Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](Cl)(Cl)Cl.C=CC[CH2:8][CH2:9]/[CH:10]=[CH:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C@@H:22]1[O:26][C@H:25]([C@@H:27]2[O:32][O:31][C@H:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:29][CH2:28]2)[CH2:24][CH2:23]1>CO>[CH3:1][O:36][C:34]([CH2:33][C@H:30]1[O:31][O:32][C@H:27]([C@H:25]2[O:26][C@H:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]/[CH:15]=[CH:14]\[CH:13]=[CH:12]/[CH2:11][CH2:10][CH:9]=[CH2:8])[CH2:23][CH2:24]2)[CH2:28][CH2:29]1)=[O:35]
Reactant: C=CCCC/C=C/C=C\CCCCCCCC[C@H]1CC[C@@H]([C@H]2CC[C@@H](CC(=O)O)OO2)O1
Reactant: ClC(Cl)Cl
Solvent: CO
Product: C=CCC/C=C\C=C/CCCCCC[C@@H]1CC[C@@H]([C@@H]2CC[C@@H](CC(=O)OC)OO2)O1

Procedure:
colorless oil; [α]D25 −50.8° (c 0.39, CHCl3); IR (film) 1745, 1640, 1200, 1060 cm−1; UV (MeOH) λmax235 (ε=22000) nm- 1H NMR (CDCl3) 6.25 (m, 2H, H-18 and H-19), 5.82 (ddt, J=16.9, 10.3, 6.6 Hz, 1H, H-23), 5.44 (m, 2H, H-17 and H-20), 5.03 (ddd, J=16.9, 1.7, 1.6 Hz, 1H, H-24), 4.97 (bd, J=10.3 Hz, 1H, H-24), 4.54 (dddd, J=11.1, 7.7, 5.9, 2.2 Hz, 1H, H-3), 4.06 (ddd, J=11.1, 5.4, 2.4 Hz, 1H, H-6), 3.87 (m, 2H, H-7 and H-10), 3.69 (s, 3H, CH30-), 2.47 (dd, J=15.6, 7.7 Hz, 1H, H-2), 2.36 (dd, J=15.6, 5.9 Hz, 1H, H-2), 2.28 (bdd, J=14.7, 7.4, 2H, H-21), 2.15 (m, 2H, H-16), 2.13 (m, 2H, H-22), 1.99 (m, 1H, H-9), 1.95 (m, 1H, H-8), 1.92 (m, 1H, H-4eq), 1.77 (m, 2H, H-5ax and H-8), 1.70 (m, 1H, H-5eq), 1.58 (m, 1H, H-11),1.54 (m, 1H, H-4ax), 1.42 (m, 1H, H-9), 1.34 (m, 1H, H-11), 1.33 (m, 1H, H-12), 1.30 (m, 6H, H-13, H-14 and H-15), 1.28 (in, 1H, H-12); 13C NMR (CDCl3) 170.4 (s, C-1), 138.2 (d, C-23), 132.4 (d, C-17), 130.8 (d, C-20), 124.0 (d, C-19), 123.4 (d, C-18), 114.7 (t, C-24), 83.8 (d, C-6), 79.9 (d, C-10), 78.5 (d, C-7), 77.6 (d, C-3), 51.9 (q, CH3O—), 38.4 (t, C-2), 35.6 (t, C-11), 33.7 (t, C-22), 31.7 (t, C-9), 29.6 (t, C-13)*, 29.5 (t, C-14)*, 29.2 (t, C-15)*, 29.1 (t, C-4), 27.7 (t, C-8), 27.5 (t, C-16), 26.8 (t, C-21), 26.0 (t, C-12), 25.2 (t, C-5); EIMS (70 eV) m/z (rel. int.) 420 (2), 402 (18), 261 (25), 219 (7), 159 (15), 143 (36), 135 (29), 121 (41), 67 (100); HREIMS m/z 420.2865, C25H4005 requires m/z 420.2876.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:11]=O)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH2:22][CH2:23][C:24]#[N:25]>>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH2:22][C:23]1[C:24]([NH2:25])=[N:1][C:2]2[CH:10]=[C:6]3[O:7][CH2:8][O:9][C:5]3=[CH:4][C:3]=2[CH:11]=1
Reactant: COc1cccc(F)c1CCC#N
Reactant: Nc1cc2c(cc1C=O)OCO2
Product: COc1cccc(F)c1Cc1cc2cc3c(cc2nc1N)OCO3

