Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1I.[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Sc1ccccc1
Reactant: COC(=O)c1ccccc1I
Product: COC(=O)c1ccccc1Sc1ccccc1

Procedure:
The general procedure was used to convert Methyl-2-iodobenzoate and thiophenol to the title product. Purification by flash chromatography (hexane/ethyl acetate [6:1] as the eluent) gave the analytically pure product as a clear oil (397 mg, 81% yield). 1H NMR (300 MHz, CDCl3) δ 7.88 (dd, J=6.22, 1H; Hd), 7.47 (m, 2H; Ha, Hb), 7.33 (m, 3H; He, He′, Hf′), 7.14 (td, J=5.4, 1H; Hc), 7.04 (td, J=6.02, 1H; Hf), 6.73 (dd, J=6.78, 1H; Hg), 3.85 (s, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 166.79 (C13), 143.15 (C1), 135.47 (C6), 132.39 (C3), 132.22 (C2), 130.93 (C5), 129.65 (C7), 129.02 (C8, C12), 127.28 (C9, C11), 126.58 (C10), 124.19 (C4), 52.10 (C14). Anal. Calcd. for C14H12O2S: C, 68.83; H, 4.95; S, 13.13; Found C, 68.94; H, 5.10; S, 12.90.
Reaction SMILES: [C:1]([C:3](C)([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)[C:4](OCC)=O)#[N:2].[OH-].[Na+].[ClH:25]>>[ClH:25].[CH3:4][CH:3]([CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:13][CH2:14]1)[C:1]#[N:2]
Reactant: CCOC(=O)C(C)(C#N)C1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C#N)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
To 45 parts of cooled ethyl α-cyano-α-methyl-1-(phenylmethyl)-4-piperidineacetate were added 250 parts of a sodium hydroxide solution 2N. After stirring overnight at room temperature, the reaction mixture was cooled, neutralized with hydrochloride acid and then evaporated. The residue was taken up in 45 parts of N,N-dimethylacetamide and the whole was heated for 5 hours at 150° C. and then evaporated again, yielding 16 parts (30.3%) of α-methyl-1-(phenylmethyl)-4-piperidineacetonitrile monohydrochloride (int. 31).
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]3[N:21]=[C:22]([CH3:25])[N:23]([CH3:24])[C:13]=3[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O>CO.[C].[Pd]>[NH2:1][C:4]1[CH:27]=[CH:26][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]3[N:21]=[C:22]([CH3:25])[N:23]([CH3:24])[C:13]=3[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1
Reactant: Cc1nc2c(n1C)CCN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1-2
Agent: [Pd]
Solvent: CO
Product: Cc1nc2c(n1C)CCN(C(=O)c1ccc(N)cc1)c1ccccc1-2

Procedure:
A 1.421 g portion of 6-(4-nitrobenzoyl)-2,3-dimethyl-3,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine was dissolved in 50 ml of methyl alcohol, and the solution was mixed with 300 mg of palladium-carbon and subjected to hydrogenation under normal pressure. After completion of the hydrogen absorption, the reaction mixture was subjected to filtration and the resulting filtrate was concentrated to obtain 571 mg of 6-(4-aminobenzoyl)-2,3-dimethyl-3,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][C:14]([OH:16])=O)[C:9]2=O)=[CH:4][CH:3]=1.[C:17]1([NH:23][NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH:8]3[C:9]([C:10]=2[CH:11]=1)=[N:24][N:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](=[O:16])[CH2:13]3
Reactant: O=C(O)CC1CCc2ccc(Cl)cc2C1=O
Reactant: NNc1ccccc1
Solvent: CCO
Product: O=C1CC2CCc3ccc(Cl)cc3C2=NN1c1ccccc1
Yield: 71 %

