Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:17]=[CH:18][CH:19]=1)[C:9]([N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)=[N:10][OH:11].[H-].[Na+].I[CH:25]([CH3:27])[CH3:26].O>CN(C)C=O>[CH:25]([O:11][N:10]=[C:9]([N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)[C:8]1[CH:17]=[CH:18][CH:19]=[C:6]([O:5][CH2:4][CH2:3][C:2]([CH3:21])([CH3:20])[CH3:1])[CH:7]=1)([CH3:27])[CH3:26]
Reactant: CC(C)(C)CCOc1cccc(C(=NO)n2cncn2)c1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)ON=C(c1cccc(OCCC(C)(C)C)c1)n1cncn1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 75.7 %

Procedure:
To a solution of 1.6 g (5.6 mmol) of 1-[3-(3,3-dimethylbutoxy)benzohydroximoyl]-1H-1,2,4-triazole dissolved in 100 ml of N,N-dimethylformamide was added 0.16 g (6.7 mmol) of sodium hydride. The mixture was stirred for 20 minutes at 80° C. And then allowed to sit and cool naturally to about 50° C. To the mixture was added 1.1 g (6.5 mmol) of 2-iodopropane and stirred for 1 hour at about 50° C. The reaction mixture was allowed to sit and cool naturally to room temperature. The cooled mixture was poured into water and extracted with ethyl acetate. After being washed with water, the organic layer was dried over anhydrous magnesium sulfate. The solvent in the organic layer was removed under reduced pressure. The residue was purified by column chromatography, thus obtaining 1.4 g (yield: 87%) of the desired product having a refractive index of [nD20 ] 1.5289 at 20° C.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:13][NH2:14])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:2]=1.[F:21][C:22]([F:38])([F:37])[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[N:30][CH:31]=[C:32]([CH:36]=2)[C:33](O)=[O:34])[N:24]=1>>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:13][NH:14][C:33](=[O:34])[C:32]3[CH:36]=[C:28]([C:25]4[N:24]=[C:23]([C:22]([F:38])([F:37])[F:21])[O:27][N:26]=4)[CH:29]=[N:30][CH:31]=3)[CH2:8][CH2:9][O:10][CH2:11][CH2:12]2)[CH:2]=1
Reactant: NCC1(c2cccc(-c3ccccc3)c2)CCOCC1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCC1(c2cccc(-c3ccccc3)c2)CCOCC1)c1cncc(-c2noc(C(F)(F)F)n2)c1
Yield: 48 %

Procedure:
This compound was synthesized from (4-([1,1′-biphenyl]-3-yl)tetrahydro-2H-pyran-4-yl)methanamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (95 mg, yield 48%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.40 (br s, 1H), 8.97 (br s, 1H), 8.61-8.60 (t, J=1.9 Hz, 1H), 7.58-7.55 (m, 5H), 7.46-7.43 (t, J=7.5 Hz, 2H), 7.39-7.35 (m, 2H), 5.89-5.86 (t, J=6.1 Hz, 1H), 3.96-3.92 (m, 2H), 3.82-3.81 (d, J=6.1 Hz, 2H), 3.74-3.68 (m, 2H), 2.29-2.23 (m, 2H), 2.09-2.03 (m, 2H). MS (ESI) m/z: Calculated for C27H23F3N4O3: 508.17. found: 507.2 (M−H)−.
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[CH:5][C:4]([CH2:7][C:8](=[NH:12])OCC)=[CH:3]1.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17]>COCCOC>[ClH:1].[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:17][C:8](=[NH:12])[CH2:7][C:4]1[CH:5]=[CH:6][S:2][CH:3]=1
Reactant: CCOC(=N)Cc1ccsc1
Reactant: COC(CN)OC
Agent: Cl
Solvent: COCCOC
Product: COC(CNC(=N)Cc1ccsc1)OC
Temperature: 15 °C

