Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]2[S:11][C:12]3[CH2:19][CH2:18][O:17][C:16]4[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=4[C:13]=3[N:14]=2)[CH2:4][CH2:3]1.[C:24](Cl)(=[O:26])[CH3:25].O>N1C=CC=CC=1.C(N(C(C)C)CC)(C)C>[N:14]1[C:13]2[C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:12]=2[S:11][C:10]=1[NH:9][CH2:8][CH:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:24](=[O:26])[CH3:25])[CH2:3][CH2:4]1
Reactant: NC1CCC(CNc2nc3c(s2)CCOc2ccccc2-3)CC1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NC1CCC(CNc2nc3c(s2)CCOc2ccccc2-3)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
To a stirred solution of N2-[(4-aminocyclohexyl)methyl]-4,5-dihydrobenzo[2,3]oxepino[4,5-d][1,3]thiazol-2-amine (0.600 g, 1.49 mmol) in anhydrous pyridine (3 ml) and diisopropylethylamine was added acetyl chloride (0.130 ml, 1.83 mmol) dropwise. The solution was stirred for 30 minutes at room temperature and then poured into water (60 ml). The mixture was extracted with EtOAc, and the organic phase evaporated to afford a residue that was chromatographed on silica-gel eluting with EtOAc to yield 72% (400 mg) of the desired product as a light yellow solid: m.p. 69-72° C. 1H-NMR (CDCl3) δ 1.11 (4H, m), 1.60 (1H, broad), 1.73 (1H, broad), 1.83 (2H, m), 1.95 (3H, s), 2.05 (2H, m), 3.14 (4H, m), 3.73 (1H, broad), 4.33 (2H, t, J=4.9 Hz), 5.30 (1H, broad), 7.00 (1H, dd, J=0.9 Hz, 7.7 Hz), 7.12 (2H, m), 8.24 (1H, dd, J=0.9 Hz, 7.8 Hz). ESIMS m/z=372 (MH+).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].[CH3:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[C:10]([N+:17]([O-:19])=[O:18])[CH:9]=1.[OH-].[Na+]>O.C1C=CC=CC=1>[Br:2][CH2:3][CH2:4][NH:5][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8]([O:7][CH3:6])=[CH:9][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: NCCBr
Reactant: COc1ccc(C(=O)Cl)c([N+](=O)[O-])c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(C(=O)NCCBr)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 68 %

Procedure:
To a stirred and cooled (ice-bath) solution of 27.5 parts of 2-bromoethanamine hydrobromide in 200 parts of water is added a solution of 28.9 parts of 4-methoxy-2-nitrobenzoyl chloride in 63 parts of benzene at 5°-10° C. While stirring vigorously, there is added dropwise a solution of 10.8 parts of sodium hydroxide in 250 parts of water at 5°-10° C. Upon completion, stirring is continued for 2 hours at this temperature. The supernatant phase is decanted and the oily residue is stirred in 2-propanol. The product is filtered off and dried, yielding 27.5 parts (68%) of N-(2-bromoethyl)-4-methoxy-2-nitrobenzamide; mp. 133.8° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=1.[Cl:23][C:24]1[S:28][C:27]([C:29]([C:31]2[N:32]([CH3:36])[CH:33]=[N:34][CH:35]=2)=[O:30])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[S:28][C:27]([C:29]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]3[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)([C:31]2[N:32]([CH3:36])[CH:33]=[N:34][CH:35]=2)[OH:30])=[CH:26][CH:25]=1
Reactant: CCOc1cccc(-c2cc(OC)nc3ccc(Br)cc23)c1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)s1
Product: CCOc1cccc(-c2cc(OC)nc3ccc(C(O)(c4ccc(Cl)s4)c4cncn4C)cc23)c1
Yield: 71.8 %

Procedure:
Following the same procedure as that described in example 1E, 6-bromo-4-(3-ethoxy-phenyl)-2-methoxy-quinoline (800 mg, 2.23 mmol) and (5chloro-thiophen-2-yl)-(3-methyl-3H-imidazol-4-yl)-methanone (610 mg, 2.68 mmol) generated the title compound of 23B (810 mg, 72% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH:5]([OH:34])[CH2:6][NH:7][CH:8]([CH3:33])[CH2:9][C:10]1[CH:32]=[CH:31][C:13]([O:14][CH2:15][C:16]2O[CH:18]=[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:20](=[O:22])[CH:21]=2)=[CH:12][CH:11]=1.[NH3:38]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH:5]([OH:34])[CH2:6][NH:7][CH:8]([CH3:33])[CH2:9][C:10]1[CH:32]=[CH:31][C:13]([O:14][CH2:15][C:16]2[NH:38][CH:18]=[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:20](=[O:22])[CH:21]=2)=[CH:12][CH:11]=1
Reactant: N
Reactant: CC(Cc1ccc(OCc2cc(=O)c(OCc3ccccc3)co2)cc1)NCC(O)c1cccc(Cl)c1
Solvent: CO
Product: CC(Cc1ccc(OCc2cc(=O)c(OCc3ccccc3)c[nH]2)cc1)NCC(O)c1cccc(Cl)c1
Temperature: 120 °C

Procedure:
A solution of 2-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino]propyl] phenoxymethyl]-5-benzyloxy-4H-pyran-4-one (2 g) in methanol (10 ml) was treated with ammonia solution, SG 0.88, (5 ml) and heated to 120° C. in a sealed vessel for 18 hours. After evaporation of the solvent in vacuo the residue was crystallised from ethanol to give 2-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino]-propyl]phenoxymethyl]-5-benzyloxy-1H-pyrid-4-one (1.6 g , which was dissolved in methanol and the solution acidified with 2M hydrochloric acid solution to pH 1.5-2.0 and hydrogenated at room temperature and pressure over 10% palladium on charcoal. After filtration and evaporation of the solvent in vacuo the residue was treated with 1.2M sodium hydrogen carbonate solution (5 ml) and extracted with ethyl acetate (3×50 ml), dried (magnesium sulphate), filtered and evaporated under reduced pressure to give an oil. This was dissolved in methanol and treated with methanolic hydrogen chloride. Evaporation in vacuo gave 2-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino]propyl]phenoxymethyl]-5-hydroxy-1H-pyrid-4-one dihydrochloride as a (37:63) mixture of diastereoisomers.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:9]([N:14]([CH2:22][CH2:23][CH3:24])C(=O)OC(C)(C)C)=[C:10]([S:12][CH3:13])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl.C(OCC)(=O)C.[OH-].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[C:3]2[N:4]([C:9]([NH:14][CH2:22][CH2:23][CH3:24])=[C:10]([S:12][CH3:13])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CCCN(C(=O)OC(C)(C)C)c1c(SC)nc2c(Br)cc(C)cn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCCNc1c(SC)nc2c(Br)cc(C)cn12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
tert-Butyl N-[8-bromo-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridin-3-yl]-N-propylcarbamate was dissolved in ethyl acetate (5 mL), then a 4N hydrochloric acid-ethyl acetate solution (10 mL) was added thereto at room temperature, and the mixture was stirred at room temperature for 20 hours. Under ice-cooling, a 5N aqueous sodium hydroxide solution was added to neutralize the solution, which was extracted with ethyl acetate. The organic layers were combined, which was dried over anhydrous magnesium sulfate, and evaporated, to give the title compound (103 mg) as a yellow amorphous.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.C(O)(=[O:12])C.OO.[OH2:16]>>[CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][S:9](=[O:12])(=[O:16])[C:4]2=[CH:3][CH:2]=1
Reactant: O
Reactant: CC(=O)O
Reactant: c1ccc2sccc2c1
Agent: OO
Product: O=S1(=O)C=Cc2ccccc21

Procedure:
A solution of 40 grams of thianaphthene (Aldrich Chemical Co.), acetic acid (240 ml) and 30% hydrogen peroxide (180 ml) was heated at reflux for 15 minutes. This solution was added to water (800 ml), cooled and filtered to give thianaphthene-1,1-dioxide, m.p.--142°-143° C.
