Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([NH:10][C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:8]([CH3:9])[C:4]=2[C:3]=1[C:21]([NH2:23])=[O:22].[C:24]1(C)[CH:29]=CC(S(O)(=O)=O)=C[CH:25]=1.CC(C)=O.C(=O)(O)[O-].[Na+]>CCOC(C)=O>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[NH:10][C:7]1[N:8]([CH3:9])[C:4]2=[C:3]3[C:2](=[CH:20][CH:19]=[C:5]2[N:6]=1)[NH:1][C:24]([CH3:29])([CH3:25])[NH:23][C:21]3=[O:22]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cn1c(Nc2c(Cl)cccc2Cl)nc2ccc(N)c(C(N)=O)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Cn1c(Nc2c(Cl)cccc2Cl)nc2ccc3c(c21)C(=O)NC(C)(C)N3
Temperature: 25 °C
Reaction time: 1 h
Yield: 333.1 %

Procedure:
A mixture of 38 mg (0.11 mmol) of 5-amino-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzimidazole-4-carboxylic acid amide (Example 7), 3 mg (0.02 mmol) p-toluenesulfonic acid, and 2 mL (27 mmol) of acetone was stirred at room temperature for 1 h, then heated to reflux for 1.5 h. The reaction was cooled and poured into a mixture of saturated aqueous sodium bicarbonate and EtOAc. The aqueous phase was extracted with EtOAc, the combined organics were extracted with saturated aqueous sodium bicarbonate, brine, dried (MgSO4), treated with activated carbon, filtered, and concentrated in vacuo to afford 26 mg of an orange solid. The crude product was chromatographed over silica gel to afford 20 mg (47%) of title compound 17, mp 238-239° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]4([C:28]([O:30]C)=[O:29])[CH2:27][CH2:26][CH2:25]4)[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]4([C:28]([OH:30])=[O:29])[CH2:27][CH2:26][CH2:25]4)[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)C1(Oc2ccc(Cl)cc2C2CC(=O)NC(c3cc(F)ccc3C)C23C(=O)Nc2cc(Cl)ccc23)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC2(C(=O)O)CCC2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 70 °C
Yield: 90.9 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-cyclobutoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (200 mg, 0.33 mmol) in methanol (4 mL) was added a solution of NaOH (40 mg, 1 mmol) in water (2 mL). The mixture was heated at 70° C. for 2 h, evaporated to remove most of methanol, cooled to room temperature, and acidified to “pH” 1 with aqueous HCl solution. The precipitate was collected and dried to give product as a white solid (175 mg). m/z (M+H)+: 583
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][N:9]=2)[C:5]2[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:4]=2[O:3]1.C(OCC)(=[O:29])C>>[C:24]([C:21]1[CH:22]=[CH:23][C:4]2[O:3][C:2]([CH3:26])([CH3:1])[CH2:7][CH:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:10][N+:9]=3[O-:29])[C:5]=2[CH:20]=1)#[N:25]
Reactant: CCOC(C)=O
Reactant: CC1(C)CC(c2ccc(-c3ccccc3)cn2)c2cc(C#N)ccc2O1
Product: CC1(C)CC(c2ccc(-c3ccccc3)c[n+]2[O-])c2cc(C#N)ccc2O1

Procedure:
In an analogous manner to that described in the first paragraph of Example 7, from 3,4-dihydro-2,2-dimethyl-4-(5-phenyl-2-pyridyl)-2H-1-benzopyran-6-carbonitrile there was obtained 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2-H-1-benzopyran-4-yl)-5-phenylpyridine N-oxide of melting point 174°-176° C. (from ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.Cl[CH2:23][C:24]1[CH:33]=[CH:32][C:27]2[O:28][CH2:29][CH2:30][O:31][C:26]=2[CH:25]=1>>[O:28]1[C:27]2[CH:32]=[CH:33][C:24]([CH2:23][O:21][CH:9]3[CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10]3)=[CH:25][C:26]=2[O:31][CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(O)C1
Reactant: ClCc1ccc2c(c1)OCCO2
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(OCc2ccc3c(c2)OCCO3)C1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-hydroxy-piperidine-1-carboxylate with 6-chloromethyl-2,3-dihydro-benzo[1,4]dioxin [Brit. Pat. 566732 (1943)] there was obtained tert-butyl (3RS,4RS)-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethoxy)-4-(4-fluorophenyl)-piperidine-1-carboxylate as a colourless solid; MS: 444 (M+H)+ ;
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].C(#N)C.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(O)ccc1C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CC#N
Product: COc1cc(Oc2ccc([N+](=O)[O-])cc2)ccc1C
Yield: 95.3 %