Procedure:
A mixture of O-ethyl 3-thiopheneethanimidate hydrochloride (0.14 mol) in 1,2-dimethoxyethane (150 ml) was stirred at 15° C. 2,2-dimethoxyethanamine (0.14 mol) was added portionwise and the mixture was stirred overnight. The mixture was evaporated, yielding N-(2,2-dimethoxyethyl)-3-thiopheneethanimidamide monohydrochloride (interm. 13).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([O:35][Si](C(C)(C)C)(C)C)[CH2:9][N:10](C(OC(C)(C)C)=O)[CH2:11][CH2:12][NH:13][C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:6][CH:7]=1>Cl.O1CCOCC1>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:35])[CH2:9][NH:10][CH2:11][CH2:12][NH:13][C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(CCNc1cccc(-c2cccc(C#N)c2)c1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2cccc(NCCNC[C@H](O)c3cccc(Cl)c3)c2)c1

Procedure:
m.p. 191-206° C.; from (R)-3′-[[2-[[2-(3-chlorophenyl)-2-[[(tert-butyl)dimethylsilyl]oxy]ethyl][(tert-butoxy)carbonyl]amino]ethyl]amino]-[1,1′-biphenyl]-3-carbonitrile (173 mg) in 4 N hydrochloric acid in dioxane (10 mL).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:32]=[CH:31][C:11]3=[N:12][N:13]([C:15]4[CH:16]=[C:17]([CH:23]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]=4[OH:26])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[N:14]=[C:10]3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:44]1([CH3:51])[C:45]([CH3:50])=[CH:46][CH:47]=[CH:48][CH:49]=1>C(OCC)(=O)C>[C:1]1([S:7][C:8]2[CH:32]=[CH:31][C:11]3=[N:12][N:13]([C:15]4[CH:16]=[C:17]([CH2:18][CH2:19][C:20]([O:22][CH2:50][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:44][CH3:51])=[O:21])[CH:23]=[C:24]([C:27]([CH3:29])([CH3:28])[CH3:30])[C:25]=4[OH:26])[N:14]=[C:10]3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1C
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(-n2nc3ccc(Sc4ccccc4)cc3n2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: CCCCCCCCOC(=O)CCc1cc(-n2nc3ccc(Sc4ccccc4)cc3n2)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
Likewise, to a 250 mL round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet, condenser, and a Dean-Stark trap are charged 4.3 g (0.0096 mol) of 3-(5-phenylthio-2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyhydrocinnamic acid, 3.4 g (0.026 mol) of Exxel 8, an isomeric mixture of octanols available from Exxon Chemicals, 70 mg of p-toluenesulfonic acid, and 20 mL of xylene. The mixture is refluxed 3.5 hours, is cooled to room temperature, and a portion of ethyl acetate is added. The solution is washed once with water, twice with saturated sodium bicarbonate solution, and once with brine. After drying over anhydrous magnesium sulfate, the solvent is removed under reduced pressure to afford 5.17 g (96% yield) of the title compound as a viscous yellow oil. Analysis by nmr (CDCl3) is consistent with the structure of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)(=[O:20])=[O:19])[CH2:12][C:13]([O:15]CC)=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:31][NH:32][C:33]1[CH:38]=[CH:37][C:36]([C:39](=[NH:41])[NH2:40])=[CH:35][CH:34]=1.[OH-].[Na+]>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)(=[O:20])=[O:19])[CH2:12][C:13]([OH:15])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:31][NH:32][C:33]1[CH:34]=[CH:35][C:36]([C:39](=[NH:40])[NH2:41])=[CH:37][CH:38]=1
Reactant: CCOC(=O)CN(c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(N(CC(=O)O)S(=O)(=O)c3cccc4cccnc34)ccc21

Procedure:
Prepared analogously to Example 3 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-5-[N-(ethoxycarbonylmethyl)-quinoline-8-sulphonylamino]-benzimidazole and sodium hydroxide solution.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH3:14])[N:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].[C:22]1([CH:28]=[CH:29][CH2:30]Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH3:14])[N:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:30][CH:29]=[CH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:9]1
Reactant: ClCC=Cc1ccccc1
Reactant: Cn1ncc(N2CCNCC2)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ncc(N2CCN(CC=Cc3ccccc3)CC2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.3 %