Reaction SMILES: [CH:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[CH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=O.[S:28]1[CH2:32][C:31](=[O:33])[NH:30][C:29]1=[O:34].C(O)(=O)C1C=CC=CC=1.N1CCCCC1.Cl>C1(C)C=CC=CC=1>[O:34]=[C:29]1[NH:30][C:31](=[O:33])[C:32](=[CH:1][C:3]2[CH:4]=[CH:5][C:6]([O:7][C:8]3[CH:9]=[CH:10][C:11]([C:14](=[CH:18][C:19]4[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=4)[C:15]([OH:17])=[O:16])=[CH:12][CH:13]=3)=[CH:26][CH:27]=2)[S:28]1
Reactant: Cc1ccc(C=C(C(=O)O)c2ccc(Oc3ccc(C=O)cc3)cc2)cc1
Reactant: O=C1CSC(=O)N1
Agent: Cl
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: Cc1ccc(C=C(C(=O)O)c2ccc(Oc3ccc(C=C4SC(=O)NC4=O)cc3)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 39 (4.0 g, 11.2 mmol), thiazolidine-2,4-dione (1.31 g, 11.2 mmol), and benzoic acid (1.64 g, 13.4 mmol) in 100 mL toluene was added piperidine (1.66 mL, 16.8 mmol). The mixture was vigorously refluxed with Dean Stark apparatus for 1.5 h under argon then cooled to room temperature. 5% HCl was added to pH 1. The solid was filtered, recrystallized out of toluene, filtered, and washed with hexane before drying under vacuum to a yellow solid (quantitative). 1H NMR (400 MHz, DMSO-d6) δ 12.70 (br s, 1H), 12.59 (br s, 1H), 7.80 (s, 1H), 7.75 (s, 1H), 7.67 (d, J=8.8 Hz, 2H), 7.22 (d, J=9.2 Hz, 2H), 7.18 (d, J=7.6 Hz, 2H), 7.12 (d, J=9.2 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 6.99 (d, J=8.0 Hz, 2H), 2.25 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12](B3OC(C)(C)C(C)(C)O3)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[C:32]2=[C:33](Br)[CH:34]=[C:35]([CH:36]3[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]3)[N:31]2[N:30]=[CH:29][N:28]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C>[NH2:26][C:27]1[C:32]2=[C:33]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:34]=[C:35]([CH:36]3[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]3)[N:31]2[N:30]=[CH:29][N:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Br)c3c(N)ncnn23)C1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 100 °C
Yield: 38.1 %

Procedure:
To a stirred suspension of Intermediate C (2.62 g mg, 7.85 mmol) and tert-butyl 3-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)pyrrolidine-1-carboxylate (2.50 g, 6.54 mmol) in degassed DMF (6.7 mL) was added solid potassium phosphate (4.16 g, 19.62 mmol) followed by water (833 uL, 49 mmol). The reaction mixture was taken through three purge-fill cycles using nitrogen and vacuum. The reaction was then heated (100° C.) for 1 h and then cooled to rt. The mixture was partitioned between ethyl acetate (200 mL) and H2O (100 mL). The layers were separated and the organic layer was washed 6 times with brine to remove DMF (50 mL each), dried (Na2SO4), and concentrated to dryness. The crude residue was purified by ISCO® chromatography using a gradient of 50 to 100% ethyl acetate in dichloromethane to afford 1.27 g (38%) of the desired product as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1 H), 7.93 (s, 1 H), 7.80 (d, 1 H), 7.59 (s, 1 H), 7.35-7.30 (m, 4H), 7.15 (d, 1 H), 6.66 (s, 1H), 5.64 (s, 2 H), 3.9-3.7 (m, 1 H), 3.50-3.30 (m, 4H), 2.42 (m, 1H), 2.13 (m, 1H), 1.38 (s, 9H); ES-MS m/z 510.3 [M+H]+, HPLC RT (min) 3.16.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.ON1C2C=CC=CC=2N=N1.[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][NH:26]1>CN(C=O)C>[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][N:26]1[C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1)=[O:13]
Reactant: O=C(O)c1ccc2cnccc2n1
Reactant: c1ccc2c(c1)CCNC2
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc2cnccc2n1)N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (1.0 mL) at room temperature was added sequentially 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 1,2,3,4-tetrahydroisoquinoline (55.6 μL, 0.431 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum. Flash column chromatography of the residue (100% ethyl acetate) afforded the desired product as a white solid (79.1 mg, 95%): m.p. 98-100° C.