Procedure:
A mixture of 12 g of 7-chloro-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetic acid and 8.1 g of phenylhydrazine in 150 ml of ethanol is refluxed under heating for 14 hours. Then the ethanol is distilled off under reduced pressure, 100 ml of acetic acid is added to the residue and the mixture is refluxed under heating for 7 hours. After the acetic acid is distilled off, the residue is extracted with chloroform. The extract is washed with water, dried over magnesium sulfate anhydride and then the chloroform is distilled off to give crystals. The precipitated crystals are collected by filtration and recrystallized from alcohol to give 11.1 g of 9-chloro-2-phenyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one as colorless prisms, melting at 120°-122° C.
Reaction SMILES: [CH3:1]/[C:2](/[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])=[CH:17][CH:16]=1)=[CH:3]\[C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][CH:5]=1.[OH-].[K+].Cl>C(O)C.O.CCOCC>[CH3:1]/[C:2](/[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])=[CH:19][CH:20]=1)=[CH:3]\[C:4]1[CH:14]=[CH:13][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccc(/C=C(\C)c2ccc(OCC=C(C)C)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CC(C)=CCOc1ccc(/C(C)=C/c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 100 mg of ethyl 4-(E-2-methyl-2-(4-(3-methyl-2-butenoxy)phenyl)ethenyl)-benzoate in 3 ml of ethanol under argon is added dropwise a solution of 50 mg of potassium hydroxide in 3 ml of ethanol and 1 ml of water. The mixture is stirred at room temperature for 18 hours, cooled and acidified with 3N hydrochloric acid. The resulting precipitate is dissolved in ether, the ether solution washed with saturated aqueous sodium chloride and concentrated to give a solid which is recrystallized from aqueous methanol to give 4-(E-2-methyl-2-(4-(3-methyl-2-butenoxy) phenyl)ethenyl) benzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[CH:5]=[CH:4][N:3]=1.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[N:10][O:11][C:12]=2[CH2:13][Br:20])[CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1onc(-c2ccccc2)c1-c1ccnc(Br)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: BrCc1onc(-c2ccccc2)c1-c1ccnc(Br)c1
Reaction time: 18 h
Yield: 56.9 %

Procedure:
A stirred solution of the above Compound 17a (404 mg, 1.28 mmol), N-bromosuccinimide (239 mg, 1.35 mmol) and AIBN (11 mg, 0.064 mmol) in CCl4 (3 mL) was heated to reflux and placed under a 300 W lamp for 18 h. The solution was diluted with CH2Cl2 (15 mL), extracted with H2O (3×10 mL), brine (40 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (SiO2, 15–20% EtOAc-hexanes) provided the title compound (287 mg, 0.728 mmol, 57%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[C:11](Br)[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)[CH2:4][CH2:3]1.CC(C)([O-])C.[K+].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C(O)(C)(C)C>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[C:11]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)[CH2:4][CH2:3]1
Reactant: CN1CCC(=C2c3ccccc3C=C(Br)c3ccccc32)CC1
Reactant: C1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CN1CCC(=C2c3ccccc3C=C(N3CCCCC3)c3ccccc32)CC1

Procedure:
1-Methyl-4-(10-bromo-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 2.87 g. (0.0079 mole), 50 ml. of a 0.4M solution of potassium t-butoxide in t-butanol, and 20 ml. of dry piperidine is stirred and refluxed under anhydrous conditions for 6 hours. The reaction mixture is cooled and partitioned between 350 ml. of benzene and 50 ml. of water. The benzene layer is then extracted 5 more times with 50 ml. each of water. The benzene layer is then dried over anhydrous MgSO4, filtered, and the benzene evaporated. This gives a single spot on t.l.c. and is used directly in the next step.
Reaction SMILES: N=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH:5]=[C:4]([CH3:17])[S:3]1.C(NCC)C>CN(C)C=O>[F:16][C:13]([F:14])([F:15])[C:9]1[CH:8]=[C:7]([N:6]2[CH:5]=[C:4]([CH3:17])[S:3][CH2:2]2)[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CC1=CN(c2cccc(C(F)(F)F)c2)CS1
Temperature: 25 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
A solution of 2-imino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (1.29 g, 5.0 mmol) and diethylamine (1.21 g, 16.5 mmol) in N,N-dimethylformamide (10 ml) charged in a reaction flask was reacted with the chlorotrifluoloethylene, which was made to flow into the flask (ca. 0.7 liter/hr), with vigorous stirring at room temperature for 6 hours. After completion of the reaction, the reaction mixture was subjected to a similar post-treatment as described above, which afforded 2-chlorofluoroacetylimino)-3-(3-trifluoromethylphenyl)-5-methylthiazoline (1.19 g, 3.4 mmol, yield 67% ).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:31]([NH:35][CH3:36])[CH:32]([CH3:34])[CH3:33]>>[CH2:31]([N:35]([CH3:36])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)[CH:32]([CH3:34])[CH3:33]
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Reactant: CNCC(C)C
Product: CC(C)CN(C)CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1

