Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[NH:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:21][CH2:20][C:17]2([CH2:19][CH2:18]2)[C@H:16]([OH:22])[CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([Si:28]([CH3:31])([CH3:30])Cl)([CH3:27])([CH3:26])[CH3:25].N1C=CN=C1>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][C:9](=[O:23])[NH:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:21][CH2:20][C:17]2([CH2:18][CH2:19]2)[C@H:16]([O:22][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:31])[CH3:30])[CH2:15]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(NCCCN1CCC2(CC2)[C@H](O)C1)OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CN(CCCNC(=O)OCc2ccccc2)CCC12CC2
Temperature: 60 °C
Yield: 82 %

Procedure:
To a solution of [3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-carbamic acid benzyl ester (examples 74/75A; 3.90 g, 12.2 mmol in N,N-dimethylformamide (50 mL) was added tert-butyl-dimethylchlorosilane (2.77 g, 18.3 mmol), imidazole (2.08 g, 30.6 mmol), and 4-(dimethylamino)pyridine (14 mg, 0.12 mmol) at RT. The reaction mixture was heated at 60° C. for 24 h, then partitioned between sat. aq. NaHCO3 solution and EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; EtOAc/MeOH 19:1) afforded the title compound (4.34 g, 82%). Light yellow oil, MS: 433.4 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][C:25](Cl)=[O:26]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH:10]([CH2:14][O:15][CH2:24][C:25]2=[O:26])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: OCC1CN(Cc2ccccc2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1COCC2CN(Cc3ccccc3)CCN12
Temperature: 25 °C
Reaction time: 12 h
Yield: 35.2 %

Procedure:
To a mixture of (4-benzylpiperazin-2-yl)methanol (6.4 g, 30 mmol) prepared according to J. Med. Chem. 1993, 36, 2075-2083, water (100 ml) and tetrahydrofuran (100 ml) were successively added potassium carbonate (8.3 g, 60 mmol) with chloroacetyl chloride (3.6 mL, 45 mmol), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethanol (100 ml), potassium hydroxide (2 g) was added, and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (2.6 g, yield 35%) as a yellow oil. MS 247 (M+1).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[N:30]1([C:35]2[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:17]([C:14]1[CH:13]=[CH:12][C:11]([CH:7]2[C:6]3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[C:3]([CH3:29])=[C:2]([C:37]4[CH:38]=[CH:39][CH:40]=[C:35]([N:30]5[CH2:31][CH2:32][CH2:33][CH2:34]5)[CH:36]=4)[C:10]=3[O:9][CH2:8]2)=[CH:16][CH:15]=1)([CH3:19])[CH3:18]
Reactant: OB(O)c1cccc(N2CCCC2)c1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1cccc(N3CCCC3)c1)OCC2c1ccc(C(C)C)cc1
Yield: 17 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (3-(1-pyrrolidinyl)phenyl)boronic acid, the title compound was obtained in the same manner as in Example 107. Yield: 17%. Melting point: 206-207° C. (ethyl acetate-hexane).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Cl[C:32]1[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:35]=[CH:34][C:33]=1[S:42](C1C=CC=C(C(F)(F)F)C=1Cl)(=[O:44])=[O:43]>O1CCCC1.C(OCC)(=O)C>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:42]([C:33]3[CH:34]=[CH:35][CH:36]=[C:37]([C:38]([F:39])([F:40])[F:41])[CH:32]=3)(=[O:44])=[O:43])[C:8]=2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:18][CH:19]=1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1Cl)c1cccc(C(F)(F)F)c1Cl
Reactant: COc1ccc(-c2c(C(=O)OC(C)(C)C)[nH]c3ccccc23)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(C(=O)OC(C)(C)C)n(S(=O)(=O)c3cccc(C(F)(F)F)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
To a stirring solution of tert-butyl-3-(4-methoxyphenyl)indole-2-carboxylate (Example 105, 75 mg, 0.23 mmol) in tetrahydrofuran (0.4 mL) was added potassium tert-butoxide (1 M in tetrahydrofuran, 0.4 mL) in one aliquot. After 10 minutes chloro[3-(trifluoromethyl)phenyl]sulfone (113 mg, 0.46 mmol) was added. The reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted with ethyl acetate (4 mL) and quenched with water (2 mL). The organic phase was extracted with ethyl acetate (3×4 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product was filtered through a plug of silica gel (30% ethyl acetate/hexane) to provide tert-butyl 3-(4-methoxyphenyl)-1-{[3-(trifluoromethyl)phenyl]sulfonyl}indole-2-carboxylate (45 mg, 37%), which was used in the next step without further purification.
Reaction SMILES: C(OC([NH:11][NH:12][C:13](=[O:32])[C@@H:14]([CH2:20][NH:21][C:22](OCC1C=CC=CC=1)=[O:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=O)C1C=CC=CC=1.CC[OH:35]>[Pd]>[NH:12]([C:13]([C@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][N:21]([OH:35])[CH:22]=[O:23])=[O:32])[NH2:11]
Reactant: CCCCC[C@H](CNC(=O)OCc1ccccc1)C(=O)NNC(=O)OCc1ccccc1
Reactant: CCO
Agent: [Pd]
Product: CCCCC[C@H](CN(O)C=O)C(=O)NN
Reaction time: 5 h