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 6-amino-1,3-benzodioxole 5-carbaldehyde and 3-(2-fluoro-6-methoxyphenyl)propionitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[N+:15]([C:11]1[C:2]([Cl:1])=[C:3]2[C:8](=[CH:9][C:10]=1[Cl:12])[NH:7][C:6](=[O:13])[C:5](=[O:14])[NH:4]2)([O-:17])=[O:16]
Reactant: O=c1[nH]c2cc(Cl)cc(Cl)c2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])c(Cl)c2[nH]c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
The method of Cheeseman, supra. was adapted. 5,7-Dichloro-1,4-dihydroquinoxaline-2,3-dione (239 mg, 1.03 mMol) was dissolved in concentrated H2SO4 (3mL) at 0° C. for 30 min, and KNO3 (125.3 mg, 1.24 mMol, Baker) was added to this solution. The mixture was stirred at 0° C. for 3 h and then was stirred at room temperature for 30 h. It was then poured into ice water (15 g). A precipitate came out and was collected by filtration, was dissolved in 1N KOH (10 mL) and the red precipitate was removed by filtration. The solution then was acidified to pH=2 with 4N HCl to give a cream precipitate, which was collected by filtration, then was dried in the air at 50° C. for 4 h to afford the pure 6-nitro-5,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (231 mg, 80%), as yellow microcrystals. mp: 320°-25° C. (dec. from 290° C.). IR (KBr, cm-1): 3467, 3140, 3055, 2946, 1717, 1693, 1541. NMR (1H, DMSO-d6): δ 7.221 (s, 1H), 11.932 (s, 1H), 12,312 (s, 1H). HRMS: calcd. for C8H3N3O4Cl2 (M+) m/z: 274.9499, found: 274.9509.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C@@H:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:17]([CH3:26])([CH3:25])[O:16][C:15]3=[O:27])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:4][N:3]=1.[O:34]1CCOCC1.Cl>O>[CH3:25][C:17]1([CH3:26])[O:16][C:15](=[O:27])[N:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[C:2](=[O:34])[NH:3][CH:4]=[C:5]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH:6]=3)=[CH:9][CH:10]=2)[C@H:18]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C1COCCO1
Reactant: CC1(C)OC(=O)N(c2ccc(-c3cc(-c4ncccn4)cnc3F)cc2)[C@H]1c1ccccc1
Agent: Cl
Solvent: O
Product: CC1(C)OC(=O)N(c2ccc(-c3cc(-c4ncccn4)c[nH]c3=O)cc2)[C@H]1c1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A resealable tube was charged with (S)-3-(4-(2-fluoro-5-(pyrimidin-2-yl)pyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (0.034 g, 0.077 mmol), dioxane (2.0 mL), and water (0.667 mL). Concentrated HCl (37%) (0.167 mL) was added, the system was flushed with argon, the tube was sealed, and the reaction mixture was stirred at 100° C. for 1.5 hours. The reaction mixture was next partitioned between EtOAc and saturated aqueous NaHCO3 solution. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford (S)-5,5-dimethyl-3-(4-(2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl)phenyl)-4-phenyloxazolidin-2-one (0.034 g, 0.078 mmol, 100% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (s, 3H), 1.65 (s, 3H), 5.48 (s, 1H), 7.18-7.45 (m, 6H), 7.48-7.59 (m, 2H), 7.65-7.75 (m, 2 H), 8.32 (d, J=2.45 Hz, 1H), 8.43 (d, J=2.54 Hz, 1H), 8.80 (d, J=4.89 Hz, 2H), 12.13 (br. s., 1H). m/z (ESI) 439 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:9]=[O:10])=[CH:11][C:12]=1[N+:18]([O-:20])=[O:19])[CH:2]([CH3:4])[CH3:3]
Reactant: O=[N+]([O-])O
Reactant: CC(C)Cc1ccc(C=O)cc1
Agent: O=S(=O)(O)O
Product: CC(C)Cc1ccc(C=O)cc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
4-Isobutyl benzaldehyde (7 g, 0.0431 mol) is added drop wise to a mixture of concentrated sulfuric acid & nitric acid (68-72%) (9:1, 60 mL) at 0-5° C. Reaction mixture is allowed to stir at this temperature for 2 hrs, then poured into crushed ice. It is then extracted with ethyl acetate (3×40 mL). Combined organic layer is dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography (silica gel, 230-400 mesh, ethyl acetate:n-hexane 1:19) to yield 4-isobutyl-3-nitrobenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(CCl)n1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Agent: Cl
Product: Cc1cccc(Cn2cc(C#Cc3cccc(Cl)c3)nc2C)n1