Procedure:
The product from Example 44E and isobutyl(methyl)amine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 8.70 (m, 1H), 8.23 (d, J=1.8 Hz, 1H), 7.98 (m, 3H), 7.59 (d, J=8.7 Hz, 1H), 6.85 (s, 1H), 3.0-3.8 (m, 14H), 2.98 (s, 3H), 2.2 (m, 1H), 1.09 (d, J=6.6 Hz, 6H); MS (DCI) m/z 422 (M+H)+;
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[O:14][C:13](=[O:15])[NH:12][C:11]1=[O:16])([O-])=O.[ClH:17]>CO.[Fe]>[ClH:17].[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[O:14][C:13](=[O:15])[NH:12][C:11]1=[O:16]
Reactant: O=C1NC(=O)C(c2ccccc2[N+](=O)[O-])O1
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: Nc1ccccc1C1OC(=O)NC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-(2-Nitrophenyl)oxazolidine-2,4-dione (5.0 g., 22.5 mmoles) was taken up in a mixture of methanol (11.5 ml.) and conc. hydrochloric acid (12.3 ml.). Powdered iron (3.77 g., 67.5 mmoles) was added over 30 minutes, during which an exothermic reaction brought the temperature to reflux and the mixture became homogeneous. The mixture was cooled to room temperature and stirred for 3 hours. Additional iron powder (1.2 g.) was added and the mixture stirred for 0.5 hour, poured into 100 ml. of water and extracted with three portions of ethyl acetate. The combined ethyl acetate extracts were back washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a foamed solid. The crude product was taken up in 55 ml. of ethanol, cooled to 0° C., perfused with hydrogen chloride for 10 minutes (crystallization began at this stage), diluted with ether and filtered to recover purified 5-(2-aminophenyl)oxazolidine-2,4-dione hydrochloride [2.52 g., m.p. 205° -209° C. (dec); m/e 192].
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C(O)(=O)C1C(=CC=CC=1)C(O)=[O:16].C1(=O)OC(=O)C2=CC=CC=C12>Cl>[OH:16][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(O)c1ccccc1C(=O)O
Agent: Cl
Agent: O=C1OC(=O)c2ccccc21
Product: O=C1c2ccccc2C(=O)N1O
Yield: 70 %

Procedure:
To a flask was added 50 mL of 2N hydrochloric acid, and powdery phthalimide (7.4 g, 0.05 mol) was slowly added thereto with stirring. Then, the mixture was stirred at 97° C. for 3 hours to obtain an aqueous solution containing phthalic acid. Phthalic acid was recovered by condensing and filtering the aqueous solution. Then, to a flask, were added the phthalic acid, 100 mL of pyridine and 0.5 g of sulfuric acid, and stirred for 3 hours at 100° C. with distilling off water formed by reaction to obtain a mixture containing phthalic anhydride. Hydroxylamine hydrochloride NH2OH.HCl (6.9 g, 0.1 mol) was added to the mixture and stirred at 50° C. for 3 hour to form N-hydroxyphthalimide (5.74 g, yield 70%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15]Cl)[CH:6]=[C:5]2[CH:19]=[O:20].[C:21]([O-:24])(=[O:23])[CH3:22].[Na+].[I-].[Na+]>CS(C)=O.O>[C:21]([O:24][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][N:7]1[CH:6]=[C:5]([CH:19]=[O:20])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[C:8]1=[O:12])(=[O:23])[CH3:22]
Reactant: CC(=O)[O-]
Reactant: CC(C)(CCl)Cn1cc(C=O)c2cc(Br)ccc2c1=O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)OCC(C)(C)Cn1cc(C=O)c2cc(Br)ccc2c1=O
Temperature: 100 °C
Reaction time: 10 h
Yield: 52.1 %

Procedure:
A solution of 6-bromo-2-(3-chloro-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinoline-4-carbaldehyde (Example 1d, 0.45 g) in dimethylsulfoxide (10 mL) was treated with sodium acetate (0.343 g) under nitrogen. The resulting mixture was stirred at 100° C. for 10 h. Sodium iodide (1 eq) was added and the reaction heated at 120° C. for 30 h. The reaction mixture was diluted with water (250 mL) and the solid filtered off and dried to afford the subtitle compound (0.25 g) as a solid.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)([CH2:31]OS(C)(=O)=O)[CH2:25]OS(C)(=O)=O)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:43])=[N:5]1)([CH3:3])[CH3:2]>C(N)(C)C>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([O:23][C:24]5([C:37]6[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=6)[CH2:31][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:25]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:43])=[N:5]1)([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(COS(C)(=O)=O)(COS(C)(=O)=O)c4ccccc4)cc2OCC3)n(C(C)C)n1
Solvent: CC(C)N
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC4(c5ccccc5)CN(C(C)C)C4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Yield: 71.4 %