Procedure:
To a solution of N′-{(R)-2-[(Benzyloxyformylamino)methyl]heptanoyl]-hydrazinecarboxylic acid benzyl ester (1 mmol) in EtOH (10 mL) was added 10% Pd/C (50 mg). The mixture was subjected to hydrogenation for 5 hours at room temperature and then filtered through Celite. The filtrate was evaporated and purified by hplc to afford N-[(R)-2-(Hydrazinocarbonyl)-heptyl]-N-hydroxy-formamide as a glass. MH+218.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[F:19]>C(O)(=O)C>[Br:18][C:16]1[CH:15]=[CH:14][C:13]([F:19])=[C:12]([C:11]2[NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=3[N:10]=2)[CH:17]=1
Reactant: COc1ccc(N)c(NC(=O)c2cc(Br)ccc2F)c1
Solvent: CC(=O)O
Product: COc1ccc2[nH]c(-c3cc(Br)ccc3F)nc2c1
Temperature: 80 °C
Yield: 62.6 %

Procedure:
Method 6—Step b A mixture of N-(2-Amino-5-methoxy-phenyl)-5-bromo-2-fluoro-benzamide (1.45 g, 4.28 mmol) in acetic acid (15 mL) was heated at 80° C. overnight. Solvent was removed under reduced pressure and the crude purified by precipitation from AcOEt (20 mL), dried, recovered with a mixture of dichloromethane (20 mL) and methanol (1 mL) and washed with saturated NaHCO3 solution (3×5 mL), the organic layer recovered by filtration through phase separator, and the solvent removed under reduced pressure to obtain 0.86 g of the title compound (63%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:27](=[O:28])[N:4]2[C@@H:5]([C:11]([O:13][CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[C@@:6]([Cl:10])([CH3:9])[CH2:7][S:8][C@H:3]12.C(N(CC)CC)C.[O:36]([CH2:43][C:44](Cl)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[Cl:10][C@@:6]1([CH3:9])[C@H:5]([C:11]([O:13][CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:12])[N:4]2[C:27](=[O:28])[C@@H:2]([NH:1][C:44](=[O:45])[CH2:43][O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@H:3]2[S:8][CH2:7]1
Reactant: O=C(Cl)COc1ccccc1
Reactant: C[C@@]1(Cl)CS[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@]1(Cl)CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 86.2 %