Reaction SMILES: Cl[C:2](=O)[CH2:3][C:4]([O:6]C)=[O:5].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH2:19])(=[O:18])=[O:17].[OH-].[Na+].Cl>C(OCC)C.CN(C)C(=O)C>[O:17]=[S:16]1(=[O:18])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:2]([CH2:3][C:4]([OH:6])=[O:5])=[N:19]1
Reactant: COC(=O)CC(=O)Cl
Reactant: Nc1ccccc1S(N)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: O=C(O)CC1=NS(=O)(=O)c2ccccc2N1
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
Methyl 3-chloro-3-oxopropionate (3.36 mL, 31.3 mmol) was added to a solution of 2-aminobenzenesulfonamide (4.91 g, 28.5 mmol) in a 1:1 mixture of N,N-dimethylacetamide and diethylether (100 mL) at 0° C. The cloudy reaction mixture was stirred at 0° C. for 3 h, and then was partitioned between half-saturated aqueous sodium bicarbonate (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and were concentrated in vacuo. The residue was then dissolved in water (75 mL) containing sodium hydroxide (3.42 g, 85.5 mmol) at 25° C. The mixture was heated at 100° C. for 1 h, and then was cooled to 0° C. Concentrated (12.0 M) aqueous hydrochloric acid solution (10.0 mL, 120 mmol) was added dropwise via addition funnel over 10 min, resulting in the formation of a white precipitate. The reaction mixture was stirred at 0° C. for an additional 15 min, and then was filtered through a medium frit. The collected material was washed with water (30 mL) and was air-dried overnight to afford the desired product, (1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (6.37 g, 26.6 mmol, 93%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 3.58 (2H, s), 7.30 (1H, d, J=7.4 Hz), 7.44 (1H, t, J=8.2 Hz), 7.64-7.68 (1H, m), 7.79 (1H, dd, J1=1.5 Hz, J2=7.8 Hz), 12.19 (1H, s).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([N:28]([CH3:38])[S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:26]=[CH:27][C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:41][N:40]=[N:39][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[CH:24]=[C:25]([N:28]([CH3:38])[S:29]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)(=[O:31])=[O:30])[CH:26]=[CH:27][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1nc2ccc(N(C)S(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2ccc(N(C)S(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 41 from 4'-[[2-n-propyl-6-(N-benzenesulphonyl-methylamino)-benzimidazol-1-yl]methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1O)[CH:5]=[O:6].C([O:13][Si:14](OCC)(OCC)OCC)C>C1(C)C=CC=CC=1>[C:5](=[C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([O-:1])[CH:3]1[O-:13])=[O:6].[Si+4:14].[C:5](=[C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([O-:1])[CH:3]1[O-:13])=[O:6]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: CCO[Si](OCC)(OCC)OCC
Solvent: Cc1ccccc1
Product: O=C=C1C=CC=C([O-])C1[O-]
Product: [Si+4]
Temperature: 100 °C

Procedure:
A solution of 3,4-dihydroxybenzaldehyde (27.6 g, 200 mmol) and toluene (220 mL) was dehydrated by distilling 5 mL of the solution. Thereafter, 20.8 g (100 mmol) of tetraethoxysilane (TEOS) was added to the solution while stirring. The mixed solution was refluxed for 1 hour, and then, while the distillation temperature was 100° C. or higher, distilled until the amount of the solution became half. After the distillation, solid content of the product was isolated by suction filtering using a membrane suction filter. The residual solid content was heated to 100° C. under vacuum using a vacuum dryer so that remaining volatile components were completely removed. The solid content (3,4-dihydroxybenzaldehyde-silicon complex) was black in color. The yield amount was 30.0 g (100 mmol), and the yield percentage was 100%. 15 g of 3,4-dihydroxybenzaldehyde-silicon complex was dissolved into 100 mL of 1:9 dimethylsulfoxide/ethanol to produce a coating liquid.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[NH:14])[NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH:15]([CH:17]([CH2:23][C:24]([O:26][CH2:27]C)=[O:25])[C:18](OCC)=O)=[O:16].C[O-].[Na+].C(O)(=O)C>CO.O>[OH:16][C:15]1[C:17]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][N:13]=[C:12]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=2)[N:14]=1