Procedure:
A solution of methanesulfonic acid 2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-3-methanesulfonyloxy-2-phenylpropylester (41.5 mg, 0.0657 mmol) in isopropylamine (0.7 mL) was heated at 140° C. for 12 h using microwave irradiation. After cooling to RT, the crude reaction mixture was evaporated and then purified by column chromatography (C18, gradient 20-50% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3/MeOH. Further purification by column chromatography (Si-PCC, gradient 2-10% MeOH in DCM) affording 275 as a colourless gum (11.7 mg, 36%). LCMS (Method K): RT 3.17 min [M+H]+ 499.1. 1H NMR (CD3OD, 400 MHz): δ 8.22 (1H, d, J=9.0 Hz), 7.62 (1H, s), 7.59-7.57 (2H, m), 7.40-7.36 (2H, m), 7.31-7.27 (1H, m), 6.47 (1H, dd, J=9.0, 2.5 Hz), 6.21 (1H, d, J=2.5 Hz), 5.82 (1H, septet, J=6.7 Hz), 4.43-4.38 (4H, m), 3.88 (2H, d, J=9.2 Hz), 3.67 (2H, d, J=9.2 Hz), 2.58 (1H, septet, J=6.2 Hz), 2.34 (3H, s), 1.49 (6H, d, J=6.7 Hz), 1.02 (6H, d, J=6.2 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[N:14]=[C:15]([CH3:19])[CH:16]=[C:17](O)[C:12]3=[CH:11][C:10]=2[CH3:20])=[C:5]([CH3:21])[CH:4]=1.P(Br)(Br)[Br:23].C([O-])(O)=O.[Na+]>BrC1C=CC=CC=1.C(Cl)(Cl)Cl>[Br:23][C:17]1[C:12]2[N:13]([C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:21])=[C:10]([CH3:20])[CH:11]=2)[N:14]=[C:15]([CH3:19])[CH:16]=1
Reactant: COc1ccc(-c2c(C)cc3c(O)cc(C)nn23)c(C)c1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: Brc1ccccc1
Product: COc1ccc(-c2c(C)cc3c(Br)cc(C)nn23)c(C)c1
Temperature: 25 °C

Procedure:
A solution of 7-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrrolo[1,2-b]pyridazin-4-ol (0.16 g, 0.567 mmol) and phosphorus tribromide (0.27 mL, 2.83 mmol) in bromobenzene (3.0 mL) was refluxed for 5 h. After cooling down to room temperature, the mixture was diluted with CHCl3. Saturated NaHCO3 solution was added to neutralize and separated immediately. The aqueous layer was extracted with CHCl3 (2×). The combined CHCl3 solution was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (silica gel, 1/20 EtOAc/hexane) to afford 0.14 g (64%) of light yellow oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J=8 Hz, 1H), 6.82 (d, J=3 Hz, 1H), 6.76 (dd, J=3, 8 Hz, 1H), 6.59 (s, 1H), 6.49 (s, 1H), 3.79 (s, 3H), 2.28 (s, 3H), 2.12 (s, 3H), 1.98 (s, 3H); MS m/z 347.1 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].CO[C:17](=O)[C:18]1C=C(N2CCCCC2)C=C[C:19]=1N.N1CCCCC1.S(=O)(=O)(O)O.[BH4-].[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([NH:10][CH2:17][CH2:18][CH3:19])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: COC(=O)c1cc(N)ccc1[N+](=O)[O-]
Reactant: COC(=O)c1cc(N2CCCCC2)ccc1N
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: CCCNc1ccc([N+](=O)[O-])c(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
5-Amino-2-nitro-benzoic acid methyl ester (compound A′) (800 mg) was dissolved in dry THF (15 ml). Propionaldehyde (compound D) (870 μl) dissolved in a mixed liquid composed of 3 M sulfuric acid (4 ml) and THF (1 ml) was added to the solution at room temperature. Subsequently, sodium borohydride (231 mg) was added thereto at 0° C., and the mixture was stirred at room temperature for 3 hr. Thereafter, distilled water was added thereto, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate and was then concentrated. The residue was purified by column chromatography using a hexane-acetone system to give 2-nitro-5-propylamino-benzoic acid methyl ester as a useful intermediate (608 mg, yield 63%).
Reaction SMILES: [CH3:1][N:2]([CH:4]=[C:5]([C:8](=O)[CH2:9][CH3:10])[C:6]#[N:7])C.Cl.C(N)=[NH:14].C(N(CC)CC)C>C(O)C>[CH2:9]([C:8]1[C:5]([C:6]#[N:7])=[CH:4][N:2]=[CH:1][N:14]=1)[CH3:10]
Reactant: N=CN
Reactant: CCC(=O)C(C#N)=CN(C)C
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1ncncc1C#N
Yield: 35 %