Procedure:
To a solution of 4-methyl-3-(methyloxy)phenol (Intermediate 18, 0.800 g) in dry acetonitrile (60 mL) potassium carbonate (1.600 g, 11.58 mmol) and then 1-fluoro-4-nitrobenzene (817 mg, 5.79 mmol) were added and the reaction mixture was refluxed for 6 hours. The solid was filtered off and the solvent evaporated affording the title compound (1.43 g) as an orange solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[N:8]([CH3:17])[C:7]2[CH:18]=[CH:19][C:20]([C:22]3[CH:26]=[CH:25][NH:24][CH:23]=3)=[N:21][C:6]1=2)[CH3:4].[CH3:27]I.O>CN(C=O)C>[CH2:3]([N:5]1[C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[N:8]([CH3:17])[C:7]2[CH:18]=[CH:19][C:20]([C:22]3[CH:26]=[CH:25][N:24]([CH3:27])[CH:23]=3)=[N:21][C:6]1=2)[CH3:4]
Reactant: CCN1c2ncccc2C(=O)N(C)c2ccc(-c3cc[nH]c3)nc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1c2ncccc2C(=O)N(C)c2ccc(-c3ccn(C)c3)nc21
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.008 g, 60% in oil) was added to a solution of 5,11-dihydro-11-ethyl-5-methyl-2-(3-pyrrolyl)-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.065 g) in dry DMF (3 mL) and stirred for 30 min. Methyl iodide (0.2 mL) was added and the reaction mixture was stirred for an additional 2 h. Water was added and the product was extracted with CH2Cl2, dried (anhyd Na2SO4), filtered, and evaporated. The residue was chromatographed over silica gel (ethyl acetate/hexanes, 1:1) and was further purified by preparative plate chromatography (ethyl acetate/hexanes, 1:1) to give 0.040 g of the title compound, mp 187°-188° C.
Reaction SMILES: [CH:1]1[C:15](=[O:16])[N:14]=[C:13]2[N:3]([C@@H:4]3[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@@H:5]3[O:12]2)[CH:2]=1.C[O-].[Mg+2].C[O-].C(O)(=[O:24])C>CO>[C@@H:4]1([N:3]2[CH:2]=[CH:1][C:15](=[O:16])[NH:14][C:13]2=[O:12])[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@H:5]1[OH:24]
Reactant: O=c1ccn2c(n1)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Temperature: 150 °C

Procedure:
2,2'-anhydro uridine (1, 75 g, 331.56 mmol) was added to the freshly prepared solution of 15% magnesium methoxide (1218.75 ml, 1.66 mol) in methanol. The mixture was refluxed at 150° C. for five hours. The mixture was cooled down to room temperature and then to 5° C. on ice bath. The pH was adjusted to 7 by using glacial acetic acid. The solution was roto-evaporated to a foam. This solid was refluxed with ethyl alcohol (1500 ml) for two hours. The solid was filtered and filtrate was roto-evaporated to a solid mass. The isolated yield of the compound was 78.75 g (92%). The product was >95% pure by HPLC. The yield after quantitation against uridine was 89%. The structure of the compound was confirmed by 1H-NMR and elemental analysis. Table 1 shows the PMR results of the compounds.
Reaction SMILES: [CH3:1][C:2](C)([CH:4]=[CH2:5])[OH:3].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH:25]([Cl:28])([Cl:27])[Cl:26]>>[Cl:26][C:25]([Cl:28])([Cl:27])[CH2:5][CH2:4][CH:2]([OH:3])[CH3:1]
Reactant: ClC(Cl)Cl
Reactant: C=CC(C)(C)O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CC(O)CCC(Cl)(Cl)Cl
Yield: 69 %