Procedure:
0.75 g (3.3 mmoles) of 4-chloro-2-methyl-5-(1-piperazinyl)-3(2H)-pyridazinone prepared as described hereinafter under the title "Preparation of the starting substances" and 0.91 g (6.6 mmoles) of anhydrous potassium carbonate are suspended in 5 ml of anhydrous dimethyl formamide. Then a solution of 0.5 g (3.3 moles) of 3-phenyl-2-propenyl chloride in 5 ml of anhydrous dimethyl formamide are dropped to the suspension, and the reaction mixture is stirred at room temperature for 24 hours. The dimethyl formamide is evaporated in vacuo, a slight amount of water is added to the residue and the solution thus obtained is extracted with ethyl acetate. The organic phase is dried and evaporated and the residue is crystallized from ethanol. Thus 0.55 g (49%) of the desired compound is obtained. M.p.: 98°-100° C. Its monohydrochloride salt melts at 218°-220° C.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[C:35]([NH:37][CH3:38])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[C:35]([NH:37][CH3:38])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(C(=O)NC)C3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(C(=O)NC)C3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-methylaminocarbonyl-cyclohexylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [C:1]12([NH:11][C:12](=[O:28])[CH:13]=[CH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21]C(=O)C)=[C:17]([N+:25]([O-:27])=[O:26])[CH:16]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH-].[Na+]>CO>[C:1]12([NH:11][C:12](=[O:28])[CH:13]=[CH:14][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([N+:25]([O-:27])=[O:26])[CH:16]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CC(=O)Oc1ccc(C=CC(=O)NC23CC4CC(CC(C4)C2)C3)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(C=Cc1ccc(O)c([N+](=O)[O-])c1)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1 g of N-(1-adamantyl)-4-acetoxy-3-nitrocinnamamide (prepared as described in Example 1) was dissolved in 30 ml of methanol; 30 ml of a 4N aqueous solution of sodium hydroxide were then added, and the resulting mixture was stirred for 3 hours at room temperature. At the end of this time, the methanol was removed by distillation under reduced pressure. Addition of 3N aqueous hydrochloric acid to the residue afforded crystals of the title compound, melting at 162°-163° C.
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[CH3:14][S:15]([NH:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)(=[O:17])=[O:16]>C(O)C>[CH3:14][S:15]([NH:18][CH2:19][CH2:20][CH2:21][S:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1)(=[O:17])=[O:16]
Reactant: Sc1cccc2nccn12
Reactant: CS(=O)(=O)NCCCOS(C)(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)NCCCSc1cccc2nccn12
Yield: 47 %

Procedure:
To a solution of 5-mercaptoimidazo[1,2-a]pyridine (1.50 g, 10 mmoles) and 4M sodium methylate (2.93 ml, 12 mmoles) in ethanol (50 ml) was added 3-methylsulfonylamino-1-methylsulfonyloxypropane (2.77 g, 12 mmoles) at room temperature and the mixture was heated under reflux for 16 hours. After cooling, the solvent was distilled off. The residue was dissolved in chloroform, washed with an aqueous saturated sodium bicarbonate solution and dried. After the solvent was distilled off, the residue was purified by column chromatography [eluent: ethyl acetate/ethanol (50:1)] to obtain 1.34 g of the desired product (47.5%, pale yellow crystals).
Reaction SMILES: N[C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:13].N([O-])=[O:15].[Na+]>S(=O)(=O)(O)O.O>[OH:15][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:13]
Reactant: Cc1ccc2c(=O)[nH]ccc2c1N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1ccc2c(=O)[nH]ccc2c1O
Temperature: 0 °C
Yield: 85.5 %

Procedure:
5-Amino-6-methylisoquinolin-1(2H)-one (1.00 g, 5.74 mmol) was dissolved in 75% sulfuric acid (18.2 ml). Mixture cooled to 0° C. and treated with a solution of sodium nitrite (0.416 g, 6.03 mmol) in concentrated sulfuric acid (2.28 ml). After the mixture had been stirred for 1 hour at this temperature, water (36.0 ml) was added and the mixture warmed to 65° C. overnight. The mixture was then diluted with 150 mL water. The resulting precipitate was filtered and washed with an additional portion of water and Et2O. A brown solid was collected: 5-hydroxy-6-methylisoquinolin-1(2H)-one (0.860 g, 85.5% yield). MS (M+H)+ 176.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[Br:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](Cl)(=[O:23])[CH3:22]>>[CH2:1]([N:8]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=[CH:12][C:11]=1[Br:20])[C:21](=[O:23])[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: FC(F)(F)c1ccc(Br)c(CNCc2ccccc2)c1
Product: CC(=O)N(Cc1ccccc1)Cc1cc(C(F)(F)F)ccc1Br

Procedure:
Benzyl-(2-bromo-5-trifluoromethyl-benzyl)-amine and acetyl chloride were reacted as described in Example 11, Step 2 to provide N-benzyl-N-(2-bromo-5-trifluoromethyl-benzyl)-acetamide.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>[Cl-].[Na+].O>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 110 °C

Procedure:
A mixture of 1-fluoro-3-nitrobenzene (282 mg, 2.00 mmol), 1-methylpiperazine (401 mg, 4.00 mmol), potassium carbonate (276 mg, 2.00 mmol), and DMF (3 mL) was stirred and heated at 110° C. for 24 h. After cooling to rt, the mixture was poured into brine (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were extracted with aqueous HCl (1 N, 2×20 mL). The acidic extracts were basified by aqueous NaOH until pH>10. The basified aqueous solution was extracted with EtOAc (2×30 mL). The extracts were then washed with H2O (3×20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give the title compound as yellow oil. 1H NMR (CD3OD, 400 MHz): δ=2.22 (s, 3H), 2.48 (t, 4H, J=5.0 Hz), 3.16 (t, 4H, J=5.2 Hz), 7.16-7.18 (m, 1H), 7.27 (t, 1H, J=8.2 Hz), 7.46-7.49 (m, 1H), 7.57 (t, 1H, J=2.2 Hz). MS (ES+): m/z 222.26 (100) [MH+]. HPLC: tR=1.55 min (ZQ2000, polar—5 min).
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH2:7][C:8]([OH:10])=O)[C:4]([OH:6])=[O:5]>O>[O:10]=[C:8]1[S:1][CH2:2][CH:3]([C:4]([OH:6])=[O:5])[CH2:7]1
Reactant: O=C(O)CC(CS)C(=O)O
Solvent: O
Product: O=C1CC(C(=O)O)CS1

Procedure:
Cyclisation of mercaptomethylbutanedioic acid by heating at from 100° C. to 160° C., with the removal of water, to form tetrahydro-5-oxo-3-thiophenecarboxylic acid of formula V (US 90-583537; Suppl. Vol.18, E III/IV, p. 5265).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[S:12][C:13]([S:16][C:17]#N)=[CH:14][N:15]=2)=[N:8][CH:9]=1.SC[C@H]([C@@H](CS)O)O.ClC1[CH:33]=[CH:32][N:31]=[C:30]([C:34]([O:36][CH3:37])=[O:35])[C:29]=1[F:38].[OH-].[Na+]>CO>[F:38][C:29]1[C:30]([C:34]([O:36][CH3:37])=[O:35])=[N:31][CH:32]=[CH:33][C:17]=1[S:16][C:13]1[S:12][C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][O:2][CH3:1])=[CH:9][N:8]=2)=[N:15][CH:14]=1
Reactant: COCc1ccc(Nc2ncc(SC#N)s2)nc1
Reactant: COC(=O)c1nccc(Cl)c1F
Agent: O[C@H](CS)[C@H](O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCc1ccc(Nc2ncc(Sc3ccnc(C(=O)OC)c3F)s2)nc1
Temperature: 23 °C
Reaction time: 0.17 h
Yield: 38.9 %

Procedure:
A suspension of N-(5-(methoxymethyl)pyridin-2-yl)-5-thiocyanatothiazol-2-amine (0.109 g, 0.392 mmol) in methanol (15 mL) was bubbled with argon for 10 minutes and then treated with dithiothreitol (0.079 g, 0.510 mmol). The reaction was stirred at 23° C. for 10 minutes, then methyl 4-chloro-3-fluoropicolinate (0.0743 g, 0.392 mmol) was added, followed by aq. NaOH (1N, 0.43 mL, 0.431 mmol). The resulting brown solution was stirred for 45 minutes, then concentrated to about one quarter of the volume, diluted in water (15 mL) and neutralized with aq. sat. ammonium chloride. The precipitate was filtered to give the crude title material (0.062 g, 39%) as a solid which was used as such in the next reaction. HPLC ret. time (Condition A): 1.625 min. LC/MS (M+H)+: 407.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:12]=[CH:11][C:10](I)=[CH:9][C:8]=1[F:14])[CH2:4][CH3:5])[CH3:2].[CH3:15][C:16]1[C:17](=[O:23])[NH:18][CH:19]=[C:20]([CH3:22])[CH:21]=1.CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I.C(Cl)Cl>[CH2:1]([N:3]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:18]2[CH:19]=[C:20]([CH3:22])[CH:21]=[C:16]([CH3:15])[C:17]2=[O:23])=[CH:9][C:8]=1[F:14])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1ccc(I)cc1F
Reactant: Cc1c[nH]c(=O)c(C)c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCN(CC)Cc1ccc(-n2cc(C)cc(C)c2=O)cc1F
Temperature: 110 °C
Yield: 13.6 %

Procedure:
To a solution of N-ethyl-N-(2-fluoro-4-iodobenzyl)ethanamine (1.72 g, 5.60 mmol) in dioxane (50 mL) was added 3,5-dimethyl-pyridone (0.69 g, 5.60 mmol), N,N′-dimethyl ethane-1,2-diamine (0.20 g, 2.24 mmol), CuI (0.21 g, 1.12 mmol) and potassium phosphate (2.38 g, 11.20 mmol) under N2. The reaction mixture was heated at 110° C. for 9 h, then cooled to rt and poured into CH2Cl2 (200 mL). The mixture was filtered, and the filtrate was washed with water (200 mL×3) and brine (200 mL). The organic phase was concentrated in vacuo. The residue was purified by a silica gel column chromatography (CH2Cl2/MeOH (V/V)=10:1) to give the title compound as a yellow solid (0.23 g, 14%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[CH:4]=1.[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2=[O:24]>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2([OH:24])[C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[CH:4]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COc1cc(Br)cc(OC)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C2(O)C(=O)Nc3ccc(Cl)cc32)c1
Yield: 60.6 %

Procedure:
This compound is prepared according to the procedure described in step A of Preparation 1.6, starting with 1.2 g of magnesium, 9.5 g of 1-bromo-3,5-dimethoxybenzene, 50 ml of THF and a solution of 3 g of 5-chloro-1H-indole-2,3-dione in 50 ml of THF. 3.2 g of the expected product are obtained after crystallization from iso ether; m.p.=191° C.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][N:6](C(OC(C)(C)C)=O)[N:7]=C(C)C>C1COCC1>[ClH:1].[ClH:1].[F:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][NH2:7]
Reactant: CC(C)=NN(Cc1ccccc1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: NNCc1ccccc1F
Reaction time: 0.5 h