Procedure:
A mixture of crude 2-((dimethylamino)methylene)-3-oxopentanenitrile (0.98 equiv.), formamidine hydrochloride (2.0 equiv.) and triethyl amine (2.0 equiv.) in ethanol (1.0 M) was refluxed for 36 h. The solvent was removed and the residue was purified by silica column chromatography (20% ethyl acetate in petroleum ether) to afford the title product (35% yield). 1H-NMR (400 MHz, CDCl3) δ (ppm) 9.20 (s, 1H), 8.83 (s 1H), 2.98 (d, J=7.6 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H); MS (ESI) m/z 134.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>CO.[C].[Pd]>[NH2:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([CH3:1])[CH:10]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Methyl-4-nitrobenzoic acid (741 g, 5 mmol) was dissolved in methanol (20 mL), 10% palladium-carbon (100 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. The reaction solution was filtered through celite and, thereafter, the filtrate was concentrated under reduced pressure to obtain 4-amino-2-methylbenzoic acid as a crude material. In accordance with Reference Example 23 and Reference Example 14, from 4-amino-2-methylbenzoic acid obtained, there was obtained 4-[(tert-butyldimethylsilanoyloxy)methyl]-3-methylaniline (0.33 g).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([Cl:8])=[N:6][S:5][N:4]=1.[NH2:9][CH2:10][CH2:11][SH:12].[O-]CC.[Na+]>C(O)C>[Cl:8][C:7]1[C:3]([CH2:2][S:12][CH2:11][CH2:10][NH2:9])=[N:4][S:5][N:6]=1
Reactant: Clc1nsnc1CBr
Reactant: NCCS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NCCSCc1nsnc1Cl

Procedure:
3-Methyl(1,2,5)thiadiazole is chlorinated for 4 days in acetonitrile at 25° to give 4-chloro-3-methyl(1,2,5)thiadiazole (oil) which is treated with N-bromosuccinimide in carbon tetrachloride to give 3-bromomethyl-4-chloro(1,2,5)thiadiazole (oil), the 100 MHz n.m.r. in CDCl3 had singlet at 4.66δ. 3-Bromomethyl-4-chloro(1,2,5)thiadiazole was treated with cysteamine and sodium ethoxide in ethanol to give 2-(4-chloro-3(1,2,5)thiadiazolylmethylthio)ethylamine (oil). A 60 MHz n.m.r. spectrum (CDCl3) gave a singlet at 3.91 attributed to the Het--CH2 --S protons.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:26])[CH:5]=[C:6]([Br:25])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:10]=1.ClCCl.B(Br)(Br)Br>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([OH:26])[CH:5]=[C:6]([Br:25])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH:10]=1
Reactant: COc1ccc(Oc2c(Br)cc(O)cc2Br)cc1Cc1ccc(F)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Oc1cc(Br)c(Oc2ccc(O)c(Cc3ccc(F)cc3)c2)c(Br)c1
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a stirred solution of 3,5-dibromo-4-[3′-(4-fluorobenzyl)-4′-methoxyphenoxy]phenol (1.66 gm, 3.44 mmol), dichloromethane 100 mL, was added boron tribromide (8.6 mL, 8.60 mmol) in an ice/water bath. The reaction was stirred overnight under a nitrogen atmosphere. The reaction was diluted with ethyl acetate 60 mL, filtered and washed with water 2× with 10 mL and brine 3×10 mL. The ethyl acetate was dried over Na2SO4, filtered and concentrated under reduced pressure. 3,5-Dibromo-4-[3′-(4-fluorobenzyl)-4′-hydroxyphenoxy]phenol (1.06 gm, 66%) was obtained by flash chromatography using SiO2 eluted with a step gradient of hexane-ethyl acetate[3:1] 2L and hexane-ethyl acetate [3:2]; 1H NMR (300 MHz, DMSO-d6): δ 10.24 (s, 1H), 9.14 (s, 1H), 7.22 (m, 2H), 7.08 (m, 4H), 6.69 (td, J=8.7 Hz, 1H), 6.54 (d, J=3.3 Hz, 1H), 6.55 (dd, J=8.4, 3.3 Hz, 1H), 6.35 (dd, J=9, 3 Hz, 1H), 3.80 (s, 2H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=methylene chloride-hexanes (1:1); Rf=0.55.