Procedure:
To a solution of 17.2 g of dimethyl vinyl carbinol in 150 ml of chloroform was added 0.8 g of benzoyl peroxide and, in an autoclave, the mixture was reacted at 135° C. and in a nitrogen atmosphere for 18 hours. Then, the unreacted dimethyl vinyl carbinol and chloroform were removed by distillation under reduced pressure. As the residue was obtained 30.1 g of a dark-reddish viscous fluid. This residue was subjected to vacuum distillation to obtain 28.2 g (yield 69%) of 1,1,1-trichloro-4-pentanol. Gas-chromatographic analysis of this product showed its purity to be 95.4%. mass spectrometric data suggested that the impurity comprised 1,1,3-trichloro-4-methyl-4-pentanol. The following procedures were used for structural identification of 1,1,1-trichloro-4-methyl-4-pentanol.
Reaction SMILES: [CH3:1][C:2](=[CH2:35])[CH2:3][C@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:10][CH2:9][CH2:8][N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[C:6](=[O:28])[NH:5]1.I[C:37]1[CH:42]=[CH:41][N:40]([CH3:43])[C:39](=[O:44])[CH:38]=1>>[CH3:43][N:40]1[CH:41]=[CH:42][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:8][CH2:9][CH2:10][C@:4]([CH2:3][C:2]([CH3:1])=[CH2:35])([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[NH:5][C:6]3=[O:28])[CH3:12])=[CH:18][CH:17]=2)=[CH:38][C:39]1=[O:44]
Reactant: C=C(C)C[C@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)N1
Reactant: Cn1ccc(I)cc1=O
Product: C=C(C)C[C@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(-c3ccn(C)c(=O)c3)cc2)C(=O)N1

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 10 Step 3 using (S)-4-(2-methylallyl)-4-phenyl-1-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-diazepan-2-one and 4-iodo-1-methylpyridin-2(1H)-one.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[N:19]1([C:25]2[O:26][C:27]3[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=3[N:29]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[O:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[N:19]1[CH2:20][CH2:21][N:22]([C:7]([C:6]2[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:23][CH2:24]1
Reactant: c1ccc2oc(N3CCNCC3)nc2c1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc3ccccc3o2)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.2) and 2-piperazin-1-yl-benzoxazole hydrochloride. The crude material was triturated with diethyl ether to yield the title compound as a colorless solid.
Reaction SMILES: I[C:2]1[C:3](=[O:20])[N:4]([CH2:8][C:9]2[CH:19]=[CH:18][C:12]3[N:13]=[C:14]([S:16][CH3:17])[S:15][C:11]=3[CH:10]=2)[CH:5]=[CH:6][N:7]=1.[NH3:21]>CS(C)=O>[NH2:21][C:2]1[C:3](=[O:20])[N:4]([CH2:8][C:9]2[CH:19]=[CH:18][C:12]3[N:13]=[C:14]([S:16][CH3:17])[S:15][C:11]=3[CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CSc1nc2ccc(Cn3ccnc(I)c3=O)cc2s1
Reactant: N
Solvent: CS(C)=O
Product: CSc1nc2ccc(Cn3ccnc(N)c3=O)cc2s1
Temperature: 150 °C
Yield: 27 %

