Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:15][CH:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=O.O>C1(C)C=CC=CC=1>[CH3:15][C:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]=1[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Reactant: CC1C(=O)CCC1=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=C(Nc2ccc(C3=NNC(=O)CC3)cc2)CCC1=O

Procedure:
3.4 g of 4,5-dihydro-6-(4-aminophenyl)-3(2H)-pyridazinone and 2.0 of 2-methylcyclopentane-1,3-dione were suspended in 30 ml of toluene, to which a catalytic amount of p-toluene sulfonate-hydrate was add while the resulting suspension was heated to reflux with stirring for 8 hours, with removal of water as an azcotropic mexture. After cooled, deposited crude crystal was collected by filtrating, and purified by silica gel column chromatography (eluting solvent: chloroform:methanol=10:1), 4.7 g of the title compound was obtained. m.p. 284°-285° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:19]=[CH:18][C:12]([C:13](OCC)=[O:14])=[CH:11][CH:10]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][OH:14])=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1ccc(OCCOCCOC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOCCOc1ccc(CO)cc1
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of ethyl 4-[2-(2-methoxyethoxy)ethoxy]benzoate (Step 1, 1.0 g, 3.73 mmol) in 18 mL dry THF was added dropwise a solution of lithium aluminium hydride (1M in THF, 5.6 mL, 5.59 mmol) at 0° C. After the addition was completed, stirring of the reaction mixture was continued for 1 h at rt. Then, 1 g Celite was added, as was 5 mL water with caution. After the addition of sodium hydroxide (1N aq., 2 mL), the precipitate which had formed was removed by filtration. After some washing of the precipitate with ethyl acetate, the organic layer was separated from the filtrate and the aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo to yield the title compound (710 mg, 84%): 1H NMR (400 MHz, CDCl3) δ 7.28 (d, 2H), 6.90 (d, 2H), 4.61 (s, 2H), 4.14 (t, 2H), 3.86 (t, 2H), 3.72 (t, 2H), 3.58 (t, 2H), 3.39 (s, 3H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[OH-].[Na+]>>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccn3)ccc21
Yield: 91 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 91% of theory, C25H25N7O3 (471.5) ##EQU37##
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][NH:11][CH2:12][CH3:13])=[O:9])[C:5]([NH:14][C:15]([C:17]2[N:18]([C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[N:19]=[C:20]([Br:22])[CH:21]=2)=[O:16])=[C:4]([CH3:30])[CH:3]=1.Cl[C:32]([O:34][CH3:35])=[O:33]>N1C=CC=CC=1>[CH3:35][O:34][C:32]([N:11]([CH2:12][CH3:13])[NH:10][C:8]([C:6]1[C:5]([NH:14][C:15]([C:17]2[N:18]([C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[N:19]=[C:20]([Br:22])[CH:21]=2)=[O:16])=[C:4]([CH3:30])[CH:3]=[C:2]([Cl:1])[N:7]=1)=[O:9])=[O:33]
Reactant: COC(=O)Cl
Reactant: CCNNC(=O)c1nc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Solvent: c1ccncc1
Product: CCN(NC(=O)c1nc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [6-chloro-2-(N′-ethyl-hydrazinocarbonyl)-4-methyl-pyridin-3-yl]-amide (10-a) (320 mg) was dissolved in pyridine (4 mL), methyl chloroformate (190 μL) was added and the reaction mixture was stirred at room temperature. After 30 min, 1 h and 1.5 h, methyl chloroformate (each 95 μL) was added. After 1 h stirring at room temperature, the reaction mixture was quenched with water and 3× co-evaporated with toluene. The residue was dissolved in water and ethyl acetate, the layers were separated and the aqueous layer was extracted 2× with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The residue was purified by column chromatography (silica 60, hexane/ethyl acetate=2:1, Rf=0.10) to afford 308 mg of the title compound (10) of the present invention of the formula
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[CH:20]=[CH:19][C:18]=2[F:26])=[CH:5][CH2:4][CH2:3]1.CO>[Pd]>[CH3:27][C:2]1([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]1[C:7]1[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:8]=1[C:17]1[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[CH:20]=[CH:19][C:18]=1[F:26]
Reactant: CCOc1ccc(F)c(-c2ccc(C(=O)OC)cc2C2=CCCC2(C)C)c1
Agent: [Pd]
Solvent: CO
Product: CCOc1ccc(F)c(-c2ccc(C(=O)OC)cc2C2CCCC2(C)C)c1
Reaction time: 23 h
Yield: 99.1 %

Procedure:
To a stirred solution of 66.25A (0.400 g, 1.09 mmol) in MeOH (10.00 mL, 1.09 mmol) at 23° C. was added palladium on carbon (0.116 g, 1.09 mmol). The reaction was placed under an atmosphere of hydrogen and stirred for 23 hours. The mixture was then filtered and concentrated in vacuo. The initial product was then purified on silica gel (0-20% EtOAc in hexanes) to yield 66.25B as a colorless oil (0.400 g, 99.5% yield).
Reaction SMILES: [C:1]([C:3]1[C:7](I)=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2].[CH:21]([Sn](CCCC)(CCCC)CCCC)=[CH2:22].O.CCOCC>CN(C)C=O.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>[C:1]([C:3]1[C:7]([CH:21]=[CH2:22])=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Temperature: 75 °C
Reaction time: 3 h

Procedure:
A solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (58 g) in dimethylformamide (350 ml) containing vinyltri-n-butyltin (1 16 ml) and tetrakis(triphenylphosphine)palladium(0) (3.5 g) was stirred at 75° C. for 3 hours. The reaction mixture was poured into water (600 ml) and ether (600 ml). The organic layer was separated, washed with water (×5), brine (700 ml), dried (Na2SO4) and evaporated. The residue was recrystallised from propan-2-ol to give the title compound as a pale brown solid, m.p.75-6° C.
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].[OH-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO.O>[CH2:24]([C:3]1([OH:4])[C:5]2[O:9][C@@H:8]3[C@@:7]45[CH2:21][CH2:20][N:18]([CH3:19])[C@@H:15]([C@@H:14]4[CH:13]=[CH:12][C@@H:10]3[OH:11])[CH2:16][C:17]([C:6]5=2)=[CH:1][CH2:2]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1CC[C@]23C4=C5O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1CC4=CCC5(O)Cc1ccccc1
Reaction time: 3.5 h
Yield: 70.1 %

Procedure:
A solution of morphine (14.27 g, 50.0 mmol), NaOH (2.04 g, 51.0 mmol), and benzylbromide (8.47 g, 49.5 mmol) in MeOH (150 ml) and water (50 ml) was stirred at rt. for 3.5 hr., evaporated in vacuo to remove MeOH. The residue was extracted with CH2Cl2 (120 ml). The extract was dried over anhydrous Na2SO4 and evaporated in vacuo to dryness to give a crude residue, which was chromatographed on silica gel (column: d=6.5 cm, I=10.5 cm; eluting solvent: 15% MeOH in CH2Cl2) to obtain 3-benzylmorphine (13.1 g, 70% yield). The Rf value in TLC and the IR spectrum of the product were comparable to those obtained from an authentic sample.
Reaction SMILES: [CH:1]1([C:6]2[N:7]=[C:8]([N:17]3[CH2:22][CH2:21][CH:20]([CH2:23][C:24](O)=[O:25])[CH2:19][CH2:18]3)[C:9]3[CH2:14][S:13](=[O:16])(=[O:15])[CH2:12][C:10]=3[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[NH4+].[NH4+].C1C=CC2N(O)N=[N:39]C=2C=1.CCN=C=NCCCN(C)C.[ClH:54].O1CCOCC1>C1COCC1.CN(C=O)C>[ClH:54].[CH:1]1([C:6]2[N:7]=[C:8]([N:17]3[CH2:18][CH2:19][CH:20]([CH2:23][C:24]([NH2:39])=[O:25])[CH2:21][CH2:22]3)[C:9]3[CH2:14][S:13](=[O:15])(=[O:16])[CH2:12][C:10]=3[N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CC1CCN(c2nc(C3CCCC3)nc3c2CS(=O)(=O)C3)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: NC(=O)CC1CCN(c2nc(C3CCCC3)nc3c2CS(=O)(=O)C3)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 246 mg of [1-(2-cyclopentyl-6,6-dioxo-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperidin-4-yl]acetic acid, 75 mg of ammonium carbonate, 0.11 g of HOBt, 0.16 g of EDCI, and 6 ml of DMF was stirred at ambient temperature for 3 days. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with EtOAc. The organic phase obtained was washed with a saturated aqueous sodium bicarbonate and brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica-gel column chromatography (chloroform-MeOH) to yield a foamy product. This product was dissolved in THF, here was added 4M HCl-dioxane solution, the solution was concentrated under reduced pressure, the residue was washed with ether to yield 184 mg of [1-(2-cyclopentyl-6,6-dioxo-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperidin-4-yl]acetamide hydrochloride.
Reaction SMILES: C(OC(OCC)CCN)C.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O[CH:40](OCC)[CH2:41][CH2:42][NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])C.[NH2:54][CH:55]([C:59]1[N:60]([CH2:70][C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[C:61](=[O:69])[C:62]2[C:67]([CH3:68])=[N:66][S:65][C:63]=2[N:64]=1)[CH:56]([CH3:58])[CH3:57].C(O[BH3-])(=O)C.[Na+]>C1COCC1.C(O)(=O)C.C1(C)C=CC=CC=1.O>[C:46]([O:45][C:44](=[O:50])[NH:43][CH2:42][CH2:41][CH2:40][NH:54][CH:55]([C:59]1[N:60]([CH2:70][C:71]2[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=2)[C:61](=[O:69])[C:62]2[C:67]([CH3:68])=[N:66][S:65][C:63]=2[N:64]=1)[CH:56]([CH3:58])[CH3:57])([CH3:47])([CH3:48])[CH3:49]
Reactant: Cc1nsc2nc(C(N)C(C)C)n(Cc3ccccc3)c(=O)c12
Reactant: CCOC(CCNC(=O)OC(C)(C)C)OCC
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CCOC(CCN)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1nsc2nc(C(NCCCNC(=O)OC(C)(C)C)C(C)C)n(Cc3ccccc3)c(=O)c12
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To (3,3-diethoxypropyl)amine (1.00 equiv) in THF (2 volumes) was charged di-t-butyldicarbonate (1.05 equiv) in THF (3 volumes). The reaction was heated to 45° C. and held for ½ h. Analysis showed the disappearance of starting material, and the resulting solution was heated to 65° C. p-Toluene sulphonic acid (0.1 equiv) and water (5 volumes) were charged over 10 mins, heating continued at 65° C. and held for ½ hour. Analysis showed disappearance of tert-butyl (3,3-diethoxypropyl)carbamate. Toluene (15 volumes) charged, layers separated and washed with water (5 volumes). A fraction of the solution obtained (0.95 equivs) was charged to a solution containing 6-(1-amino-2-methyl-propyl)-5-benzyl-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one (method 30) (1 equiv), toluene (5 volumes) and molecular sieves (1 weight equivalent). The reaction mixture was stirred overnight at room temperature until the reaction was complete. THF (2.5 volumes) were charged followed by sodium acetoxyborohydride (2.0 equiv) and the resulting mixture held overnight until reaction was complete. Aqueous acetic acid (20% v/v, 2.5 volumes) were charged over 10 minutes, stirred at room temperature for 10 minutes, filtered and washed with water (2.5 volumes). The layers were separated and the organic layer was concentrated under vacuo at 50° C. Further toluene was charged (2.5 volumes) and the solvent removed. The product was obtained as an orange oil (typical yield 92%). m/z 486 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]2=[CH:7][N:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[F:14][C:11]1[CH:12]=[CH:13][C:8]2[N:9]([C:5]([CH2:3][OH:2])=[N:6][CH:7]=2)[CH:10]=1
Reactant: COC(=O)c1ncc2ccc(F)cn12
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ncc2ccc(F)cn12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 117.8 %

Procedure:
In a round-bottomed flask, 6-fluoro-imidazo[1,5-a]pyridine-3-carboxylic acid methyl ester (223 mg, 1.15 mmol) was dissolved in THF (7 ml). The solution was cooled to 0° C. and lithium aluminum hydride (1.0 M in THF, 1.4 ml, 1.4 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1.5 h then sodium sulfate decahydrate was carefully added. When gas evolution had ceased, the ice bath was removed, sodium sulfate was added and the mixture was stirred vigorously for 30 min at room temperature. The suspension was filtered over Celite and rinsed with ethyl acetate and methanol. The filtrate was concentrated to give 225 mg of (6-fluoro-imidazo[1,5-a]pyridin-3-yl)-methanol as a brown solid which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[CH:16]1([C:19](=[S:21])[NH2:20])[CH2:18][CH2:17]1>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:19]([CH:16]2[CH2:18][CH2:17]2)[S:21][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)=[O:15]
Reactant: NC(=S)C1CC1
Reactant: COC(=O)C(=O)C(Cl)c1cccc(F)c1
Product: COC(=O)c1nc(C2CC2)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of 3-chloro-3-(3-fluoro-phenyl)-2-oxo-propionic acid methyl ester with cyclopropanecarbothioic acid amide. LC-MS: tR=1.02 min; [M+H]+=278.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[C:17](=[O:34])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH3:35][O:36][CH2:37][C:38](O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([N:21]([CH2:38][CH2:37][O:36][CH3:35])[CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[C:17](=[O:34])[CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1NC1CCN(c2ccncc2)CC1
Reactant: COCC(=O)O
Product: COCCN(C1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O

Procedure:
Similarly to Method B in Example 43 and using 4-(6-chloronaphthalene-2-sulfonyl)-1-[1-(4-pyridyl)-4-piperidinylamino}-2-piperazinone (200 mg) and methoxyacetic acid (4 ml) instead of acetic acid, the title compound (123 mg) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]=[O:13].[OH-].[Na+].S([O-])([O-])=[O:17].[Na+].[Na+]>O1CCCC1.[C].[Pd]>[CH3:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:12]([OH:17])=[O:13]
Reactant: Cc1c(C=O)ccc2c1OCCO2
Reactant: O=S([O-])[O-]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)ccc2c1OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
In 5 ml of tetrahydrofuran was dissolved 0.8 g of 5-methyl-1,4-benzodioxan-6-carbaldehyde, then 27 ml of a 1% sodium hydroxide aqueous solution was added dropwise to the solution and further 0.5 g of a 10% palladium-carbon was added thereto, and the mixture was refluxed under heating for 1.5 days. The mixture was cooled to room temperature, 10 ml of a 10% sodium sulfite aqueous solution was added thereto and after stirring for 30 minutes, the mixture was filtered and the tetrahydrofuran was removed under reduced pressure. The residue was adjusted to pH 3 with a 5% hydrochloric acid and extracted with diethyl ether. The diethyl ether layer was washed successively with water and saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain 0.53 g of the titled 5-methyl-1,4-benzodioxan-6-carboxylic acid (yield: 61%).
Reaction SMILES: [Na].[OH-].[K+].Br[CH2:5][CH2:6][C:7](=[O:19])[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1.[CH3:20][CH:21]1[C:25](=[O:26])[CH2:24][CH2:23][C:22]1=[O:27]>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][CH2:8][C:7](=[O:19])[CH2:6][CH2:5][C:21]2([CH3:20])[C:25](=[O:26])[CH2:24][CH2:23][C:22]2=[O:27])[CH:16]=[CH:15][CH:14]=1
Reactant: CC1C(=O)CCC1=O
Reactant: COc1cccc(CCCC(=O)CCBr)c1
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Product: COc1cccc(CCCC(=O)CCC2(C)C(=O)CCC2=O)c1

Procedure:
Add sodium (0.05 g) to a 0.12% methanolic potassium hydroxide solution (15 cc). To this solution add 1-bromo-6-(m-methoxyphenyl)hexan-3-one (0.9 g) in methaol (5 cc) and 2-methylcyclopentane-1,3-dione (0.4 g), and reflux the mixture for 6 hours. After working up as in the preparation of the title compound in a previous example, obtain the crude Michael adduct 2-(6-m-methoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione as a yellow gum.
Reaction SMILES: [ClH:1].[C:2]([NH:10][C:11]1[S:12][CH2:13][C@@H:14]2[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C@:15]2([C:27]2[S:31][N:30]=[CH:29][CH:28]=2)[N:16]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CC(O)C.CC(OC)(C)C>[ClH:1].[S:31]1[C:27]([C@:15]23[CH2:17][NH:18][CH2:19][C@H:14]2[CH2:13][S:12][C:11]([NH:10][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:16]3)=[CH:28][CH:29]=[N:30]1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccns2)C1
Agent: Cl
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: O=C(NC1=N[C@@]2(c3ccns3)CNC[C@H]2CS1)c1ccccc1
Reaction time: 18 h
Yield: 98 %

Procedure:
Hydrogen chloride 6 M in 2-propanol (1.65 L, 9.9 mol) is added to tert-butyl (4aR,7aR)-2-benzamido-7a-isothiazol-5-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (200 g, 449.9 mol) in 2-propanol (1.6 L) at 22° C. and stirred for 18 hours. The mixture is concentrated to give a white solid. The solid is diluted with MTBE (1 L), stirred at 22° C. for 1 hour, filtered and dried under vacuum to constant weight to give the title compound (170 g, 98%). ES/MS (m/e): 345.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.CC([O-])(C)C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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]>[C:22]([O:21][C:19]([N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([OH:7])=[O:6])[CH2:15][CH2:14]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)c1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)O)c2)CC1
Temperature: 110 °C
Yield: 42.2 %

Procedure:
The mixture of ethyl 3-bromobenzoate (500 mg, 2.33 mmol), tert-butyl piperazine-1-carboxylate (433 mg, 2.33 mmol) and NaOtBu (268 mg, 2.78 mmol), Pd2(dba)3 (20 mg, 0.034 mmol) and Xantphos (20 mg, 0,034 mmol) in anhydrous dioxane (10 mL) was heated to 110° C. for 10 h. The mixture was concentrated and the residue was partitioned in water, the solution was adjusted to pH=5, and extracted with DCM. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford the title compound that was used for next step (300 mg, Yield 42.2%). LCMS (m/z): 307.1 (M+1).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]([F:22])([F:21])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1.CN(C)[CH:25]=[O:26]>O1CCCC1>[F:9][C:10]([F:21])([F:22])[C:11]1[CH:12]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:14]=[CH:15][C:16]=1[CH:25]=[O:26]
Reactant: FC(F)(F)c1cccc(C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of 100 ml (0.21 mol) of lithium diisopropylamide in tetrahydrofuran is cooled under argon to -70° and at this temperature there are added dropwise thereto while stirring 31 ml (0.2 mol) of 1,3-bis(trifluoromethyl)benzene. The resulting dark red, viscous suspension is stirred at -70° for a further 30 minutes and then 31 ml (0.4 mol) of N,N-dimethylformamide are allowed to flow in rapidly. The internal temperature rises to -20° as a consequence of the exothermic reaction in spite of continuous cooling. The violet solution obtained is then processed further as described in Example 3a). 2,4-Bis(trifluoromethyl)-benzaldehyde is obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][C:5](=[O:7])[N:6]=1.[F:8][C:9]1[CH:27]=[C:26]([CH:28]=O)[CH:25]=[CH:24][C:10]=1[O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]#[N:23])=[CH:14][CH:13]=1>>[F:8][C:9]1[CH:27]=[C:26]([CH:28]=[C:4]2[S:3][C:2](=[NH:1])[NH:6][C:5]2=[O:7])[CH:25]=[CH:24][C:10]=1[O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]#[N:23])=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2F)c2ccccc12
Reactant: NC1=NC(=O)CS1
Product: N#Cc1ccc(Oc2ccc(C=C3SC(=N)NC3=O)cc2F)c2ccccc12

Procedure:
4-[2-Fluoro-4-(2-imino-4-oxo-thiazolidin-5-ylidenemethyl)-phenoxy]-naphthalene-1-carbonitrile was prepared using 2-amino-thiazol-4-one and 4-(2-Fluoro-4-formyl-phenoxy)-naphthalene-1-carbonitrile following General Procedure C. 1H NMR (400 MHz, DMSO-d6) δ 9.54 (br, 1H), 9.25 (br, 1H), 8.42 (d, J=8.21 Hz, 1H), 8.15 (d, J=8.21 Hz, 1H), 8.08 (d, J=7.82 Hz, 1H), 7.91 (m, 1H), 7.81 (m, 1H), 7.7 (dd, J=12.13 and 2.34 Hz, 1H), 7.64 (s, 1H), 7.49-7.57 (2H), 6.93 (d, J=7.83 Hz, 1H). LC/MS (m/z) [M+1]+390.2 (calculated for C21H13FN3O2S 390.1).