Procedure:
The title compound, MS: m/e=322.4 (M+H30), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2-chloromethyl-6-methyl-pyridine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[F:10][C:11]([F:17])([F:16])[CH2:12][C:13](O)=[O:14].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:13](=[O:14])[CH2:12][C:11]([F:17])([F:16])[F:10])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: O=C(O)CC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CC(F)(F)F)Nc1ccc(Cl)cc1F
Reaction time: 8 h
Yield: 90 %

Procedure:
4-Chloro-2-fluoroaniline (3 g, 20.7 mmol), 3,3,3-trifluoropropanoic acid (2.6 g, 20.7 mmol) and Et3N (5.8 mL) were dissolved in 50 mL of DCM. To this solution was added HATU (8.6 g, 22.7 mmol) slowly and then stirred overnight. The organic phases was washed with aq. NH4Cl (50 mL), NaHCO3 solution (50 mL) and brine (100 mL). The combined organic phases were evaporated and purified by column chromatography (PE/EA=5/1) to give N-(4-chloro-2-fluorophenyl)-3,3,3-trifluoropropanamide which was pure enough for next step. (4.7 g, yield: 90%) was a yellow solid. MS obsd. (ESI+) [(M+H)+] 256.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:17][CH:18]=[O:19])[CH:6](O)[C:7](=[CH2:15])[CH2:8][CH2:9][N:10]([C:12](=[O:14])[CH3:13])[CH3:11])[CH3:2].S(Br)([Br:23])=O.O>ClCCl>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:17][CH:18]=[O:19])[CH:6]=[C:7]([CH2:15][Br:23])[CH2:8][CH2:9][N:10]([C:12](=[O:14])[CH3:13])[CH3:11])[CH3:2]
Reactant: C=C(CCN(C)C(C)=O)C(O)C(NC=O)C(=O)OCC
Reactant: O=S(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C=C(CBr)CCN(C)C(C)=O)NC=O
Reaction time: 1 h

Procedure:
15.8 g (55.2 mmol) of 6-(N-acetyl-N-methylamino)-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 150 ml of dichloromethane, and 5.1 ml (66.2 mmol) of thionyl bromide are added dropwise at room temperature. After one hour, 100 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, 1N KHCO3 solution and again with water, dried over MgSO4, filtered and concentrated by evaporation. 6-(N-acetyl-N-methylamino)-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a yellowish-orange oil which is reacted further in the crude state.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]2[C:12]([NH:15][CH3:16])=[N:13][NH:14][C:8]=2[N:7]([CH2:17][CH2:18]O)[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]2[C:12]([NH:15][CH3:16])=[N:13][NH:14][C:8]=2[N:7]([CH2:17][CH2:18][Cl:23])[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCn1c(=O)c2c(NC)n[nH]c2n(CCO)c1=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCn1c(=O)c2c(NC)n[nH]c2n(CCCl)c1=O
Yield: 94 %

Procedure:
To a suspension of 5-butyl-7-(2-hydroxyethyl)-3-methylaminopyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (2.5 g, 8.9 mM) in chloroform (30 ml) and pyridine (4 ml, 50 mM) was added thionyl chloride (3,7 ml, 50 mM) at room temperature. The solution was refluxed for 2 hours and concentrated to dryness under reduced pressure to give a syrup. The syrup was poured onto ice-water to give colorless powder. Recrystallization from DMF/methanol/water gave colorless crystals (2.5 g, 94%), m.p. 270°-272° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[Cl:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([Cl:17])[C:9]=1[N:18]=[C:19]=S.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([Cl:17])[C:9]=1[N:18]=[C:19]1[NH:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1]1
Reactant: NCCCCN
Reactant: O=[N+]([O-])c1cc(Cl)c(N=C=S)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Cl)c(N=C2NCCCCN2)c(Cl)c1
Temperature: 25 °C
Yield: 30.3 %

Procedure:
A solution of 1.76 g (0.02 mol) of 1,4-diaminobutane in 10 mL of toluene was cooled to -10° C. and 2,6-dichloro-4-nitrophenylisothiocyanate (2.45 g, 0.01 mol) in 10 mL of toluene was added dropwise over 30 minutes. The resulting mixture was stirred an additional hour then heated at reflux overnight. The reaction was cooled to room temperature and was treated with 30 mL 1M HCl. The aqueous phase was brought to pH 9 with 1M NaOH and the resulting yellow precipitate was filtered, washed with water then hexane and air dried to give 0.92 g (30%) of the product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH:6]([C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)[CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:2].O.C([O-])=O.[NH4+]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH:6]([C:22]1[CH:27]=[N:26][C:25]([CH3:28])=[N:24][CH:23]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH3:2]
Reactant: CCOC(=O)CC(C=CCCCCCNC(=O)OC(C)(C)C)c1cnc(C)nc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC(CCCCCCCNC(=O)OC(C)(C)C)c1cnc(C)nc1
Yield: 92 %

Procedure:
A solution of 24-5 (650 mg, 1.60 mmol), water (100 mg), ammonium formate (512 mg, 8.12 mmol), and 10% palladium on carbon (75 mg) in ethanol (40 mL) was heated to 90 ° C. for 1 hour. The reaction mixture was filtered through celite and the filtrate evaporated in vacuo to afford the title compound 24-6 (600 mg). The crude product was used directly in the next reaction. ESLRMS m/e 408 g/mole (M++H, C22H37N3O4=408 g/mole.)
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].[SH:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:27]([CH:22]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][O:20][C:18](=[O:19])[CH2:17][CH2:16][S:15][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6])[CH3:28]
Reactant: CCCCC(CC)COC(=O)CCS
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC(CC)COC(=O)CCSc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Reaction time: 16 h
Yield: 82.7 %

Procedure:
Methyl 3-fluoro-4-nitrobenzoate (8.72 g, 43.8 mmol) was added to a suspension of 2-ethylhexyl 3-sulfanylpropanoate (10.5 g, 48.2 mmol) and potassium carbonate (9.08 g, 65.7 mmol) in DMF (50 mL) at room temperature, and the mixture was stirred for 16 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 7:3) to give the title compound (14.4 g, yield 83%).
Reaction SMILES: [Li+].[OH-].BrC1C=C(C=CC=1)C[O:8][C:9](=[O:27])[C:10]1[CH:15]=[C:14]([I:16])[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=2)=[C:12]([I:26])[CH:11]=1.Cl>C1COCC1>[I:16][C:14]1[CH:15]=[C:10]([CH:11]=[C:12]([I:26])[C:13]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1)[C:9]([OH:27])=[O:8]
Reactant: O=C(OCc1cccc(Br)c1)c1cc(I)c(OCc2cccc(Br)c2)c(I)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(I)c(OCc2cccc(Br)c2)c(I)c1
Reaction time: 17 h
Yield: 96.6 %

Procedure:
A 1.2 M solution of LiOH (0.5 mL, 0.6 mmol) was added to a solution of 4-(3-bromobenzyloxy)-3,5-diiodobenzoic acid 3-bromobenzyl ester (Example 1)(363 mg, 0.5 mmol) in 4 mL THF. The biphasic solution was stirred for 17 hours, after which time the reaction mixture was poured into 1 M HCl (15 mL). The resulting white precipitate was isolated by filtration, rinsed with water, and dried in vacuo, yielding the title compound as a white powder (270 mg, 97%); 1H NMR (CDCl3) δ 8.48 (s, 2H), 7.80 (br. s, 1H), 7.58-7.49 (m, 4H), 7.38-7.28 (m, 3H), 5.31 (s, 2H), 5.01 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C:28]1([C:33]2[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=2)[O:32][CH2:31][CH2:30][O:29]1>>[CH3:27][C:28]1([C:33]2[CH:40]=[CH:39][C:36]([CH2:37][NH:38][C:3]3[C:4]4[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6][C:5]=4[CH:17]=[CH:18][C:2]=3[Cl:1])=[CH:35][CH:34]=2)[O:29][CH2:30][CH2:31][O:32]1
Reactant: CC1(c2ccc(CN)cc2)OCCO1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: CC1(c2ccc(CNc3c(Cl)ccc4c3CCN(C(=O)C(F)(F)F)CC4)cc2)OCCO1
Yield: 68 %

Procedure:
Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.47 mmol) with 4-(2-methyl-[1,3]dioxolan-2-yl)-benzylamine (prepared by following the procedure described in J. Med. Chem. 1978, 21, 507) (182 mg, 0.94 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 19:1 and 9:1) to give 6-{4-(2-methyl-[1,3]dioxolan-2-yl)-benzylamino}-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (150 mg, 68%). GC-MS m/z 468 (M+).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([C:16]([F:19])([F:18])[F:17])[CH:8]=1>[Pd]>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([C:16]([F:18])([F:17])[F:19])[CH:8]=1
Reactant: C[C@H]1CCCN1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: [Pd]
Product: C[C@H]1CCCN1c1ccc(N)c(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
A flask charged with (S)-2-methyl-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine (2.45 g, 8.9 mmol) and palladium on carbon (245 mg, 10 wt %) was flushed with N2 followed by evacuating under vacuum. Methanol (15 mL) was added under inert atmosphere followed by evacuating under vacuum. The reaction mixture was stirred overnight under an atmosphere of H2. The palladium catalyst was removed by filtration and solvent was removed under reduced pressure to give (S)-4-(2-methylpyrrolidin-1-yl)-2-(trifluoromethyl)aniline in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ 6.78 (d, J=8.8 Hz, 1H), 6.70-6.67 (m, 1H), 6.47 (d, J=2.7 Hz, 1H), 4.68 (s, 2H), 3.76-3.69 (m, 1H), 3.32-3.27 (m, 1H), 3.02-2.96 (m, 1H), 2.05-1.94 (m, 2H), 1.93-1.84 (m, 1H), 1.64-1.58 (m, 1H), 1.05 (d, J=6.1 Hz, 3H). LC/MS: m/z 245.1 (M+H)+ at 0.48 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH:6]1([C:9](=[O:27])[C:10](=[CH:23]OCC)[C:11]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])=[O:12])[CH2:8][CH2:7]1.Cl.[NH2:29]O>C(O)C>[CH:6]1([C:9]2[O:27][N:29]=[CH:23][C:10]=2[C:11](=[O:12])[C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[CH2:8][CH2:7]1
Reactant: CCOC=C(C(=O)c1ccc(SC)cc1OC)C(=O)C1CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cc(SC)ccc1C(=O)c1cnoc1C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium acetate (7.87 g) was added to a stirred mixture of 3-cyclopropyl-2-ethoxymethylene-1-[2-methoxy-4-(methylsulphenyl)phenyl]propan-1,3-dione (30.6 g) and hydroxylamine hydrochloride (8.0 g) in ethanol. The mixture was stirred at room temperature overnight, then evaporated to dryness. The residue was dissolved in ethyl acetate, washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was triturated with ether and filtered to give 5-cyclopropyl-4-[2-methoxy-4-(methylsulphenyl)benzoyl]isoxazole as a white solid, m.p. 107.5°-108.5° C.
Reaction SMILES: [F:1][CH2:2][C:3]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])([CH2:6][CH2:7][CH2:8]OS(C)(=O)=O)[C:4]#[N:5].[I-:25].[Na+]>CC(C)=O.CCOCC>[F:1][CH2:2][C:3]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])([CH2:6][CH2:7][CH2:8][I:25])[C:4]#[N:5]
Reactant: CS(=O)(=O)OCCCC(C#N)(CF)N1C(=O)c2ccccc2C1=O
Reactant: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: N#CC(CF)(CCCI)N1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h

