Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CN(C=O)C>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: C1COCCN1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CN(C)C=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCOCC3)n2n1
Temperature: 25 °C
Yield: 45.3 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 43 mg, 0.125 mmol) and morpholine (43 mg, 0.499 mmol) in DMF (0.5 mL) was stirred at 100° C. for 3 h. After cooling to room temperature, the mixture was diluted with DMF and then purified by preparatory HPLC (20-35% MeCN/H2O+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (22.4 mg, 45%). Melting point (242.8-242.9° C.). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6H), 2.38 (s, 3H), 3.69-3.78 (m, 4H), 3.80-3.88 (m, 4H), 6.18 (s, 1H), 7.34 (s, 1H), 7.60 (d, J=8.84 Hz, 2H), 7.99 (d, J=8.84 Hz, 2H), 10.87 (s, 1H); ESI-MS: m/z 396.2 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH:9]([CH3:13])[CH2:10][CH2:11][CH3:12])[CH:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.C(Cl)Cl>O1CCCC1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH3:8][CH:3]([CH:2]([O:1][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][O:14]1)[CH:9]([CH3:13])[CH2:10][CH2:11][CH3:12])[C:4]([O:6][CH3:7])=[O:5]
Reactant: C1=COCCC1
Reactant: CCCC(C)C(O)C(C)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCC(C)C(OC1CCCCO1)C(C)C(=O)OC
Reaction time: 8 h
Yield: 121.2 %

Procedure:
200 mg (1.06 mmol) of methyl (+)-3-hydroxy-2,4-dimethylheptanoate was dissolved in 4 ml of tetrahydrofuran, and 134 mg (1.59 mmol) of dihydropyran and 1 mg of pyridinium p-toluenesulfonate were added, and the mixture was reacted overnight at room temperature. Since TLC showed that the starting materials still remained, 5 mg of pyridinium p-toluenesulfonate and 3 ml of methylene chloride were added, and the reaction was further carried out overnight at room temperature. The reaction mixture was extracted with ether. The ethereal layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with an aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, filtered, and concentrated to give 350 mg of crude methyl (+)-2,4-dimethyl-3-tetrahydropyranyloxy-1heptanoate (6).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:15])[CH3:14].C(O)(=O)C.[Br:20]Br.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Br:20][C:6]1[CH:5]=[CH:4][C:3]([NH:12][C:13](=[O:15])[CH3:14])=[C:2]([CH3:1])[C:7]=1[C:8]([F:10])([F:11])[F:9]
Reactant: CC(=O)Nc1cccc(C(F)(F)F)c1C
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(Br)c(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-[2-methyl-3-(trifluoromethyl)phenyl]acetamide (6.2 g) and acetic acid (40 ml) was added an acetic acid solution (10 ml) of bromine (1.8 ml) under water-cooling. The reaction liquid was stirred at room temperature overnight and then at 50° C. for 2 hours. In addition, to the reaction liquid was added bromine (1.5 ml) under water-cooling, followed by stirring at 50° C. for 1 day. In addition, to the reaction liquid was added bromine (2.0 ml) under water-cooling, followed by stirring at 50° C. for 1 day. In addition, to the reaction liquid was added bromine (2.0 ml) under water-cooling, followed by stirring at 50° C. for 1 day. In addition, to the reaction liquid was added bromine (2.0 ml) under water-cooling, followed by stirring at 50° C. for 4 days. The reaction liquid was poured into ice water (about 200 g), ethyl acetate was added thereto, followed by neutralization with potassium carbonate. A liquid-separation operation was carried out, and the organic layer was washed with an aqueous sodium thiosulfate solution and saturated brine in this order, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to obtain N-[4-bromo-2-methyl-3-(trifluoromethyl)phenyl]acetamide (9.0 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([O:14]C(=O)CC)(=[O:13])[CH2:11][CH3:12].C([O-])(=O)CC.[Na+]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:11]([CH3:12])[C:10]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CCC(=O)OC(=O)CC
Reactant: O=Cc1ccc(F)cc1
Agent: CCC(=O)[O-]
Agent: [Na+]
Product: CC(=Cc1ccc(F)cc1)C(=O)O
Temperature: 140 °C
Reaction time: 20 h

Procedure:
p-Fluorobenzaldehyde (200 g, 1.61 mol), propionic anhydride (3.5 g, 2.42 mol) and sodium propionate (155 g, 1.61 mol) are mixed in a one liter three-necked flask which had been flushed with nitrogen. The flask is heated gradually in an oil-bath to 140° C. After 20 hours, the flask is cooled to 100° C. and poured into 8 l of water. The precipitate is dissolved by adding potassium hydroxide (302 g) in 21 of water. The aqueous solution is extracted with ether, and the ether extracts are washed with potassium hydroxide solution. The combined aqueous layers are filtered, are acidified with concentrated HCl, and are filtered. The collected solid, p-fluoro-α-methylcinnamic acid, is washed with water, and is dried and used as obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10]C(O)=O)=[CH:5][C:4]=1[CH3:14])#[N:2].C([N:17](CC)CC)C>C(O)(C)(C)C>[NH2:17][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([CH3:14])[CH:5]=1
Reactant: CCN(CC)CC
Reactant: Cc1cc(CCC(=O)O)ccc1C#N
Solvent: CC(C)(C)O
Product: Cc1cc(CCN)ccc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5.20 g 3-(4-Cyano-3-methyl-phenyl)-propionic acid and 4.57 ml triethylamine in 100 ml tert-butanol 9.10 g diphenylphosphorylazide were given and the mixture heated under reflux overnight. The cooled reaction mixture was evaporated in vacuo. The resulting residue was dissolved in 150 ml ethyl acetate, washed with 50 ml citric acid/brine=1:1 and 50 ml saturated NaHCO3 solution and then dried over MgSO4. The residue was dissolved in 50 ml dichloromethane and 20 ml trifluoroacetic acid were added. The reaction mixture was stirred at room temperature for two hours. The solvent was removed in vacuo. The residue was coevaporated four times with portions of 100 ml toluene. The resulting brown residue was taken up in 50 ml acetonitrile and stirred at room temperature. The solid material was filtered off and dried in vacuo to obtain 2.45 g 4-(2-Amino-ethyl)-2-methyl-benzonitrile as its trifluoroacetate salt. The filtrate was evaporated in vacuo, the resulting residue was taken up in 100 ml diethyl ether and stirred at room temperature. The solid material was filtered off and dried in vacuo to obtain 1.17 g 4-(2-Amino-ethyl)-2-methyl-benzonitrile as its trifluoroacetate salt.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[C:10](OCC)(=[O:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[O-]CC.[Na+]>[O:4]=[C:3]1[CH2:5][C:10](=[O:19])[CH2:11][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:2]1[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCOC(=O)C=Cc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C1C(=O)CC(=O)CC1c1ccccc1

Procedure:
To a cooled solution of sodium ethoxide (from 2.3 g. sodium and absolute ethanol, 30 ml.) was added with shaking ethyl acetoacetate (13 g.). When homogeneous the mixture was treated with ethyl cinnamate (17.8 g.) and then heated under reflux for 18 hrs. After cooling the solution, the precipitated enolate salt (formula III) was collected by filtration and washed with acetone. Dissolution in cold water, followed by acidification with 2N-sulphuric acid (to convert the enolate salt to the corresponding dione II) afforded crystalline ethyl 2,4-dioxo-6-phenylcyclohexanecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][C:12]([CH3:14])=O)[C:7]=2[CH:15]=1.[CH3:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[CH3:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([N:27]3[CH2:28][CH2:29][N:30]([CH:12]([CH3:14])[CH2:11][C:8]4[C:7]5[CH:15]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[O:10][CH:9]=4)[CH2:31][CH2:32]3)[CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2
Reactant: Cc1cc(N2CCNCC2)c2ncccc2c1
Reactant: COc1ccc2occ(CC(C)=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc2occ(CC(C)N3CCN(c4cc(C)cc5cccnc45)CC3)c2c1

Procedure:
6-methyl-8-{4-[2-(5-methoxy-1-benzofuran-3-yl)-1-methylethyl)piperazin-1-yl]quinoline was prepared by generally following the procedure outlined in example 38, step 2, starting from the 1-(5-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 6-methyl-8-piperazino quinoline (227.0 mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodium triacetoxyborohydride (422 mg, 2 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a yellow oil. Yield: 62 mg (14%); (M+H): 416; 1HNMR (400 MHz, CDCl3): δ□8.82˜8.81 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H): 8.02˜8.00 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 7.99˜6.58 (m, 7H); 3.87 (s, 3H); 3.46˜2.62(m, 11H); 2.5 (s, 3H); 1.15˜1.13 (d, J=6.0 Hz, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.CN(C)C=O.OC[C:32]1[CH2:33][C@@H:34]2[C@H:37]([CH:38]=1)[C@@:36]([CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])([CH2:39][N+:40]([O-:42])=[O:41])[CH2:35]2>O>[Cl:24][CH2:20][C:32]1[CH2:33][C@@H:34]2[C@H:37]([CH:38]=1)[C@@:36]([CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])([CH2:39][N+:40]([O-:42])=[O:41])[CH2:35]2
Reactant: CC(C)(C)OC(=O)C[C@]1(C[N+](=O)[O-])C[C@@H]2CC(CO)=C[C@@H]21
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@]1(C[N+](=O)[O-])C[C@@H]2CC(CCl)=C[C@@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triphenylphosphine (1.85 g, 7.05 mmol) and carbon tetrachloride (0.78 mL, 8.14 mmol) were added to a dimethylformamide solution (8.0 mL) of tert-butyl(±)-[(1R,5R,6R)-3-(hydroxymethyl)-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (807 mg, 2.71 mmol), and the mixture was stirred at room temperature for 1 hour. To the reaction solution, water was added, followed by extraction with diethyl ether. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. Then, the obtained crude product of tert-butyl(±)-[(1R,5R,6R)-3-(chloromethyl)-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate was dissolved in dimethylformamide (10 mL). To the solution, sodium thiomethoxide (570 mg, 8.14 mmol) was added with stirring at 0° C., and the mixture was stirred at this temperature for 4 hours. The reaction solution was diluted with ethyl acetate and separated into aqueous and organic layers. The organic layer was washed with a 1 M aqueous sodium hydroxide solution, water, and saturated saline and then dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. Then, the obtained crude product was purified by silica gel column chromatography to obtain the compound of interest as an oil substance (632 mg, 71%).
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=[CH:17][C:12]=2[S:11][CH:10]([CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:9]1=[O:34])(C)(C)C.CSC.Cl>ClCCl>[CH2:21]([O:20][C:18]([C:15]1[CH:16]=[CH:17][C:12]2[S:11][CH:10]([CH2:23][CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[C:9](=[O:34])[N:8]([CH2:7][C:6]([OH:35])=[O:5])[C:13]=2[CH:14]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1ccc2c(c1)N(CC(=O)OC(C)(C)C)C(=O)C(CCCc1ccc(OC)cc1)S2
Agent: Cl
Solvent: ClCCl
Solvent: CSC
Product: CCOC(=O)c1ccc2c(c1)N(CC(=O)O)C(=O)C(CCCc1ccc(OC)cc1)S2
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
Under ice-cooling, a boron trifluoride-diethyl ether complex (26.6 ml) was added dropwise to a solution of ethyl 4-(2-tert-butoxy-2-oxoethyl)-2-[3-(4-methoxyphenyl)propyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (13.16 g) and dimethyl sulfide (26.3 ml) in dichloromethane (250 ml). The resulting mixture was slowly warmed up to room temperature and then stirred overnight. The mixture was poured into a 1N aqueous hydrochloric acid solution and extracted with chloroform. The oil layer was washed twice with a 1N aqueous hydrochloric acid solution, dehydrated over anhydrous sodium sulfate and then concentrated under reduced pressure. {6-(Ethoxycarbonyl)-2-[3-(4-methoxyphenyl)propyl]-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl}acetic acid (10.64 g) was obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]([O:24]C)=[O:23])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:16])[F:17])[C:11](=[O:20])[N:10]([CH2:21][C:22]([OH:24])=[O:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
The enantiomerically pure ester from Example 6A (1.6 g, 4.21 mmol) was dissolved in 77 ml of methanol and admixed with 17 ml of a 1M solution of lithium hydroxide in water. The mixture was stirred at RT for 1 h and then concentrated on a rotary evaporator. The residue was diluted with 100 ml of water and acidified to a pH of 1-2 using 1N hydrochloric acid. The precipitated product was isolated by filtration, washed in succession with water and cyclohexane and sucked dry. After further drying in an HV, the title compound (1.1 g, 71% of theory) was obtained.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH3:5].[CH2:6]([NH-:11])[CH2:7][CH:8]([CH3:10])[CH3:9].Cl>O1CCCC1.CO>[CH2:6]([NH:11][CH2:5][CH2:4][CH2:3][S:2][CH3:1])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CCCSC
Reactant: CC(C)CC[NH-]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CSCCCNCCC(C)C
Reaction time: 8 h

Procedure:
The amide from (a) (1.9 g) in tetrahydrofuran (20 ml) was treated under nitrogen at 0° with boranetetrahydrofuran complex (1 Molar in tetrahydrofuran 20 ml) and stirred overnight. 2 Molar hydrogen chloride in methanol (20 ml) was added and the mixture was boiled for 30 minutes, evaporated and the residue partitioned between ethyl acetate and water. The aqueous layer was basified and extracted with ether. The dried extract was evaporated to give the amine an oil (1.6 g). Rf3A=0.72, Rf7B=0.63, Rf4A=0.74
Reaction SMILES: [H-].[Li+].[C:3]1([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C>[C:3]1([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]2[CH:11]=[CH:12][C:13](=[O:16])[N:14]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:15]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CBr
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)c[nH]1
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(C(c2ccccc2)c2ccccc2)ccc1=O
Reaction time: 0.25 h

Procedure:
To a suspension of LiH (45.6 mg) in DMF (6.0 mL) was added portionwise 5-(diphenylmethyl)-2(1H)-pyridinone (500 mg) at ambient temperature and the mixture was stirred at the same temperature for 15 minutes. Ethyl bromoacetate (255 μL) was added dropwise to the mixture. The mixture was stirred at ambient temperature for 14 hours. The reaction was quenched with 1M HCl aqueous solution (10.0 mL) and the mixture was extracted with EtOAc (30 mL). The organic layer was washed successively with saturated NaHCO3 aqueous solution and brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=3:2) to afford 5-(diphenylmethyl)-1-ethoxycarbonylmethyl-2(1H)-pyridinone (574 mg) as a colorless amorphous.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].N(OC(C)(C)C)=O.N[C:16]1[S:17][C:18]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([Cl:26])[C:19]=2[N:20]=1.Cl>[Cu](Cl)Cl.C(#N)C>[Cl:26][C:21]1[C:19]2[N:20]=[C:16]([CH:3]=[CH:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[S:17][C:18]=2[CH:24]=[C:23]([F:25])[CH:22]=1
Reactant: C=CC(=O)OCC
Reactant: Nc1nc2c(Cl)cc(F)cc2s1
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CC#N
Product: CCOC(=O)C=Cc1nc2c(Cl)cc(F)cc2s1
Reaction time: 72 h

Procedure:
150 g (1.48 mol) of ethyl acrylate, 11.4 g (85 mmol) of copper (II) chloride and 11.4 g (0.11 mol) of tert-butyl nitrite were added to a solution of 12 g (59 mmol) of 2-amino-4-chloro-6-fluorobenzothiazole in 0.4 1 of acetonitrile. Stirring was carried out for 3 days, after which the mixture was acidified with dilute hydrochloric acid. The product was extracted with methyl tert-butyl ether, after which the extracts were dried over magnesium sulfate and finally evaporated down. Purification of the crude product was effected by means of column chromatography over silica gel (eluent: 19:1 cyclohexane/methyl tert-butyl ether). Yield: 9,0 g.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH:12]([CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH2:16]([O:15][C:13](=[O:14])[CH:12]([NH:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[CH:3]2)[CH2:18][CH2:19][CH2:20][CH3:21])[CH3:17]
Reactant: CCCCC(Br)C(=O)OCC
Reactant: Nc1ccc2[nH]ncc2c1
Product: CCCCC(Nc1ccc2[nH]ncc2c1)C(=O)OCC

Procedure:
2-(1H-Indazol-5-ylamino)-hexanoic acid ethyl ester was prepared from 1H-indazol-5-ylamine and ethyl 2-bromohexanoate similarly to the method described in Example 3, step 1 above, (6.81 g, 24.8 mmol, 65%) as a beige solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:12][SH:13])=[O:9])[C:3]([OH:5])=[O:4].[CH3:21][As:22]([CH3:24])Cl.N1C=CC=CC=1>COCCOC>[CH3:21][As:22]([CH3:24])[S:13][CH2:12][C@@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[NH:10][C:8](=[O:9])[CH2:7][CH2:6][C@@H:2]([C:3]([OH:5])=[O:4])[NH2:1]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Reactant: C[As](C)Cl
Solvent: COCCOC
Solvent: c1ccncc1
Product: C[As](C)SC[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 500 mL flask, 7 g of glutathione was used as received from the Aldrich Chemical Co., purity 98% and dissolved in 250 mL of 1,2-dimethoxyethane. To this solution was added 3.3 g of dimethylchloroarsine. This was followed by the addition of 3.5 g of pyridine (redistilled after drying over NaOH pellets). The solution was refluxed for one hour after which time it was stirred at room temperature for three hours.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)#[CH:12].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:12]#[C:11][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1
Reactant: C#Cc1ccccn1
Reactant: Cc1nc(N)nc(Cl)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(Cl)c1C#Cc1ccccn1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 1.5 g (5.6 mmol) 4-chloro-5-iodo-6-methyl-pyrimidin-2-ylamine (GP3) and 0.84 mL (8.4 mmol) 2-ethynyl-pyridine using 106 mg (0.57 mmol) CuI, 390 mg (0.56 mmol) PdCl2(PPh3)2 and 7.8 mL (56 mmol) triethylamine in 10 mL dry DMF. Additional amounts are added after 24 h and 48 h reaction time, respectively. For the work-up the solvent is removed in vacuo and the product is purified by chromatography on silica gel using a DCM/MeOH gradient. Yield: 2.0 g (>100%, approximately 70% pure).
Reaction SMILES: Cl.[CH:2]1([NH:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])O.[Na+].O.[CH3:15][C:16]1[O:17][C:18]([CH3:25])=[C:19]([CH3:24])[C:20]=1[C:21](Cl)=[O:22]>ClCCl>[CH:2]1([N:7]([C:21]([C:20]2[C:19]([CH3:24])=[C:18]([CH3:25])[O:17][C:16]=2[CH3:15])=[O:22])[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: ONC1CCCC1
Reactant: Cc1oc(C)c(C(=O)Cl)c1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1oc(C)c(C(=O)N(O)C2CCCC2)c1C
Temperature: 25 °C

Procedure:
27.5 Parts of N-cyclopentylhydroxylamine hydrochloride is dissolved in 200 parts of dichloromethane; a solution of 33.6 parts of sodium hydrogen carbonate in 300 parts of water is then added. At room temperature and while stirring thoroughly, 34.5 parts of 2,4,5-trimethylfuran-3-carboxylic chloride is dripped into this mixture. After the mixture has been stirred for 2 hours the dichloromethane phase is separated, dried over anhydrous sodium sulfate and evaporated. There is obtained 36 parts of N-cyclopentyl-2,4,5-trimethylfuran-3-hydroxamic acid in the form of an oil.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH:3]([CH3:5])[CH3:4].COCCOC[C:13]1[C:26]2[NH:27][N:28]=[C:24]3[C:25]=2[C:16]([C:17](=[O:30])[C:18]2[C:23]3=[CH:22][CH:21]=[CH:20][C:19]=2[OH:29])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:4][CH:3]([CH3:5])[CH2:2][CH2:1][O:29][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[C:17](=[O:30])[C:16]1[C:25]3[C:24]2=[N:28][NH:27][C:26]=3[CH:13]=[CH:14][CH:15]=1
Reactant: COCCOCc1ccc2c3c(n[nH]c13)-c1cccc(O)c1C2=O
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCOc1cccc2c1C(=O)c1cccc3[nH]nc-2c13
Temperature: 80 °C

Procedure:
Isopentyl bromide is added to a mixture of 3-(2-methoxyethoxymethyl)-7-hydroxyanthra[1,9cd]pyrazol-6(2H)-one and potassium carbonate in dimethylformamide at room temperature. After stirring the mixture for sixteen hours, water is added, and the mixture was extracted with ethyl acetate (×2). The combined organic layer is washed with aqueous sodium bicarbonate, water, 1N hydrochloric acid, and brine, dried and evaporated. The reside is taken in 6N hydrochloric acid and heated at 80° C. for 4 hours. After cooling, the mixture is extracted with ethyl acetate (×2), and the combined organic layer is washed with brine, dried, and evaporated. The residue is purified by column chromatography to afford the title compound as yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl)#[N:2].[OH-].[Na+].ClCl.CO>CN(C)C=O>[C:4]1([CH:5]=[CH:5][C:4]2[C:3]([C:1]#[N:2])=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([C:1]#[N:2])=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#Cc1ccccc1CCl
Agent: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1ccccc1C=Cc1ccccc1C#N
Temperature: 20 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
30.4 g (0.2 mole) of o-cyanobenzyl chloride are dissolved in 70 g of dimethylformamide, and 24 g (0.6 mole) of sodium hydroxide powder are added at the same time as nitrogen is passed in. The mixture is stirred at 20° C. for about 6-10 hours until all the organically bound chlorine has reacted, 70 g of methanol are added dropwise, and the precipitate is filtered off with suction at 0° C. and is washed with methanol and then with water until no chlorine ions are detectable in the water from the wash. Drying gives 17.8 g of stilbene-2,2'-dicarbonitrile in the form of white crystals.