Procedure:
To a solution of benzhydryl 7β-amino-3β-chloro-3α-methylcepham-4α-carboxylate (209 mg) in methylene chloride (3 ml) is added triethylamine (56 mg), and the mixture is mixed with a solution of phenoxyacetyl chloride (79 mg) in methylene chloride (2 ml) under ice cooling. After being left to stand for 2 hours, the mixture is washed successively with dilute hydrochloric acid, 5% aqueous sodium hydrogen carbonate, and water, then dried, and evaporated in vacuo. Recrystallization of the residue with a mixture of ether and petroleum ether gives benzhydryl 3β-chloro-3α-methyl-7β-phenoxyacetamidocepham-4α-carboxylate (220 mg). Yield: 82%.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:14]=[O:15])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-:3])=[O:2].Br[Mg][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[N+:1]([C:4]1[C:5]([CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[OH:15])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-:3])=[O:2]
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1ccc2cccnc2c1[N+](=O)[O-]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(C(O)c2ccccc2)ccc2cccnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A solution of 8-nitro-quinoline-7-carbaldehyde (Intermediate 204) (1.14 g, 5.64 mmol) in dry THF (10 ml) was cooled to 0° C. in an ice bath. Bromo(phenyl)magnesium (1 M in THF; 5.64 ml) was added and the reaction mixture was stirred at room temperature for 30 min. The reaction was quenched with sat. ammonium chloride (10 ml) and the resulting organic phase was extracted with EtOAc (20 ml). The combined organic phases were washed with brine (10 ml), dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with heptane/EtOAc (60:40) as the eluent, to give the title compound (1.09 g, 60%).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[N+:16]([O-])([OH:18])=[O:17].[NH4+].[OH-]>>[N+:16]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])([O-:18])=[O:17]
Reactant: Nc1ccccc1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: O=C(O)c1ccccc1N[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a solution of concentrated sulfuric acid (2 mL) was slowly added 2-aminobenzoic acid (CXXIV) (1.0 g, 7.24 mmol). A mixture of concentrated sulfuric acid (1.5 mL) and fuming nitric acid (1.5 mL) was then slowly added and the reaction was stirred at room temperature overnight. The reaction mixture was poured into crushed ice and treated with aqueous NH4OH until pH 3.0. The yellow-orange solid was washed with cold water and dried to produce 2-(nitroamino)benzoic acid (CXXV) as a yellow solid (1.0 g, 5.46 mmol, 75.4% yield). The crude product was used for the next step without further purification. ESIMS found for C7H6N2O4 m/z 183.9 (M+H).
Reaction SMILES: [CH3:1][O:2][Si:3]([CH2:8][N:9]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C[Si](OC)(OC)OC)([O:6][CH3:7])[O:4][CH3:5].[Cl-]>>[C:18]1([NH:9][CH2:8][Si:3]([O:6][CH3:7])([O:2][CH3:1])[O:4][CH3:5])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CO[Si](CN(C[Si](OC)(OC)OC)c1ccccc1)(OC)OC
Agent: [Cl-]
Product: CO[Si](CNc1ccccc1)(OC)OC

Procedure:
A yield of 331.2 g, i.e., 75.9% of theory, is obtained, with a product purity of about 96.5%. The product contains about 3.5% of N,N-bis[trimethoxysilylmethyl]-phenylamine as an impurity. The resulting product possesses a chloride content of approximately 100 ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11]>N1C=CC=CC=1>[CH2:13]([O:12][C:10]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1)=[O:11])[CH3:14]
Reactant: Nc1cccc(Br)n1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cccc(Br)n1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
10.0 g (1.0578 mole) of 2-amino-6-bromopyridine was dissolved in 40 ml dry pyridine and 6.4 ml (0.067 mole) of ethyl chloroformate was added dropwise while the solution was stirred and cooled in an ice-bath to maintain the reaction temperature at 15°-18° C. After 4 hours at room temperature, the reaction mixture was poured into 150 ml of ice water and kept at 0° C. overnight. Impure 2-ethoxycarbonylamino-6-bromopyridine was obtained by filtration and subsequently recrystallized from 2:1 methanol-water solution, giving an 88% yield of white solid, m.p=70.2°-71.0° C.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:18]4=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]4[CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1>C1COCC1.CO.[Pt](=O)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13]3[C:18]4=[N:19][S:20](=[O:23])(=[O:24])[CH2:21][CH2:22][N:17]4[CH2:16][CH2:15][CH2:14]3)=[CH:11][CH:12]=2)=[CH:25][CH:26]=1
Reactant: Cc1ccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)cc1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 69.5 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 9-[4-(4-methylphenoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (278 mg) in THF (dry) (30 mL) and MeOH (30 mL) and the mixture was stirred at 50° C. under hydrogen for 3 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). The filtrate was concentrated and the residue was crystallized from MeCN/IPE to give the title compound (195.4 mg) as colorless crystals.
Reaction SMILES: [NH2:1][OH:2].[C:3]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]([CH3:19])[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:7]([F:22])[CH:6]=1)#[N:4]>CCO>[NH2:4][C:3](=[N:1][OH:2])[C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]([CH3:19])[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])=[C:7]([F:22])[CH:6]=1
Reactant: NO
Reactant: CN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1F
Solvent: CCO
Product: CN(CC(=O)OC(C)(C)C)Cc1ccc(C(N)=NO)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.7 %

