Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.I[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1>O1CCCC1.C(OCC)C.[Cl-].[Zn+2].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: c1cscn1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(-c2nccs2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a −70° C., stirred solution of thiazole (270 μL, 3.8 mmol) in tetrahydrofuran (10 mL) is added n-butyl lithium (2.6 mL of a 1.6 M solution in hexanes, 4.2 mmol). After 30 min, zinc chloride (11.4 mL of a 1.0 M solution in diethyl ether, 11.4 mmol) is added. The reaction mixture is warmed to 0° C. and methyl 4-iodobenzoate (1 g, 3.8 mmol) and palladium(0) tetrakis(triphenylphosphine) (530 mg, 0.4 mmol) are added. The reaction mixture is heated at 70° C. for 20 h under argon, cooled to room temperature, and then partitioned between ethyl acetate and water. The organic layer is washed with water, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (3:1 hexanes/ethyl acetate) yields the title compound. 1H NMR (300 MHz, CDCl3) δ 8.14–8.03 (m, 4H), 7.93–7.92 (m, 1H), 7.42–7.41 (m, 1H), 3.95 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10](I)[CH:11]=[CH:12][CH:13]=1.N1CCCCC1.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>C1COCC1.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>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH:11]=[CH:12][CH:13]=1
Reactant: COCCOCOc1cccc(I)c1
Reactant: C#C[Si](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: COCCOCOc1cccc(C#C[Si](C)(C)C)c1
Reaction time: 2 h

Procedure:
3-(2-Methoxy-ethoxymethoxy)-phenyliodide (12.1 g, 39 mmol, 96) and tetrakis(triphenylphosphine)palladium (1.2 g, 1.0 mmol) and cuprous iodide (0.096 g, 0.5 mmol) are dissolved in THF (120 mL) and to this is added piperidine (12 mL) and (trimethylsilyl)acetylene (8 mL, 57 mmol). This mixture is degassed and is then stirred for 2 hours. The reaction is then diluted with ether and washed twice with water and brine and the organic layer dried over magnesium sulfate. The solvent is removed in vacuo to give the title compound. MS (EI) 206 (M)+.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[C:22](=[O:37])[N:23]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][C:28]=2[CH3:36])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:33][C:30]1[CH:31]=[CH:32][C:27]([N:23]2[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:22]2=[O:37])=[C:28]([CH3:36])[CH:29]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(N)ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
62 g (121 mmol) of the compound from Example 25A are dissolved in 2 l of a 1:1 mixture of ethanol and ethyl acetate, and 46 g (726 mmol) of ammonium formate and 0.6 g of palladium on carbon are added. The mixture is heated at 80° C. After 45 min, the mixture is allowed to cool and filtered through silica gel. The filter cake is washed with ethyl acetate and the filtrate is evaporated to dryness under reduced pressure. This gives 36 g (61% of theory) of the desired product.
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[C:11]([O-:14])(=[O:13])[CH3:12].[K+].CS(C)=O>O>[C:11]([O:14][CH:3]([CH:1]=[CH2:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:13])[CH3:12]
Reactant: C=CC(Cl)c1ccccc1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C=CC(OC(C)=O)c1ccccc1
Temperature: 40 °C
Reaction time: 48 h

Procedure:
In a one liter 3-neck round bottom flask equipped with a condenser, mechanical stirrer and thermometer, 108 grams (0.708 mol) of vinylbenzyl chloride (60/40 m-/p-) and 808 grams (0.815 mol) of potassium acetate were added, followed by 250 mLs of DMSO. The mixture was stirred at 40° C. for 48 hours. After allowing to cool to room temperature, the mixture was diluted with water and poured into a separatory funnel. The organic layer was separated, followed by an extraction of the aqueous layer with chloroform. The combined organic layer was then washed with water, dried over magnesium sulfate and placed on the rotary evaporator to remove the chloroform. 120 grams of the vinylbenzyl acetate product was recovered, to which 10 mg of MEHQ was added as an inhibitor.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:15][CH3:16])=[C:12]([OH:14])[CH:13]=1.Cl>CCO>[CH3:16][O:15][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:13][C:12]=1[OH:14]
Reactant: COc1ccc(N)cc1O
Reactant: Brc1nccs1
Agent: Cl
Solvent: CCO
Product: COc1ccc(Nc2nccs2)cc1O
Yield: 62 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(thiazol-2-ylamino)phenol; 2-bromothiazole (0.27 mL, 3.05 mmol), 5-amino-2-methoxyphenol (212 mg, 1.52 mmol) and 37% HCl solution (0.26 mL, 3.05 mmol) in 10% aqueous EtOH solution (5 mL) was stirred at 90° C. for 24 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 1/1) in 62% yield (210 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][C:42]([NH2:45])=[N:43][CH:44]=2)O1>>[O:28]1[CH2:27][CH2:26][N:25]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:39]3[CH:40]=[N:41][C:42]([NH2:45])=[N:43][CH:44]=3)[N:3]=2)[CH2:30][CH2:29]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)cn1

Procedure:
2-Chloro-6-((4-Boc-piperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidine (200 mg) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine 7 following General Procedure A followed by Boc removal with 1N HCl in dioxane to generate 159 after reversed phase HPLC purification. MS (Q1) 413 (M)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:15][CH:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:17]1>CN(C)C=O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([N:18]2[CH2:17][CH:16]([CH2:15][O:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=3)[O:20][C:19]2=[O:21])=[CH:27][CH:26]=1
Reactant: O=C1OC(CCl)CN1c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC2CN(c3ccc(Cl)cc3)C(=O)O2)cc1
Temperature: 40 °C
Reaction time: 48 h
Yield: 48 %

Procedure:
A 1.52 g quantity of methyl 4-hydroxy-benzoate was added to a suspension of 0.42 g of 60% sodium hydride in anhydrous N,N-dimethylformamide (15 ml) with ice-cooling in a stream of nitrogen. To the mixture was added dropwise an anhydrous N,N-dimethylformamide (15 ml) solution of 2.46 g of 5-(chloromethyl)-3-(4-chlorophenyl)-2-oxooxazolidine obtained in Reference Example 7 at the same temperature, and the mixture was stirred at 40° C. for 48 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with ethyl acetate. The extract was washed with water, dried with magnesium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and purified by hexane-ethyl acetate gradient elution to give 1.75 g of the title compound (compound 51) in a yield of 48%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:3]=1.CC(C)([O-])C.[Na+].C(=[NH:35])(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:15][N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:4]2[N:3]=[C:2]([NH2:35])[CH:7]=[CH:6][CH:5]=2)[CH2:10][CH2:11]1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CN1CCC(Oc2cccc(Cl)n2)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CN1CCC(Oc2cccc(N)n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
Combine 2-chloro-6-(1-methyl-piperidin-4-yloxy)-pyridine (preparation 46, 7.0 g, 31.0 mmol), Pd2(dba)3 (1.41 g, 1.5 mmol), (±)-BINAP (1.92 g, 3.0 mmol), sodium tert-butoxide (4.15 g, 43.0 mmol), and benzophenone imine (6.9 mL, 37.0 mmol), heat at 80° C. in 200 mL of toluene. After 18 hr., cool the reaction to room temperature, and partition between ethylacetate and water. Extract with ethylacetate (1×), and methylene dichloride (2×), combine organics and dry over MgSO4, and concentrate. Dissolve residue in of 1:1 1 N aqueous HCl/THF (200 mL), stir at room temperature. After 2 hr., adjust aqueous layer to pH>10 with 5 N NaOH. Partition between ethylacetate and water, extract aqueous layer with ethylacetate (1×) and methylene dichloride three times. Combine organics, dry over MgSO4, concentrate, and further purify by chromatography (silica gel, eluting with 0-20% 2 M NH3 in methanol/ethylacetate), to obtain the title compound (6.3 g, 99% yield). Mass spectrum (ion spray): m/z=208.1 (M+1); Anal calcd for C11H17N3O.HCl.0.85H2O: Theory: C, 51.00; H, 7.67; N, 16.22. Found: C, 50.72; H, 7.27; N, 16.22.
Reaction SMILES: B.C1COCC1.[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=O)[NH:12][C:11]2=O.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[ClH:34].O1CCOCC1>C1COCC1.CO.CCN(CC)CC>[ClH:34].[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][NH:12][CH2:11]2
Reactant: O=C1NC(=O)c2cc(Br)ccc21
Agent: B
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: Brc1ccc2c(c1)CNC2
Temperature: 0 °C
Reaction time: 16 h
Yield: 42.8 %

Procedure:
In a dried 500 mL three necked round bottom flask equipped with a reflux condenser and addition funnel was taken BH3-THF (160 mL) solution with dry THF (50 mL). The mixture was cooled to 0° C. To this cold solution 5-bromo-1H-isoindole-1,3(2H)-dione (8.0 g, 35.4 mmol) in dry THF (100 mL) was added gradually and allowed to warm to room temperature. After 10 min at room temperature the mixture was refluxed for 16 h. The reaction mixture was then cooled to 0° C. and quenched with methanol. (Caution: vigorous foaming will occur). 20-30 mL of 2N HCL was added and refluxed the mixture for 1 h. Cooled the mixture and basified with NaOH solution and extracted with ethyl acetate. Combined organic extracts were washed with water, saturated NaCl solution, dried over Na2SO4 and concentrated under vacuo. To the crude product in MeOH (150 mL), Et3N (12 mL) and di-tert-butyl dicarbonate (13.8 g, 63.23 mmol) were added and stirred at room temperature for 16 h. The reaction mixture was then concentrated under vacuo. The crude product was diluted with CH2Cl2 (200 mL), washed with water, saturated NaCl solution, and dried over Na2SO4. Crude product was purified by column chromatography using 20% ethyl acetate in hexanes as eluant to afford a colourless solid. To this dioxane-HCl was added at room temperature and stirred for 10 min, the solid obtained was then filtered and dried to give 3.0 g (42.8%) of 5-bromoisoindoline hydrochloride salt as an ash colour solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6].[CH2:12](O)[CH2:13][CH2:14]C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([O:2][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCO
Reactant: COC(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCCOC(=O)c1ccccc1N
Reaction time: 8 h
Yield: 97 %

Procedure:
453 parts of anthranilic acid methyl ester, 444 parts of n-butanol and 11 parts of potassium carbonate are heated together and the methanol thus formed is distilled off over a column. A subsequent intermediate fraction contains both methanol and n-butanol. Finally, the excess quantity of n-butanol is distilled off, preferably in vacuo towards the end of this operational step. The reaction time lasts for about 8 hours. After filtration of the catalyst there are obtained 562 parts of anthranilic acid n-butyl ester (nD25 1.545; accoding to gas chromatography of 99-100% purity). Yield: 97% of the theory.
Reaction SMILES: [C:1]1([C@@:7]([OH:21])([CH2:18][CH2:19][CH3:20])[CH2:8][NH:9][C@H](C2C=CC=CC=2)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCO.[OH-].[OH-].[Pd+2]>[NH2:9][CH2:8][C@:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:21])[CH2:18][CH2:19][CH3:20]
Reactant: CCC[C@@](O)(CN[C@@H](C)c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCC[C@@](O)(CN)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
To a solution of (25)-2-phenyl-1-{[(1S)-1-phenylethyl]amino}pentan-2-ol (0.954 g, 3.37 mmol) in EtOH (34 mL) was added Pd(OH)2/C (10%, 644 mg), then stirred at room temperature under 1 atmosphere of H2 overnight. The reaction was filtered through Celite, washed with EtOH, and the filtrate was concentrated to afford the desired product (609 mg, 100%) as an oil: 1H NMR (400 MHz, CDCl3) δ ppm 7.35-7.40 (2H, m), 7.32 (2H, t, J=7.71 Hz), 7.21 (1H, t, J=7.20 Hz), 3.10 (1H, d, J=12.38 Hz), 2.86 (1H, d, J=12.63 Hz), 2.58 (3H, s), 1.65-1.76 (2H, m), 1.28-1.39 (1H, m), 0.96-1.07 (1H, m), 0.82 (3H, t, J=7.33 Hz); [α]D20° C.=+4.2° (c=1, EtOH).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:29])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[N:5][CH:4]=1)#[N:2].Cl.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[NH2:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[N:5][CH:4]=[C:3]([C:1]#[N:2])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:29])[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ncc(C#N)cc32)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: N#Cc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
To a solution of 75 mg of tert-butyl (1-(2-(7-cyano-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate in 5 mL of ethyl acetate, 7 mL of a 4 mol/L hydrogen chloride/ethyl acetate was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was alkalified with a saturated aqueous sodium hydrogen carbonate solution, the solvent was distilled off under reduced pressure, and the resultant residue was then purified by silica gel column chromatography using silica gel; Chromatorex-NH made by Fuji Silysia Chemical Ltd., and an eluent of chloroform to obtain 34 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-cyano-1,5-naphthyridin-2(1H)-one as a light yellow solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[CH:14]([CH3:16])[CH3:15])(=O)=O.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.CS(C)=O.[C:59]([O:62][CH2:63]C)(=[O:61])C>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:59]([O:62][CH3:63])=[O:61])=[C:8]([CH:14]([CH3:16])[CH3:15])[CH:9]=1
Reactant: CC(C)c1cc(Br)ccc1OS(=O)(=O)C(F)(F)F
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Br)cc1C(C)C
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A mixture of 4-bromo-2-isopropylphenyl trifluoromethanesulfonate (0.705 g), palladium acetate (0.0228 g), 1,3-bis-(diphenylphosphino)propane (0.0419 g) and triethylamine (0.628 mL) in methanol (6 mL)/dimethylsulfoxide (9 mL) was stirred at 55° C. overnight under an atmosphere of carbon monoxide. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: diethyl ether/n-hexane=1/10) to afford methyl 4-bromo-2-isopropylbenzoate (0.355 g).
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH:10]([OH:34])/[CH:11]=[CH:12]/[C:13]1[N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+:36]>CO>[OH:1][CH:2]([CH2:9][CH:10]([OH:34])/[CH:11]=[CH:12]/[C:13]1[N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][C:4]([O-:6])=[O:5].[Na+:36]
Reactant: CCOC(=O)CC(O)CC(O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2c(=O)n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc2c1=O

Procedure:
A solution of a 1:1 mixture of the erythro- and threo-diastereoisomers of ethyl (E)-3,5-dihydroxy-7-[4-(4-fluorophenyl)-2-isopropyl-1-oxo-1,2-dihydroisoquinolin-3-yl]hept-6-enoate (0.18 g; prepared as described in Example 4) in methanol, (10 ml) was treated with aqueous sodium hydroxide solution (2.0M; 0.77 ml) at room temperature. After 90 minutes the solution was evaporated to dryness and the residue was azeotroped on the rotary evaporator with ethyl acetate (2×20 ml). The residue was triturated with diethyl ether (25 ml) and the product was filtered off, to give sodium (E)-3,5-dihydroxy-7-[4-(4-fluorophenyl)-2-isopropyl-1-oxo-1,2-dihydroisoquinolin-3-yl]hept-6-enoate in the form of a pale yellow solid (0.18 g). [Elemental analysis: C, 58.4; H, 5.55; N, 2.62; H2O, 10.0%; calculated for C25H25O5NFNa:3 H2O: C, 58.25; H, 6.06; N, 2.72; H2O, 10.49%].
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[CH:9][CH:8]=1.[C:23](Cl)(=[O:25])[CH3:24]>ClCCl>[C:23]([C:12]1[CH:13]=[C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])[C:15]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:6][CH3:5])[CH:16]=2)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: COc1ccc2cccc(CCNC(C)=O)c2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc2cc(C(C)=O)cc(CCNC(C)=O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.45 mol (60 g) of aluminium chloride are added at 0° C. to a solution of 0.16 mol (40 g) of N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide (described in Patent EP 447 285) in 350 ml of dichloromethane. 0.21 mol (15.3 ml) of acetyl chloride is then added dropwise at 0° C. The reaction medium is stirred at room temperature for 1 hour and then poured onto ice. The organic phase is decanted and concentrated to yield the expected compound.
Reaction SMILES: B([O-])=O.[Li+].[Cl:5][C:6]1[CH:7]=[C:8]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:9][NH:10][C:11](=[O:24])[NH:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18][C:19](OCC)=[O:20])[N:17]=1.[Cl-].[NH4+]>C1COCC1.O>[Cl:5][C:6]1[CH:7]=[C:8]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:9][NH:10][C:11]([NH:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18][CH2:19][OH:20])[N:17]=1)=[O:24]
Reactant: CCOC(=O)Cc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Agent: O=B[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CCO)cs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Lithium boranate (7 mg, 322 μmol) was added to a solution of Ethyl 2-(2-(3-(3,4-dichlorobenzyl)ureido)thiazol-4-yl)acetate (Example 35) (58 mg, 150 μmol) in dry THF (4 ml) at 0° C. The reaction mixture was stirred for 3 hours at this temperature and then allowed to warm to ambient temperature overnight. Then, saturated aqueous ammonium chloride solution (3 ml) was added and the mixture was stirred for 2 hours. The salts were dissolved by addition of a few drops of water, and the mixture was extracted several times with ethyl acetate. The combined organic layers were partitioned with brine and then dried over sodium sulfate, filtered, and volatiles removed in vacuo. The crude material was purified by column chromatography (silica gel, acetone/ethyl acetate, 1:20, 1:15, 1:10), yielding the title compound in 60% (32 mg, 92 mmol). 1H NMR (300 MHz, CD3OD) δ 2.80 (t, 2H), 3.81 (t, 2H), 4.40 (s, 2H), 6.60 (s, 1H), 7.24 (dd, 1H), 7.42-7.48 (m, 2H). MS (ES+): M/Z 346 and 348 (M+H).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].[CH3:11][N:12]1CCOCC1.C(OC(Cl)=O)C(C)C.CN.C1COCC1.C[O-].[Na+]>C(O)CO.COC.CO>[CH3:11][NH:12][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([SH:1])[CH:3]=1
Reactant: CN1CCOCC1
Reactant: O=C(O)c1cccc(S)c1
Agent: CC(C)COC(=O)Cl
Agent: CN
Agent: COC
Solvent: OCCO
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(S)c1
Reaction time: 1 h

Procedure:
To a solution of 3-mercaptobenzoic acid (1.00 g, 6.49 mmol) in ethyleneglycol-dimethylether (10 ml) was added N-methylmorpholine (1.5 ml, 13.6 mmol) and iso-butylchloroformate (1.77 ml, 13.6 mmol) under a flow of nitrogen at 0° C. The clear solution quickly became a thick paste. After stirring for one hour the reaction was filtered and then treated with 2M methylamine in THF (7 ml, 14 mmol). The reaction was stirred for two days at room temperature and then treated with 0.5M sodium methoxide in methanol (14 ml). The reaction was stirred for three hours, then quenched with 2N HCl until pH=4 and concentrated in vacuo to a semi solid. This was dissolved in H2O (50 ml), basified (2N NaOH, pH=10), washed with CHCl3 (2×50 ml), acidified (2N HCl, pH=2) then extracted with CHCl3 (50 ml) and ethyl acetate (50 ml). The organic extracts were combined, dried (MgSO4) then concentrated in vacuo to a colourless oil (570 mg).
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH2:4]([O:6][C:7]([C@@H:9]1[CH2:13][S:12][C@@H:11]([CH2:14][SH:15])[CH2:10]1)=[O:8])[CH3:5]>C(OCC)C>[CH2:4]([O:6][C:7]([C@@H:9]1[CH2:13][S:12][C@@H:11]([CH2:14][S:15][CH3:3])[CH2:10]1)=[O:8])[CH3:5]
Reactant: CCOC(=O)[C@@H]1CS[C@@H](CS)C1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: CCOC(=O)[C@@H]1CS[C@@H](CSC)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
Diethylether solution of diazomethane (10 molar equivalents) was added to trans-4-ethoxycarbonyl-2-mercaptomethyltetrahydrothiophene (compound No. 15-1, 549 mg) and the mixture was stirred for 4 hours at room temperature. The mixture was concentrated in vacuo and the oil residue was purified by a silica gel column chromatography to give 407 mg (69%) of the titled compound (compound No. 18-1).