Procedure:
Aqueous hydrochloric acid (3 M, 60.64 mL, 181.92 mmol)I was added to a solution of tert-butyl 1-(2-fluorobenzyl)-2-isopropylidenehydrazinecarboxylate (17 g, 60.64 mmol) in THF (100 mL) and the mixture was heated at reflux for 3 h and concentrated. The residue was taken up in toluene and concentrated, then ether was added to the residue and the suspension was stirred for 30 min and filtered. The filter cake (12.2 g, 94%) was washed with ether and dried on the high vacuum pump. LC-MS [M-2HCl]=141.0, RT=0.25 min.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH2:8][CH2:9][CH3:10].Cl[CH2:18][CH2:19][CH2:20][N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][C:22]1=[O:31]>C(#N)C>[CH2:7]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][N:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23][C:22]2=[O:31])[CH2:13][CH2:12]1)[CH2:8][CH2:9][CH3:10]
Reactant: O=C1CCc2ccccc2N1CCCCl
Reactant: CCCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCC1CCN(CCCN2C(=O)CCc3ccccc32)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A suspension of NaH in mineral oil (55-60%) (712 mg) was added to a solution of 3,4-dihydro-1H-quinolin-2-one (2.0 g, 13.6 mmol) in N,N-dimethylformamide (50 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. then 1-bromo-3-chloropropane (1.34 mL, 13.6 mmol) was added. The slurry was stirred for additional 16 h. at ambient temperature then water (50 mL) was added and the product was extracted with diethyl ether (2×50 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The product was purified by flash-chromatography (eluent: dichloromethane) to give 1-[3-chloropropyl]-3,4-dihydro-1H-quinolin-2-one (2.41 g, 10.8 mmol). KI (2.5 g, 15 mmol), K2CO3 (2.1 g, 15 mmol) and 4-butylpiperidine (1.8 mL, 15 mmol) were added to a solution of 1-[3-chloropropyl]-3,4-dihydro-1H-quinolin-2-one (2.41 g, 10.8 mmol) in acetonitrile (50 mL). The reaction mixture was stirred at 60° C. for 16 h. The acetonitrile was evaporated in vacuo, water (50 mL) was added and the product was extracted with ethyl acetate (2×50 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash-chromatography (eluent: ethyl acetate) gave the title product. Yield: 2.06 g, 58%. Oxalate-salt was prepared from oxalic acid (1.1 eq.) in acetone. HPLC-MS: M+1+=329.5 (UV/MS(%)=100/100). 1H NMR (400 MHz, CD3OD): δ=0.89 (3H, t), 1.12-1.36 (9H, m), 1.67 (2H, broad d), 1.83 (2H, quin.), 1.97 (2H, broad t), 2.41 (2H, t), 2.59 (2H, t), 2.84-2.96 (4H, m), 3.99 (2H, t), 7.02 (1H, broad t), 7.16 (1H, broad d), 7.20 (1H, broad d), 7.25 (1H, broad t). 13C NMR (CD3OD): δ 13.2, 22.8, 24.3, 25.0, 28.9, 31.6, 31.9 (2C), 35.6, 36.2, 40.1, 53.8 (2C), 55.9, 115.2, 123.2, 127.0, 127.4, 127.9, 139.1, 171.5
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8]COC)[CH:5]=[C:4]([O:12]COC)[C:3]=1[C:16](=[O:33])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]COC)=[C:21]([O:29]COC)[CH:20]=1.Cl.CO>CO>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:12])[C:3]=1[C:16](=[O:33])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([OH:29])[CH:20]=1
Reactant: COCOc1cc(O)c(C(=O)CCc2ccc(OCOC)c(OCOC)c2)c(OCOC)c1
Agent: Cl
Solvent: CO
Product: O=C(CCc1ccc(O)c(O)c1)c1c(O)cc(O)cc1O
Temperature: 0 °C
Yield: 34.9 %

Procedure:
Then, 4.3 g of 1-[2-hydroxy-4,6-bis(methoxymethoxy)phenyl]-3-[3,4-bis(methoxymethoxy)phenyl]-1-propanone was dissolved in 16 ml of methanol, and 33 ml of a hydrochloric acid/methanol reagent was added to the solution and the mixture was refluxed for 10 minutes. Then, the reaction liquid was poured into ice water and extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dried with anhydrous sodium sulfate and filtered and the solvent was removed from the filtrate by distillation. The obtained residue was subjected to the silica gel column chromatography (160 g of 240-400 mesh silica gel, n-hexane/ethyl acetate=1/1, 0.3 kg/cm2). Fractions of 40 ml were collected and the 28th to 49th fractions were combined, and the solvent was removed by distillation to obtain 933.6 mg (yield=34.9%) of 1-(2,4,6-trihydroxyphenyl)-3-(3,4-dihydroxyphenyl)-1-propanone.