Procedure:
A 50% aqueous solution of hydroxylamine (345 mL, 5.85 mol) was added dropwise over 10 minutes into a solution of tert-butyl N-(4-cyano-2-fluorobenzyl)-N-methylglycinate (325 g, 1.17 mol) in EtOH (2.1 L). The reaction mixture was stirred at RT for 20 hours. Solvents were concentrated under vacuum and water (2 L) was added. The resulting suspension was filtered off, washed with water (1 L) and dried under vacuum to give title compound as white powder (323 g, 89%). 1H NMR (DMSO-d6, 300 MHz) δ 9.74 (s, 1H), 7.51 (dd, J=8.0, 1.6 Hz, 1H), 7.45-7.36 (m, 2H), 5.87 (s, 2H), 3.70 (s, 2H), 3.17 (s, 2H), 2.26 (s, 3H), 1.42 (s, 9H). LC/MS (Method B): 312.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([OH:25])[C:12]([C:13](=O)[CH:14]=[CH:15][CH:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH2:17]2)=[C:11]([O:26][CH2:27]C(OC)=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([OH:25])[C:12]2[C:13]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:27][O:26][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)COc1cc(OCc2ccccc2)cc(O)c1C(=O)C=CC1C=CC=CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Oc1cc(OCc2ccccc2)cc2occ(CCc3ccccc3)c12
Temperature: 25 °C
Yield: 22.6 %

Procedure:
To a solution of 4′-benzyloxy-6′-hydroxy-2′-(methoxycarbonylmethoxy)dihydrochalcone (0.53 g) in methanol (10 mL) was added sodium methoxide (28% methanol solution, 0.72 mL), and the mixture was heated for reflux overnight. The reaction mixture was cooled to room temperature and acidified by addition of 1 mol/L hydrochloric acid. The resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1-3/1) to give 6-benzyloxy-4-hydroxy-3-(2-phenylethyl)benzofuran (98 mg). This material was dissolved in dichloromethane (5 mL). To the solution were added 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (0.42 g) and boron trifluoride-diethyl ether complex (0.11 mL) successively, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-3/2) to give 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-6-benzyloxy-3-(2-phenylethyl)benzofuran (0.19 g). This material was dissolved in tetrahydrofuran (5 mL). To the solution was added 10% palladium-carbon powder (21 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 1.5 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethylacetate=2/1-3/2-1/1) to give the title compound (70 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[CH3:24][C:25]1[CH:26]=[CH:27][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:29][CH:30]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][C:6]1[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=[C:2]([NH:34][S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=2)(=[O:32])=[O:33])[N:7]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CCCC(C(=O)OC)c1c(C)nc(NS(=O)(=O)c2ccc(C)cc2)nc1-c1ccc(C)cc1
Yield: 22.8 %