Procedure:
A stirred mixture of 3-iodo-1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyrazin-2(1H)-one (750 mg, 1.81 mmol), ammonia (7 M solution in MeOH, 2 mL, 14 mmol), and DMSO (1.5 mL), was heated in a Biotage Microwave Synthesizer at 150° C. for 15 min. The mixture was cooled to and partitioned between EtOAc and a 1:1 mixture of water and brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 100% DCM to 2% MeOH in DCM to afford 3-amino-1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyrazin-2(1H)-one (149 mg) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.43 (dd, J=1.5, 8.4 Hz, 1H), 6.92 (d, J=4.7 Hz, 1H), 6.65-6.67 (br m, 3H), 5.11 (s, 2H), 2.78 (s, 3H); LCMS (ESI) m/z 305 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH2:11][C:12]1[C:13]([F:20])=[CH:14][C:15]([F:19])=[C:16]([OH:18])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:20][C:13]1[CH:14]=[C:15]([F:19])[C:16]([O:18][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:17][C:12]=1[NH2:11]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Nc1cc(O)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cn2)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 2-chloro-5-nitropyridine (5.55 g, 35 mmol), 5-amino-2,4-difluorophenol (5.08 g, 35 mmol) and potassium carbonate (4.84 g, 35 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized from diethyl ether to give the title compound (9.35 g, quantitatively) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4](O)([C:20]([F:23])([F:22])[F:21])[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[NH:7][C:6]=1[CH3:19].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:25])[C:4](=[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:7]=[C:6]1[CH3:19])[C:20]([F:23])([F:21])[F:22]
Reactant: COC(=O)C(O)(c1c(C)[nH]n(-c2cccc(OC)c2)c1=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(=C1C(=O)N(c2cccc(OC)c2)N=C1C)C(F)(F)F

Procedure:
To a toluene solution (5 ml) of 2,5-dihydro-α-hydroxy-1-(3-methoxyphenyl)-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (180 mg, 0.5 mmol), thionyl chloride (0.365 ml, 5.0 mmol) was added and the mixture was stirred under reflux for 3 hours. After concentrating the liquid reaction mixture under reduced pressure, the title compound was obtained as a reddish brown solid (171 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)#[N:2].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:23]=1)=[O:25])#[N:2]
Reactant: COC(=O)CBr
Reactant: N#Cc1ccccc1Sc1ccccc1NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.3 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 1.0 g of N-[2-(2-cyanophenylthio)phenyl]-4-hydroxybenzamide and 0.49 g of methyl bromoacetate followed by addition of 0.6 g of potassium carbonate, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was then diluted with water and crystals separated out therefrom were collected by filtration and washed with water and aqueous ethanol in that order to give 1.2 g of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH:12]=[O:13])[CH2:8][CH2:7]1)=O.Cl.[NH2:20][OH:21].C([O-])(=O)C.[NH4+].C(O)C>O>[CH:12]([N:9]1[CH2:10][CH2:11][CH:6]([C:4](=[N:20][OH:21])[C:3]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:2]=2[Cl:1])[CH2:7][CH2:8]1)=[O:13]
Reactant: O=CN1CCC(C(=O)c2ccc(Cl)cc2Cl)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: O=CN1CCC(C(=NO)c2ccc(Cl)cc2Cl)CC1
Yield: 14.1 %

Procedure:
A mixture of 105 g of 4-(2,4-dichlorobenzoyl)-1-formylpiperidine, 70 g of hydroxylamine hydrochloride, 135.0 g of ammonium acetate, 1.05 l of ethanol and 350 ml of water was stirred and heated at 130° for 40 hrs. The reaction mixture was evaporated and 2 l of water was added to the residue. The water was decanted from the oil and oil was washed two times with 500 ml water and then dissolved in about 400 ml dichloromethane. The insoluble material was collected. The dichloromethane extract was washed twice with 600 ml of water and the organic extract was evaporated. Trituration with diisopropyl ether and crystallization from acetone/ether gave 15.6 g (14.2%) of product, mp, 149°-150°.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:28][NH2:29]>>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:29][CH3:28])=[N:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: S=C(Nc1ccc(Cl)cc1)Nc1ncccc1OCc1c(Cl)cccc1Cl
Reactant: CN
Product: CNC(=Nc1ccc(Cl)cc1)Nc1ncccc1OCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of N-[3-(2,6-dichlorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (2.0 g, 0.0045 mol), yellow mercuric oxide (1.18 g, 0.0054 mol) and 33% w/w methylamine in methylated spirit (40 ml) was stirred at room temperature for 24 hours. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent and recrystallisation from acetonitrile gave the desired product. Yield 1.53 g (78%), m.p. 153°-156 ° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].CO.S(Cl)([Cl:20])(=O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([Cl:20])[C:7]=1[OH:8]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)Cc1ccc(O)c(Br)c1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)Cc1cc(Cl)c(O)c(Br)c1
Yield: 60 %