Reactant: N=C(N)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CC(C=O)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Cc1cnc(Cc2ccc([N+](=O)[O-])cc2)nc1O
Temperature: 90 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a mixture of 2-(4-nitrophenyl)ethanimidamide hydrochloride (6.06 g, 28.12 mmol) and diethyl 2-formylsuccinate (6.54 g, 32.34 mmol) in methanol (100 mL) was added sodium methoxide (28% in methanol, 11.2 mL, 56.25 mmol) at room temperature, and the reaction mixture was stirred at 90° C. overnight. After the cooling to room temperature, the reaction was quenched with acetic acid (3.38 mL, 59.06 mmol) and water (100 mL) was added to. The resulting precipitates were collected by filtration and washed with water and acetone/diisopropyl ether (3/2) to give methyl [4-hydroxy-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (5.41 g, 64%) as brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])#[N:2].C([Sn](=O)CCCC)CCC.C[Si]([N:24]=[N+:25]=[N-:26])(C)C>C1(C)C=CC=CC=1>[NH2:5][C:4]1[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=1[C:1]1[NH:26][N:25]=[N:24][N:2]=1
Reactant: N#Cc1ccccc1N
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: Nc1ccccc1-c1nnn[nH]1
Temperature: 25 °C
Yield: 17.6 %

Procedure:
To 2-cyanoaniline (5.00 g, 42.3 mmol) and dibutyltin oxide (520 mg, 2.1 mmol) dissolved in toluene (40 mL) was added trimethylsilyl azide (6.40 mL, 47 mmol). The reaction mixture was heated at ~95° C. for 70 hours, cooled to ambient temperature, concentrated under reduced pressure and partitioned between water (50 mL) and saturated sodium carbonate solution (50 mL). The organic phase was extracted with another aliquot (25 mL) of saturated sodium carbonate solution. The combined aqueous extracts were washed with ether (2×25 mL), acidified with solid citric acid to pH 4-5, and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate, decolorized with Norite, filtered and concentrated under reduced pressure to give the title compound as a solid (1.20 g). 1H NMR (DMSO-d6, 300 MHz) δ3.4 (br s, 1H), 6.68 (dt, J=1 Hz, 8 Hz, 1H), 6.90 (d, J=8 Hz, 1H), 7.25 (d,t J=1 Hz, 8 Hz, 1H), 7.73 (d, J=8 Hz, 1H), 9.0-11.0 (br, 2H). MS (DCl/NH3) m/e 162 (M+H)+, 179 (M+H+NH3)+.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[C:8]=1[CH3:17])(=O)=O.CC1C([N+]([O-])=O)=CC=C(C)C=1CCl.[H-].[Na+].O[C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:43]=1[N:42]=[C:41]([CH3:44])[CH:40]=[CH:39]2>CN(C)C=O.O>[CH3:17][C:8]1[C:9]([N+:14]([O-:16])=[O:15])=[CH:10][CH:11]=[C:12]([CH3:13])[C:7]=1[CH2:6][O:5][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:43]=1[N:42]=[C:41]([CH3:44])[CH:40]=[CH:39]2
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1COS(C)(=O)=O
Agent: Cc1ccc([N+](=O)[O-])c(C)c1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2cccc(OCc3c(C)ccc([N+](=O)[O-])c3C)c2n1
Reaction time: 0.25 h

Procedure:
To a mixture of 2,6-dimethyl-3-nitrobenzyl methanesulfonate and 2,6-dimethyl-3-nitrobenzyl chloride obtained above in N,N-dimethylformamide (13 ml) was added sodium hydride (60% in oil, 335 mg) under ice-bath cooling, and the mixture was stirred for 15 minutes. To the mixture was added 8-hydroxy-2-methylquinoline (1.27 g), and the mixture was stirred for 1 hour at ambient temperature. Water was added there to, and the resulting precipitate was collected by filtration to give 8-(2,6-dimethyl-3-nitrobenzyloxy)-2-methylquinoline (2.53 g).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7])[C:2]1([CH:10]1[CH:15]([O:16][CH3:17])[CH:14]([OH:18])[CH2:13][CH2:12][C:11]1([CH2:20][S:21][CH3:22])[OH:19])[CH3:9].[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>C(Cl)(Cl)Cl.[Ag]Br>[Br-:23].[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][CH2:22][SH+:21][CH2:20][C:11]2([OH:19])[CH2:12][CH2:13][CH:14]([OH:18])[CH:15]([O:16][CH3:17])[CH:10]2[C:2]2([CH3:9])[O:1][CH:3]2[CH2:4][CH:5]=[C:6]([CH3:7])[CH3:8])=[CH:26][CH:25]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COC1C(O)CCC(O)(CSC)C1C1(C)OC1CC=C(C)C
Agent: Br[Ag]
Solvent: ClC(Cl)Cl
Product: COC1C(O)CCC(O)(C[SH+]CCc2ccc(Br)cc2)C1C1(C)OC1CC=C(C)C
Product: [Br-]
Reaction time: 28 h
Yield: 50.1 %

Procedure:
In chloroform (0.5 ml) were dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (200 mg) and 4-bromobenzyl bromide (756 mg). To the solution was added silver bromide (11.4 mg), and the mixture was stirred for 28 hours. Insolubles were filtered off, and the solvent was distilled off. The residue was pulverized by the addition of ether. The resulting powder was dissolved in methanol (2 ml). Insolubles were filtered off, then the solvent was distilled off under reduced pressure. The residue was pulverized by the addition of ether to give 1-(4-bromobenzyl)methylsulfoniomethyl-2-(1,2-epoxy- 1,5-dimethyl-4-hexenyl)-3-methoxy-1,4cyclohexanediol bromide (176 mg: yield 50%) as colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]#[N:14])=[CH:11][C:10]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:9]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH:24]=O.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[C:13]([C:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][CH2:24][C:23]3[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:22]=3[Cl:21])=[CH:7][CH:6]=2)[N:9]=[C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=1)#[N:14]
Reactant: Cc1cccc(Cl)c1C=O
Reactant: N#Cc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cccc(Cl)c1CNc1ccc(-n2nc(-c3cccnc3)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
To a stirred solution of 1-(4-aminophenyl)-3-(3-pyridyl)-5-cyanopyrazole (130 mg, 0.5 mmol) and 2-chloro-6-methylbenzaldehyde (0.9 g) in acetic acid (4 mL) and MeOH (7 mL) at room temperature was added sodium cyanoborohydride (79 mg, 1.25 mmol). The reaction mixture was stirred at room temperature for 16 h and then concentrated under a stream of nitrogen, diluted with water, extracted into ethyl acetate, washed with sodium bicarbonate solution, water and dried (MgSO4). The residue obtained on concentration was chromatographed on silica gel (eluant, gradient of 15-25% EtOAc in CH2Cl2) to provide the title compound (152 mg, 76%). NMR (CDCl3, 400 MHz): 9.2 (s, 1H); 8.7(br, 1H); 8.4(br, 1H); 7.6-7.5 (overlapping m, 3H), 7.4-7.1(overlapping m, 5H), 6.8 (d, 2H), 4.5 (s, 2H), 2.5 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]1[CH3:11].Cl.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[CH:8][C:7]([C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=2)=[C:6]1[CH3:11]
Reactant: COCCn1c(C)ccc1C
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COCCn1c(C)cc(C(=O)c2cccnc2)c1C
Yield: 13.2 %

Procedure:
In 1,2-dichloroethane, 2-(2,5-dimethylpyrrol-1-yl)-ethyl methyl ether was reacted with nicotinoyl chloride hydrochloride in the presence of aluminum chloride. The reaction product was chromatographed on a column of silica gel using cyclohexane/ethyl acetate (1/1) as an eluent to afford compound (260) in a yield of 13.2%.