Procedure:
A solution of 2-fluoromethyl-2-phthalimido-5-methanesulfonyloxy-valeronitrile (42 g) and sodium iodide (35.7 g) in acetone (600 ml) is stirred and heated under reflux. After about 1/2 hour, the mixture solidifies. Acetone (500 ml) is added, and refluxing and stirring is continued overnight. The salts are removed by filtration and washed several times with acetone. The acetone is evaporated to give a residue which is dissolved in ether (1.5 l). The ether solution is washed subsequently with water (2×), sodium sulfite solution, and water again (3×). After drying (MgSO4) and evaporating the ether, the title compound is obtained as an oil (34.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[NH:12][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:14][N:15]=1.[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1>[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[S:33]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[NH:12][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[N:14][N:15]=1)(=[O:35])=[O:34]
Reactant: CC(C)(C)OC(=O)Nc1nnc(CSc2ccc(Cl)cc2N)[nH]1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1nnc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)[nH]1

Procedure:
Following General Procedure B, the title compound was prepared from tert-butyl (5-(((2-amino-4-chlorophenyl)thio)methyl)-4H-1,2,4-triazol-3-yl)carbamate (330 mg, 0.925 mmol) and benzofuran-2-sulfonyl chloride (200 mg, 0.925 mmol) in pyridine (2 ml).
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C:12]1[C:19](=[O:20])[N:15]2[CH2:16][CH2:17][CH2:18][N:14]2[C:13]=1[NH2:21].[NH2:22][C:23]1[C:24]([Cl:31])=[C:25]([OH:30])[C:26]([CH3:29])=[CH:27][CH:28]=1.N.OO>O.C(O)C>[NH2:21][C:13]1[N:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:20])[C:12]=1/[N:11]=[C:28]1/[C:23]([NH2:22])=[C:24]([Cl:31])[C:25](=[O:30])[C:26]([CH3:29])=[CH:27]/1
Reactant: Cc1ccc(N)c(Cl)c1O
Reactant: Nc1c(N)n2n(c1=O)CCC2
Agent: CS(=O)(=O)O
Agent: N
Agent: OO
Solvent: O
Solvent: CCO
Product: CC1=C/C(=N\c2c(N)n3n(c2=O)CCC3)C(N)=C(Cl)C1=O

Procedure:
0.58 mmol of 2,3-diamino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one dimethane sulphonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.58 mmol of 3-amino-2-chloro-6-methylphenol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[CH2:11]([NH2:15])[C:12]#[C:13][CH3:14]>>[CH3:14][C:13]1[CH:12]=[CH:11][N:15]=[C:2]2[CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[C:1]=12
Reactant: O=C1Cc2ccccc2C1
Reactant: CC#CCN
Product: Cc1ccnc2c1-c1ccccc1C2
Reaction time: 0.2 h
Yield: 22 %

Procedure:
The title compound is prepared from indan-2-one and but-2-ynylamine following a procedure analogous to that described in Step 1 of Intermediates 1 and 2; the reaction is carried out in a microwave oven at 100° C. for 12 min. Yield: 22% of theory; LC (method 1): tR=1.98 min; Mass spectrum (ESI+): m/z=182 [M+H]+.