Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:5]=[C:6]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[S:7][C:8]=1[C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10].[CH2:23](N(CC)CC)C.Cl[S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=1)(=[O:33])=[O:32].[N+](=C)=[N-]>ClCCl.CCOCC>[CH3:23][O:40][C:38]([C:37]1[CH:41]=[CH:42][C:34]([S:31]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([C:8]3[S:7][C:6]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)=[N:5][C:4]=3[CH3:3])=[O:10])[CH2:12][CH2:13]2)(=[O:33])=[O:32])=[CH:35][CH:36]=1)=[O:39]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)CC
Reactant: Cc1nc(-c2ccncc2)sc1C(=O)N1CCNCC1
Agent: C=[N+]=[N-]
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1ccc(S(=O)(=O)N2CCN(C(=O)c3sc(-c4ccncc4)nc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
To a solution of 1-[4-methyl-2-(4-pyridyl)-5-thiazolecarbonyl]piperazine dihydrochloride (180 mg) and triethylamine (253 mg) in dichloromethane (20 ml) was added 4-chlorosulfonylbenzoic acid (108 mg), and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added a solution of diazomethane in ether until the solution remained yellow. The mixture was concentrated and the residue was purified with silica gel column chromatography (ethyl acetate) to give colorless crystals of the title compound (158 mg).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:67])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47](OS(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH:46]([O:63][CH2:64][CH2:65][CH3:66])[CH2:45]2)[CH:7]([CH3:68])[CH2:6][CH2:5][C:4]1=[O:69])[CH3:2].[N-:70]=[N+:71]=[N-:72].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:67])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:70]=[N+:71]=[N-:72])[CH:46]([O:63][CH2:64][CH2:65][CH3:66])[CH2:45]2)[CH:7]([CH3:68])[CH2:6][CH2:5][C:4]1=[O:69])[CH3:2]
Reactant: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1OS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1N=[N+]=[N-]
Temperature: 70 °C
Yield: 55.9 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-(o-nitrophenylsulfonyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (111 mg) in N,N-dimethyl formamide (1.1 ml) was added an excess of sodium azide (32 mg) and the mixture heated to 70° C. After 5.5 hours the reaction was cooled to room temperature, diluted with ethyl acetate, extracted from half-saturated ammonium chloride, and washed with brine. The combined organics were dried over sodium sulfate and purified by flash chromatography on silica gel (ethyl acetate: hexane (1:2)+1% methanol) to give the title compound (52 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19])([O:13][CH3:14])=[O:12]>CC(N(C)C)=O.N1C=CC=CC=1>[CH3:14][O:13][C:11](=[O:12])[C:15]1[CH:23]=[CH:22][CH:21]=[C:17]([C:18](=[O:19])[NH:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:16]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1cccc(C(=O)Cl)c1
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cccc(C(=O)Nc2ccc([N+](=O)[O-])cc2)c1
Temperature: 0 °C
Yield: 97.2 %

Procedure:
In a 1-liter 3-necked flask fitted with an inlet tube for nitrogen, a magnetic stirrer, a dropping funnel and a thermometer there were introduced 76 g (0.5 moles) of p-nitroaniline in 600 ml of dimethylacetamide and 80 ml of pyridine. (Both solvents had previously been dried over a molecular sieve 3A). Over a period of 45 minutes 99.2 g (0.5 moles) of 3-carbomethoxybenzoyl chloride in 100 ml of dimethylacetamide were added with stirring and cooling, care being taken that the temperature did not rise to above 15° C. In the process a yellow precipitate was formed. After all the ingredients had been added, stirring was continued for 1 more hour at 20° C. The reaction mixture was poured into 2 l of ice water, filtered, washed 6 times with water and finally with methanol. After drying at 70° C. and a pressure of 133 Pa 146 g of the envisaged product were obtained in a yield of 97%. The melting point was 206°-207.6° C. In an analogous manner there were prepared:
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>CN1CCCC1=O>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1nc2ccccc2s1
Solvent: CN1CCCC1=O
Product: Oc1ccc(Nc2nc3ccccc3s2)cc1

Procedure:
The solution of 2-chlorobenzothiazole (2.47 mL, 20 mmol) and 4-aminophenol (2.18 g, 20.0 mmol) in N-methylpyrrolidone (16 mL) was heated at 160° C. for 7 h. The reaction mixture was quenched with aqueous 2N NaOH and then extracted with EtOAc. The organic layer was washed with 2N NaOH. To the combined aqueous layer was added aqueous 5N HCl until pH 6, then the product was extracted with EtOAc (2×), dried (Na2SO4) and concentrated. The crude product was dissolved in MeOH and treated with Soothed 2. Chromatograph through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 0% to 50% EtOAc in hexane, provided 4-(benzo[d]thiazol-2-ylamino)phenol as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[C:5]([CH:7]1[CH2:14][C:10]2[S:11][CH:12]=[CH:13][C:9]=2[C:8]1=O)=O.O.[NH2:23][NH2:24].C(O)(=O)C>C(O)C>[CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[C:5]1[C:7]2[CH2:14][C:10]3[S:11][CH:12]=[CH:13][C:9]=3[C:8]=2[NH:24][N:23]=1
Reactant: NN
Reactant: COc1ccc(C(=O)C2Cc3sccc3C2=O)c(OC)c1
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(-c2n[nH]c3c2Cc2sccc2-3)c(OC)c1
Temperature: 25 °C
Yield: 84 %

Procedure:
5-(2,4-Dimethoxy-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.12 g, 3.69 mmol), hydrazine monohydrate (0.7 mL, 22 mmol), glacial acetic acid (0.6 mL) and ethanol (10 mL) was heated at 100° C. under nitrogen for 4 hr. The mixture was cooled to 25° C. and concentrated under reduced pressure to give a solid which was recrystallized from ethanol to provide the corresponding 6-(2,4-Dimethoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (2.5 g, 3.1 mmol) as yellow solid in 85% yield.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]([CH3:13])([CH3:12])[C:10]#[CH:11]>C(OCC)C.O.[Cu]>[CH3:12][C:9]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)([CH3:13])[C:10]#[CH:11]
Reactant: OC1CCNCC1
Reactant: C#CC(C)(C)Cl
Agent: [Cu]
Solvent: CCOCC
Solvent: O
Product: C#CC(C)(C)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
24 mg cuprous chloride and 15 mg copper powder were added to a mixed solution of 5 ml solution of 7.3 g 4-hydroxypiperidine in diethyl ether (5 ml) and water (2.5 ml) in a nitrogen atmosphere. The mixture was ice-cooled, and 2.5 ml solution of 2.7 ml 3-chloro-3-methyl-1-butyne in diethyl ether was added dropwise thereinto at a bulk temperature of 17 to 22° C. Then, it was stirred at room temperature overnight. Water was added thereto, and the resulting mixture was extracted with diethyl ether for 5 times. The organic layers were combined, and dried over potassium carbonate and then over potassium hydroxide, and filtered. The filtrate was concentrated at normal pressure. The resulting crystalline residues were collected by filtration by adding ethyl acetate/hexane thereto to give 2.54 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[CH2:7]([O:9][C:10]([N:12]=[C:13]=[S:14])=[O:11])[CH3:8]>C(#N)C>[S:3]1[CH:4]=[N:5][N:6]=[C:2]1[NH:1][C:13]([NH:12][C:10](=[O:11])[O:9][CH2:7][CH3:8])=[S:14]
Reactant: CCOC(=O)N=C=S
Reactant: Nc1nncs1
Solvent: CC#N
Product: CCOC(=O)NC(=S)Nc1nncs1
Temperature: 24 °C
Yield: 79.4 %

Procedure:
To a stirred solution of 19.2 g (190 mM) of 2-amino-1,3,4-thiadiazole in 200 ml of acetonitrile were added in one portion 25 g (190 mM) of ethoxycarbonyl isothiocyanate. The reaction mixture was stirred at 24° C. for sixteen hours. The precipitate was collected by filtration, washed three times with ethyl acetate and dried to provide 35 g (80% yield) of [(1,3,4-thiadiazol-2-ylamino)thioxomethyl]carbamic acid, ethyl ester.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C1COCC1.C(OCC)(=O)C>[O:14]1[CH2:15][CH2:16][N:11]([C:2]2[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=2)[CH2:12][CH2:13]1
Reactant: C1COCCN1
Reactant: COC(=O)c1csc(Br)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1csc(N2CCOCC2)n1
Yield: 93.4 %

Procedure:
A solution of methyl 2-bromothiazole-4-carboxylate (0.20 g, 0.901 mmol) in THF (10 mL) was treated with morpholine (0.17 mL, 1.94 mmol) and refluxed for 18 h. The reaction was then diluted with ethyl acetate and washed with sat. NaHCO3 (1×), brine (1×) and dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (2.5×10 cm, 50% AcOEt/CH2Cl2) to give the title material (0.192 g, 92%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.44 (s, 1H) 3.82 (s, 3H) 3.75 (m, 4H) 3.45 (m, 4H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:12]=[C:11]([C:13]2[S:14][C:15]3[CH2:16][CH2:17][O:18][C:19]4[CH:26]=[C:25](Br)[CH:24]=[CH:23][C:20]=4[C:21]=3[N:22]=2)[N:10]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:9]=1)(C)(C)C.O.C([O-])(=O)C.[K+].CC1(C)C(C)(C)OB([C:47]2[CH:48]=[N:49][NH:50][CH:51]=2)O1>CC#N.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:28]([N:10]1[C:11]([C:13]2[S:14][C:15]3[CH2:16][CH2:17][O:18][C:19]4[CH:26]=[C:25]([C:47]5[CH:48]=[N:49][NH:50][CH:51]=5)[CH:24]=[CH:23][C:20]=4[C:21]=3[N:22]=2)=[N:12][C:8]([NH2:7])=[N:9]1)([CH3:30])([CH3:31])[CH3:29]
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n(C(C)(C)C)n1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)n1nc(N)nc1-c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.9 %

Procedure:
[5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-tert-butyl-1H-[1,2,4]triazol-3-yl]-carbamic acid tert-butyl ester (0.94 g, 1.8 mmol) was dissolved in MeCN (20 mL) and H2O (20 mL) and added potassium acetate (601 mg, 6.12 mmol). The reaction flask was degassed by bubbling N2 for 5 min. Charged with 4,4,5,5-tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (456 mg, 2.53 mmol) and then tetrakis(triphenylphosphine)palladium(0) (280 mg, 0.24 mmol). The reaction was subjected to microwave irradiation at 140° C. for 20 min. The reaction was cooled to r.t., filtered through a plug of Celite and diluted with water. Extracted three times with EtOAc and the combined organic portions were dried over MgSO4, filtered and concentrated. The crude residue was taken up in DCM (10 mL) and treated with trifluoroacetic acid (5 mL). Stirred at room temperature for 1 h and concentrated in vacuo. The resultant residue was taken up in a minimal amount of DMF/DMSO (1:1) and purified by rp-HPLC to provide 58 mg (10% yield) of 122. LC/MS(ESI+): m/z 408 (M+H). 1H NMR (400 MHz, DMSO) δ 12.96 (bs, 1H), 8.31 (m, 2H), 7.99 (bs, 1H), 7.50-7.39 (m, 2H), 7.34 (d, J=1.5, 2H), 5.47 (s, 2H), 4.47-4.24 (m, 4H), 3.39 (dd, J=15.8, 10.7, 4H), 1.78 (s, J=18.7, 9H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][CH:8]([CH3:10])[CH3:9])=[N:4][CH:3]=1.[C:11]1([CH3:29])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18]2[N:19]([CH:26]=[CH:27][N:28]=2)[CH:20]=[C:21](B(O)O)[CH:22]=1>>[CH2:7]([C:5]1[S:6][C:2]([C:21]2[CH:22]=[C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH3:29])[C:18]3[N:19]([CH:26]=[CH:27][N:28]=3)[CH:20]=2)=[CH:3][N:4]=1)[CH:8]([CH3:10])[CH3:9]
Reactant: Cc1ccccc1-c1cc(B(O)O)cn2ccnc12
Reactant: CC(C)Cc1ncc(Br)s1
Product: Cc1ccccc1-c1cc(-c2cnc(CC(C)C)s2)cn2ccnc12

Procedure:
Example 189 was prepared using the procedure describe for Example 34, step 4, from 5-bromo-2-isobutylthiazole and 8-o-tolylimidazo[1,2-a]pyridin-6-ylboronic acid. LCMS (Conditions C): Tr 2.86 min.; (M+H)': 348.0.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].CN1CCOCC1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:17])[C@H:5]([NH:6][S:33]([C:30]1[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=1)(=[O:35])=[O:34])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc(OC)cc1
Reaction time: 8 h
Yield: 67.6 %

Procedure:
To a suspension of D-tryptophan methyl ester hydrochloride (4 mmol) in 40 mL of methylene chloride, magnetically stirred and cooled in an ice bath, under a nitrogen atmosphere, is added 8 mmol of NMM and 4 mmol of 4-methoxybenzene sulfonyl chloride. The mixture is allowed to come to ambient temperature overnight. It is diluted with ethyl acetate and washed twice with aqueous 10% HCl, then successively with water, 1M sodium bicarbonate, and brine. The organic solution is dried over sodium sulfate and concentrated to afford 1.05 g (65%) of a white solid, m.p. 120°-122° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=[O:14])=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.IC.[C:18](=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C>[CH3:18][O:14][C:13]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([O:8][CH2:9][CH:10]2[CH2:11][CH2:12]2)[N:6]=1)=[O:15]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(Br)c(OCC2CC2)n1
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Br)c(OCC2CC2)n1
Yield: 46.7 %

Procedure:
A solution of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid (Example 9 d, 0.4 g, 1.5 mmol), iodomethane (CAN 16519-98-5, 0.42 g, 3 mmol), sodium carbonate (0.16 g, 1.5 mmol) in DMF (10 mL) was stirred overnight at room temperature. Water was poured into the reaction solution and the resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 20 g, 5% ethyl acetate in petroleum ether) to yield the title compound (0.2 g, 0.7 mmol, 48%) as white solid; MS (EI): m/e=286.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:48][C@H:49]([CH:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]1)[C:50]1[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=1>CN(C=O)C>[CH:62]1([C@@H:49]([NH:48][C:8]([C:7]2[C:2]([OH:1])=[N:3][C:4]([N:11]3[CH:15]=[CH:14][CH:13]=[N:12]3)=[N:5][CH:6]=2)=[O:10])[C:50]2[CH:51]=[CH:52][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:54][CH:55]=2)[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67]1
Reactant: CCOP(C)(=O)c1ccc([C@H](N)C2CCCCC2)cc1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1ccc([C@H](NC(=O)c2cnc(-n3cccn3)nc2O)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49 %

Procedure:
To a stirred solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 8-b, (1.187 g, 5.76 mmol) and Et3N (1.75 mg, 17.3 mmol) in DMF (15 mL) was added HATU (2.62 mg, 6.9 mmol). The mixture was stirred for 5 min at room temperature and then compound 26-e (1.7 g, 5.76 mmol) was added. The resulting mixture was stirred at room temperature for 15 hour. The mixture was then concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with 1N HCl. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel chromatography (ethyl acetate:MeOH=5/1) to provide the product, 26-f, (1.05 g, 49%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:20]([C:23]1[CH:24]=[C:25]([C:32](O)=[O:33])[C:26](=[CH:30][CH:31]=1)[C:27](O)=[O:28])([O-:22])=[O:21].C(N(C(C)C)CC)(C)C.C(N=C=NC(C)C)(C)C>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:18]3[C:32](=[O:33])[C:25]4[C:26](=[CH:30][CH:31]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=4)[C:27]3=[O:28])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN)OC2
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN1C(=O)c3ccc([N+](=O)[O-])cc3C1=O)OC2
Reaction time: 0 h

Procedure:
In a 4-ml scintillating vial, a solution of 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (58 mg, 0.2 mmol) in tetrahydrofuran (2.0 ml) was treated with 4-nitrophthalic acid (63 mg, 0.3 mmol), diisopropylethylamine (190 μl, 1.1 mmol), and 1,3-diisopropylcarbodiimide (120 μl, 0.77 mmol). The reaction mixture was shaken vigorously for 10 seconds before being stirred at 50° C. for 43 hours and at room temperature for 20 hours. The solution was diluted with ethyl acetate (25 ml), washed with 0.5N aqueous hydrochloric acid (25 ml), saturated aqueous sodium bicarbonate (25 ml), and the brine (25 ml). The organic layer was dried (MgSO4), filtered and the solvent evaporated in vacuo. Crude 2-amino-5-(5-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester was obtained as a solid and used immediately in the next step.
Reaction SMILES: ClC1C=CC([CH:8]2[C:13](=[O:14])[CH:12]=[C:11](C(F)(F)F)[N:10](C)[C:9]2=[O:20])=CC=1.P(Cl)(Cl)(Cl)=O>CCN(C1C=CC=CC=1)CC>[NH:10]1[CH:11]=[CH:12][CH:13]=[CH:8][C:9]1=[O:20].[N:10]1[CH:9]=[CH:8][C:13](=[O:14])[CH2:12][CH:11]=1
Reactant: CN1C(=O)C(c2ccc(Cl)cc2)C(=O)C=C1C(F)(F)F
Solvent: CCN(CC)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1C=CN=CC1
Product: O=c1cccc[nH]1
Temperature: 110 °C
Reaction time: 4 h
Yield: 29 %
Yield: 37 %

Procedure:
3.3 g (10.9 mmol) of 3-(4-chlorophenyl)-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyridine was added to 8.3 g (42.3 mmol) of phosphorus oxychloride and 30 ml of diethylaniline, followed by stirring at from 100 to 120° C. for 4 hours. The reaction solution was distilled off under reduced pressure, and ethyl acetate was added to the obtained residue, followed by washing with water and a saturated sodium hydrogencarbonate aqueous solution. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure, and the obtained residue was separated and purified by high performance liquid chromatography to obtain 1.3 g (yield: 37%) of the desired 2-pyridone compound (Compound No. 11-1) and 1.0 g (yield: 29%) of the 4-pyridone compound (Compound No. 13-1), respectively.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C@@H:14](/[CH:15]=[CH:16]/[C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12][C:11]1=[O:24].O[C@@H](CCCCC)/C=C/[C@H]1CCC(=O)N1CCSCCCC(O)=O.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.Cl>C1(C)C=CC=CC=1.CO>[CH3:1][O:2][C:3](=[O:25])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:11](=[O:24])[CH2:12][CH2:13][C@@H:14]1/[CH:15]=[CH:16]/[C@@H:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC(=O)/C=C/[C@H]1CCC(=O)N1CCCCOCC(=O)OC
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: CCCCC[C@H](O)/C=C/[C@H]1CCC(=O)N1CCSCCCC(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCC[C@H](O)/C=C/[C@H]1CCC(=O)N1CCCCOCC(=O)OC
Temperature: -26 °C
Reaction time: 7 h

Procedure:
A solution of the {4-[(R)-2-Oxo-5-((E)-3-oxo-oct-1-enyl)-pyrrolidin-1-yl]-butoxy}-acetic acid methyl ester prepared as in Example 1 (250 mg, 0.71 mmol) in 10 mL of anhydrous toluene was added dropwise to a −26° C. solution of (R)-2-methyl-CBS-oxazaborolidine (Aldrich, 1 M in toluene, 0.35 mL) and borane-methyl sulfide complex (10 M, 0.07 mL). The reaction was stirred under nitrogen for 7 hours at −26° C. and then a solution of hydrochloric acid in methanol (2 M, 1-2 mL) was added. The solution was warmed to room temperature and the solvents were removed via reduced pressure. The crude residue was purified via silica gel chromatography yielding 11 mg of {4-[(R)-2-((E)-(S)-3-hydroxy-oct-1-enyl)-5-oxo-pyrrolidin-1-yl]-butoxy}-acetic acid methyl ester as an oil. This was taken directly on to the next step.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12])=O.[CH3:13][C:14]1[N:15]=[C:16]([CH2:19][C:20](=O)[CH2:21][CH3:22])[S:17][CH:18]=1.[NH2:24]/[C:25](/[CH3:29])=[CH:26]\[C:27]#[N:28]>C(O)(C)C>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH:1]2[C:19]([C:16]3[S:17][CH:18]=[C:14]([CH3:13])[N:15]=3)=[C:20]([CH2:21][CH3:22])[NH:24][C:25]([CH3:29])=[C:26]2[C:27]#[N:28])=[C:4]([O:11][CH3:12])[CH:5]=1)#[N:8]
Reactant: CCC(=O)Cc1nc(C)cs1
Reactant: COc1cc(C#N)ccc1C=O
Reactant: C/C(N)=C/C#N
Solvent: CC(C)O
Product: CCC1=C(c2nc(C)cs2)C(c2ccc(C#N)cc2OC)C(C#N)=C(C)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.620 mmol) of the compound from example 3A, 100 mg (0.310 mmol, 50% purity) of the compound from example 5A and 51 mg (0.620 mmol) of 3-aminocrotononitrile are dissolved in 4 ml of isopropanol and stirred at the reflux temperature overnight. After cooling to room temperature, the volatile components are removed in a rotary evaporator, and the crude product is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 78 mg (66% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[H-].[Na+].[CH3:30]COC(C)=O>CN(C=O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]([CH3:30])[C@H:9]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(C)=O
Reactant: COC(=O)CCC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)CCC[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-methyl 5-(tert-butoxycarbonylamino)-6-(tert-butyldimethylsilyloxy)hexanoate (15 g, 40 mmol) in DMF (100 mL) was added iodomethane (17 g, 120 mmol, 3 equiv.) at 0° C. NaH (60%, 2.4 g, 60 mmol, 1.5 equiv.) was added in 3 portions. The reaction was stirred at RT for 2 h. EtOAc (150 mL) and brine (200 mL) were added to the reaction mixture. The organic layer was washed with brine (200 mL), dried, and concentrated to give (S)-methyl 5-(tert-butoxycarbonyl(methyl)amino)-6-(tert-butyldimethylsilyloxy)hexanoate (15.5 g, quant.) as a colorless oil. LRMS (M-Boc+H+) m/z 290.1.