Procedure:
To a stirred solution of ethyl 2-(3-bromo-4-hydroxyphenyl)acetate (20 g, 0.076 molo) in 200 ml of DCM was added MeOH (3.4 ml, 0.84 mol) and the mixture was refluxed. Sulfuryl chloride (6.8 ml 0.846 mol) was slowly added under over a period of 10 min. The reaction mixture was refluxed for a further 5 h. Upon completion of reaction, the mixture was poured onto crushed ice and extracted with DCM (×2). The combined organic layer were washed with 10% NaHCO3 solution and water, dried over Na2SO4, filtered and evaporated under vacuum to give ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate in 60% yield. (13.6 g). 1HNMR (CDCl3): 7.37 (s, 1H); 7.27 (s, 1H); 5.68 (bs, 1H); 4.16 (q, 2H); 3.48 (s, 2H); 1.29 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:10]([Sn](CCCC)(CCCC)C=C)[CH2:11]CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:3]([CH:10]=[CH2:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Fc1ncc(Cl)cc1Cl
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ncc(Cl)cc1Cl
Yield: 84 %

Procedure:
20.06 g of 3,5-dichloro-2-fluoropyridine (0.110 mol), 30.46 ml of tributyl-vinyl-stannane (0.103 mol), 6.00 g (0.00518 mol) of Pd(PPh3)4 are refluxed in 400 ml of toluene for five hours. The reaction mixture is washed thrice with a saturated aqueous solution of potassium fluoride 200 ml), once with water (300 ml), once with brine (300 ml). The combined aqueous phases are extracted with 100 ml of toluene. After separation, the combined organic phases are dried over magnesium sulfate, filtered, concentrated to dryness and purified on silica to yield to 15.05 g of 3,5-dichloro-2-vinylpyridine (62%) with 75% purity.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[O:16][CH:17]=[C:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[N:19]=3)[CH:6]=[CH:5][C:4]1=2.[OH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=O>>[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[O:16][CH:17]=[C:18]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][OH:27])[CH2:22][CH2:21]4)[N:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3nc(C4CCNCC4)co3)ccc21
Reactant: O=CCCCCO
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3nc(C4CCN(CCCCCO)CC4)co3)ccc21

Procedure:
The preparation was carried out as already described via a reductive amination starting from 200 mg (0.32 mmol) of 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxazol-4-yl]piperidine hydrochloride and 65 mg (0.64 mmol) of 5-hydroxypentanal. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)=[C:10]([CH2:21][NH:22][CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH2:27])[CH:25]=[CH2:26]>>[CH2:24]([NH:27][C@H:17]1[CH2:18][CH2:19][C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:9][C:10]=2[CH2:21][NH:22][CH3:23])[CH2:15][CH2:16]1)[CH:25]=[CH2:26]
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1C1CCC(=O)CC1
Reactant: C=CCN
Product: C=CCN[C@H]1CC[C@H](c2ccc(C(=O)OC(C)(C)C)cc2CNC)CC1

Procedure:
from 4-(4-tert.butoxycarbonyl-methylaminomethylphenyl)-cyclohexanone and allylamine. Colourless oil. Rf value: 0.52 (alumina, petroleum ether/ethyl acetate=3:1, v:v).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].CCN=C=NCCCN(C)C.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.N1C=CC=CC=1>O>[OH:13][C:3]1[CH:4]=[CH:5][C:6]([S:8][C:9]([F:12])([F:10])[F:11])=[CH:7][C:2]=1[NH:1][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1
Reactant: Nc1cc(SC(F)(F)F)ccc1O
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cc(SC(F)(F)F)ccc1O)c1ccncc1
Temperature: 80 °C
Yield: 40.1 %

Procedure:
A mixture of 0.70 g of 2-amino-4-(trifluoromethylthio)phenol, 0.83 g of WSC, 0.41 g of isonicotinic acid and 7 ml of pyridine was stirred while heating at 80° C. for three hours. The reaction mixture was cooled to room temperature, and then water was poured into the reaction mixture, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.42 g of N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide.