=[O:6])[CH:16]=1
Reactant: CCOC(=O)CCCCc1cc(-c2ccccc2OC)on1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1-c1cc(CCCCC(=O)O)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.4 %

Procedure:
Add a solution of LiOH.H2O (1.83 g, 43.5 mmol) in water (30 mL) to a rapidly stirred solution of 5-[5-(2-methoxy-phenyl)-isoxazol-3-yl]-pentanoic acid ethyl ester (2.64 g, 8.7 mmol) in dioxane (60 mL) and stir overnight at room temperature. After 1 hour, acidify to pH 1 with 5N HCl solution and concentrate to remove the majority of the dioxane. Partition residue between 20% i-PrOH/CHCl3 and 1N HCl solution and separate layers. Backextract from aqueous layer with 20% i-PrOH/CHCl3 and dry combined organic layers over MgSO4, and concentrate to get 2.5 grams of a yellow oil. Recrystallize from EtOAc/hexanes to afford the title compound (1.96 g, 82%). MS (IS) 276 (M+1)+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].O.[CH2:8]([NH:10][CH:11]([CH3:24])[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH3:9].[C:25](Cl)(=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CC(C)=O>[CH2:8]([N:10]([CH:11]([CH3:24])[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)[C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH3:9]
Reactant: CCNC(C)CCCc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCC(=O)N(CC)C(C)CCCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
A 500 ml 3-neck round bottom flask fitted with a thermometer and addition funnel was charged with 7.65 g of sodium carbonate and 70 ml of water. To this mixture was added 6.8 g (0.029 mol) of N-ethyl-α-methyl-4-nitrobenzenebutanamine and 70 ml of acetone. The resulting mixture was cooled to slightly below 25° C. and 4.5 ml (0.029 mol) of heptanoyl chloride and 70 ml of acetone were added while maintaining the temperature of the mixture in the range of about 20°-25° C. The suspension was stirred at room temperature overnight and evaporated to dryness under reduced pressure. The residue was slurried in water and extracted three times with diethyl ether. The organic extracts were combined, washed with water, 2N hydrochloric acid, twice with water and finally a saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to provide 7.723 g of N-ethyl-N-[1-methyl-4-(4-nitrophenyl)butyl]heptanamide as an oil.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[N:6]2.[CH3:28][N:29]([CH3:40])[CH2:30][CH2:31][NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[SH:39].C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[CH3:28][N:29]([CH3:40])[CH2:30][CH2:31][NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[N:6]2
Reactant: CN(C)CCNc1ccccc1S
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nn2ccc(I)c2c(=O)n1-c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C[C@H](NC(=O)OC(C)(C)C)c1nn2ccc(Sc3ccccc3NCCN(C)C)c2c(=O)n1-c1ccccc1
Yield: 90.5 %

Procedure:
(S)-tert-Butyl (1-(5-iodo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)carbamate (560 mg, 0.87 mmol) was treated with 2-(2-(dimethylamino)ethylamino)benzenethiol (258 mg, 1.31 mmol), potassium carbonate (181 mg, 1.31 mmol) and copper(I) iodide (250 mg, 1.31 mmol) according to the method described in Preparation 44. The crude was purified using SP1® Purification System (0%-100%, hexane-ethyl acetate) to give 432 mg (90% yield) of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:37]([C:40]1[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=1)([O-:39])=[O:38].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@H:7]([O:9][C:43]2[CH:44]=[CH:45][C:40]([N+:37]([O-:39])=[O:38])=[CH:41][CH:42]=2)[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](Oc2ccc([N+](=O)[O-])cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.6 %

Procedure:
To a solution of N-Boc-trans-4-hydroxyproline methyl ester (10.0 g, 41 mmol) 150 mL of anhydrous THF at 0° C. under N2 was added triphenylphosphine (12.7 g, 48 mmol) and 4-nitrophenol (6.7 g, 48 mmol). To this mixture was added diethylazodicarboxylate (7.7 mL, 48 mmol) dropwise over a 30 minute period. The mixture was warmed to room temperature. After stirring for 2 days, the solvent was removed in vacuo, and the crude oil treated successively with 200 mL portions of toluene and ether to remove triphenylphosphine oxide and diethylazodihydrazide by crystallization. The resulting oil was then chromatographed (SiO2, 15-50% ethyl acetate/hexanes) to provide 5.2 g (34%) of N-Boc-4-(cis)-(4-nitrophenoxy)-L-proline methyl ester as a light yellow oil.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:16](O)([CH3:18])[CH3:17])[CH:13]=[CH:14][CH:15]=1.C[Si]([N:24]=[N+:25]=[N-:26])(C)C>O>[N:24]([C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH3:8])[CH:11]=1)([CH3:18])[CH3:17])=[N+:25]=[N-:26]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1cccc(C(C)(C)O)c1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(C(C)(C)N=[N+]=[N-])c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.6 %

Procedure:
Boron trifluoride-diethyl ether complex (11.2 g, 78.9 mmols) was dropwise added to a toluene (100 ml) solution of 2-(3-methoxyphenyl)propan-2-ol (10.9 g, 65.6 mmols) and trimethylsilylazide (8.3 g, 72 mmols), at room temperature. The resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with brine, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure to give an oil of 1-(1-azido-1-methylethyl)-3-methoxybenzene (12.5 g, 100%).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH:14]1[CH2:19][CH2:20][OH:21])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:2]([O:4][CH3:5])=[O:3])[CH2:15][CH:14]1[CH2:19][CH2:20][OH:21])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCN(C(=O)OC(C)(C)C)C(CCO)C1
Yield: 77.4 %

Procedure:
A solution of methyl chloroformate (0.52 ml, 6.73 mmol) in dichloromethane (5 ml) was added dropwise over 0.1 h to a stirred solution of (RS)-1-(tert-butyloxycarbonyl)-2-(2-hydroxyethyl)piperazine (D6) (1.4 g, 6.09 mmol) and triethylamine (1.7 ml, 12.2 mmol) in dichloromethane (45 ml) at 0° C. under argon. The resultant mixture was stirred at room temperature for 18 h, washed with saturated sodium hydrogen carbonate and the organic layer dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 10-100% ethyl acetate in hexane to give the title compound as a colourless gum (1.36 g, 78%). 1H NMR (CDC13)δ: 1.48 (9H, s), 1.60-1.95 (2H, m), 2.80-3.00 (2H, m), 3.05-3.45 (2H, m), 3.50-3.70 (2H, m), 3.70 (3H, s), 3.75-4.45 (4H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:11])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[CH:12]([S:15](Cl)(=[O:17])=[O:16])([CH3:14])[CH3:13].C1CCN2C(=NCCC2)CC1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:11])[CH2:9][NH:10][S:15]([CH:12]([CH3:14])[CH3:13])(=[O:17])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(CN)c1cccc(Br)c1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(CNS(=O)(=O)C(C)C)c1cccc(Br)c1
Yield: 31 %

Procedure:
2-(3-Bromophenyl)propylamine (9.7 g, 45.3 mmol) was combined with isopropylsulfonyl chloride (6.1 mL, 54.4 mmol), and DBU (10.2 mL, 68 mmol) in a manner analogous to the procedure described in example 2 to provide the final title compound, [2-(3-bromophenyl)propyl][(methylethyl)sulfonyl]amine, (4.5 g, 31%) as a white crystalline solid. Electron spray M.S. 320 (M*−H).