Procedure:
Methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (100 mg; 0.300 mmol), p-toluenesulfonamide (0.061 mg; 0.361 mmol), palladium acetate (2 mg, 0.009 mmol) and xantphos (10 mg; 0.018 mmol) were placed in a 2 mL reaction tube and dissolved in dioxane (1 mL), the tube was purged with argon, sealed and irradiated in a microwave oven at 160° C. for 30 min. The reaction mixture was partitioned between a saturated sodium chloride solution and dichloromethane, filtered over a phase separator filter (1PS) and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (10-80%) in heptane to yield 32 mg (22%) of the title compound as a colorless oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])(=[O:14])=[O:13])=[CH:8][CH:7]=1.C(O)(=O)C.N([O-])=O.[Na+]>O>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[CH:21]=[C:20]([F:22])[C:19]([N+:1]([O-:4])=[O:2])=[CH:18][C:17]=2[F:23])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(F)ccc2F)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)Nc2cc(F)c([N+](=O)[O-])cc2F)cc1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 98.9 %

Procedure:
A stirred solution of 20 mL (0.427 mole) of 90% nitric acid (fuming) in 170 mL of water was cooled in an ice-water bath, and 22.0 grams (0.077 mole) of N-(4-methylphenylsulfonyl)-2,5-difluoroaniline was added. To this mixture was added 170 mL of acetic acid and then 0.5 gram (0.008 mole) of sodium nitrite. Upon completion of the addition, the reaction mixture was warmed to 90° C., where it stirred for about 2.5 hours. The reaction mixture was then cooled and poured into cold water. The resultant precipitate was collected by filtration and dried, yielding about 25 grams of N-(4-methylphenylsulfonyl)-2,5-difluoro-4-nitroaniline. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1.[Br:13]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][Br:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Cc1cccc(CBr)c1
Temperature: 25 °C

Procedure:
A solution of m-toly-acetic Acid methyl ester (11.41 g, 69.49 mmol), N-bromosuccinimide (12.59 g, 70.73 mmol), AIBN (100 mg) in CCl4 (200 mL) was heated at reflux for 16 h. The reaction was cooled to room temperature and aqueuos NaHCO3 (satd) was added. The aqueous solution was extracted with CH2Cl2 (2×) and the organic solution was dried (MgSO4), filtered, and concentrated. Purification by flash chromatography (hexanes to 9:1 hexanes:EtOAc) provided the title compound as a clear and colorless liquid (11.99 g). 1H NMR (CDCl3 400 MHz) δ 7.27 (m, 4H), 4.47 (s, 2H), 3.69 (s, 3H), 3.62 (s, 2H).
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1[C:18]1[CH:19]=[CH:20][C:21](=[S:24])[NH:22][N:23]=1.CC[O-].[Na+]>CCO>[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1[C:18]1[N:23]=[N:22][C:21]([S:24][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)=[CH:20][CH:19]=1
Reactant: BrCc1ccccn1
Reactant: Cc1ccc(-c2ccc(=S)[nH]n2)c(C)c1
Agent: Br
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-c2ccc(SCc3ccccn3)nn2)c(C)c1
Yield: 34.7 %

Procedure:
To a mixture of 2-(bromomethyl)pyridine hydrobromide (116 mg; 0.46 mmol) and 6-(2,4-dimethylphenyl)pyridazine-3(2H)-thione (Example 13a) (100 mg, 0.46 mmol) in EtOH (3 mL) was added EtONa (20% in EtOH, 25 μl) and the reaction was irradiated in a microwave at 140° C. for 4 min. The crude mixture was dried down and purified on silica gel (Eluent: 5% MeOH in DCM) to give 3-(2,4-Dimethylphenyl)-6-(pyridin-2-ylmethylthio)pyridazine (49 mg, 35%) as a white solid solid. 1H NMR (300 MHz, dMSO: δ 2.49 (s, 3H), 2.54 (s, 3H), 4.09 (s, 2H), 6.32-6.37 (m, 2H), 6.45-6.52 (m, 2H), 6.75-6.78 (d, 1H), 6.84-6.87 (m, 2H), 6.95-6.98 (t, 1H), 7.67-7.68 (d, 1H); MS (M+H, 308).