Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4].CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]3[CH:37]=[CH:36][NH:35][C:32]3=[N:33][CH:34]=2)O1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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][C:3]([C:5]1[S:6][C:7]([C:29]2[CH:30]=[C:31]3[CH:37]=[CH:36][NH:35][C:32]3=[N:33][CH:34]=2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4]
Reactant: COC(=O)c1sc(Br)cc1OC(C)c1ccccc1Cl
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(-c2cnc3[nH]ccc3c2)cc1OC(C)c1ccccc1Cl
Temperature: 140 °C
Yield: 45.3 %

Procedure:
5-Bromo-3-[1-(2-chloro-phenyl)-ethoxy]-thiophene-2-carboxylic acid methyl ester (200 mg, 0.53 mmol, 1.0 Eq.), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (195 mg, 0.80 mmol, 1.5 Eq.) and Pd(PPh3)4 (61 mg, 0.05 mmol, 0.1 Eq.) were dissolved in toluene (1.6 mL) and ethanol (0.4 mL). 2M K2CO3 (0.8 mL, 1.60 mmol, 3.0 Eq.) was added and the reaction heated under microwave conditions at 140° C. for 10 minutes. The reaction was partitioned between EtOAc (10 mL) and water (10 mL) and the aqueous phase extracted with EtOAc (3×10 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (ISCO Companion™, 12 g column, 0-100% EtOAc/petroleum Ether) to give the sub-title compound as a yellow solid (100 mg, 0.24 mmol, 45%); 1H NMR (400 MHz, CDCl3) δ1.75(3H, d), 3.94 (3H, s), 5.88 (1H, q), 6.64 (1H, d), 6.94 (1H, s), 7.26-7.34 (2H, m), 7.38-7.44 (2H, m), 7.71 (1H, dd), 8.17 (1H, d), 8.44 (1H, d).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([C:13]3[N:14]=[CH:15][N:16]([C:18]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:17]=3)=[O:12])[C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:37][Mg+].[Br-]>C1COCC1.CCOCC>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([C:13]3[N:14]=[CH:15][N:16]([C:18]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:17]=3)([OH:12])[CH3:37])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: C[Mg+]
Reactant: O=C(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc2c1OCCO2
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc2c1OCCO2
Yield: 98 %

Procedure:
A solution of (2,3-dihydro-benzo[1,4]dioxin-5-yl)-(1-trityl-1H-imidazol-4-yl)-methanone (Intermediate B1) (0.91 g, 1.93 mmol) in THF (80 mL) at −10° C. was treated with MeMgBr (2.6 mL, 7.68 mmol of a 3M solution in Et2O) for 45 m. The mixture was quenched with a sat. solution of NH4Cl and water. The layers were separated and the organic layer dried over MgSO4. The suspension was filtered and evaporated to dryness. The material was purified by chromatography on SiO2 with 50% EtOAc in CHCl3 to give 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-1-(1-trityl-1H-imidazol-4-yl)-ethanol as a foam 0.95 g (98%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[CH2:8][CH2:9]OS(C1C=CC(C)=CC=1)(=O)=O)([CH3:4])([CH3:3])[CH3:2].[N:29]1([CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:39][CH:38]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:25]([C:22]1[CH:21]=[C:7]([CH:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:23]=1[OH:24])[CH2:8][CH2:9][N:32]1[CH2:33][CH2:34][N:29]([CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:39][CH:38]=2)[CH2:30][CH2:31]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)Cc1ccc(CCN2CCNCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)Cc1ccc(CCN2CCN(CCc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)cc1

Procedure:
A mixture of 13.9 g. (50.2 mmole) p-toluenesulphonic acid (3,5-di-tert.-butyl-4-hydroxyphenethyl)ester, 18.4 g. (45.6 mmole) ethyl 4-[2-(piperazin-1-yl)-ethyl]-phenylacetate, 6.3 g. potassium carbonate and 300 ml. butan-2-one is heated for 8 hours while stirring at reflux temperature. For protection against oxidation, the reaction is carried out under an atmosphere of nitrogen. After cooling, the inorganic precipitate is filtered off with suction, the filtrate is evaporated and the evaporation residue is taken up in diethyl ether. From the ether solution, the hydrochloride is precipitated with hydrogen chloride-containing diethyl ether. After recrystallisation from ethanol, there are obtained 16.4 g. (62% of theory) of the desired compound as hydrochloride; m.p. 247°-250° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[C:15](#[N:20])[CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[Na+]>>[O:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[NH:2][C:15](=[NH:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:11]1
Reactant: Nc1ccccc1N1CCOCC1
Reactant: CCCCC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(=N)Nc1ccccc1N1CCOCC1

Procedure:
A mixture of 4-(2-aminophenyl)morpholine hydrochloride (6.5 g) and valeronitrile (35 ml) were heated at 160°-165° C. under nitrogen for 25 hours and then cooled. The mixture was treated with aqueous sodium hydroxide and the basified mixture was extracted with dichloromethane. The solvent was removed by evaporation and the residue distilled under a pressure of 50 mm Hg to remove half the unreacted valeronitrile. A solid separated on cooling which was separated by filtration, washed with hexane (50 ml) and recrystallised from hexane to give N-(2-morpholinophenyl)valeramidine. (m.p. 135°-136° C.).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH:5]=[CH:4][N:3]=[N:2]1.ClC(OCC)=O.CCN(CC)CC.[K+].[C:29]([O:35][CH2:36][CH3:37])(=[O:34])[CH2:30]C([O-])=O.[Mg+2].[Cl-].[Cl-]>CC#N.CCN(CC)CC>[CH2:36]([O:35][C:29](=[O:34])[CH2:30][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[C:6]([N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)[CH:7]=1)[CH3:37]
Reactant: O=C(O)c1cccc(-n2ccnn2)c1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1

Procedure:
Prepared from 3-[1,2,3]triazol-1-yl-benzoic acid [prepared by refluxing of methyl 3-azidobenzoate [CAS-No. 93066-93-4] in trimethylsilylacetylene, followed by saponification with aqueous NaOH in refluxing EtOH] by activation with ethyl chloroformate/Et3N and reaction with ethyl malonate potassium salt with Et3N and MgCl2 in CH3CN according to general procedure H (method a). Obtained as a light yellow solid (2.22 g).
Reaction SMILES: COS([O-])(=O)=O.[CH3:7][N+:8]1[N:9](C)[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C(=O)CC(C2C=CC=CC=2)=O)C=CC=CC=1.CNN>>[CH3:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]1
Reactant: Cn1c(-c2ccccc2)cc(-c2ccccc2)[n+]1C
Agent: CNN
Agent: COS(=O)(=O)[O-]
Agent: O=C(CC(=O)c1ccccc1)c1ccccc1
Product: Cn1nc(-c2ccccc2)cc1-c1ccccc1

Procedure:
The herbicidal 1,2-dimethyl-3,5-diphenylpyrazolium methyl sulfate may be prepared by condensing 1,3-diphenyl-1,3-propanedione with methylhydrazine to form 2-methyl-3,5-diphenylpyrazole, which is then methylated with dimethyl sulfate as described in U.S. Pat. No. 3,882,142, and illustrated in Flow Diagram I below:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])S(C2C=CC(C)=CC=2)(=O)=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH:40]=[O:41])[CH:35]=1.[Cl-].[NH4+]>[Br-].C([N+]1C(C)=C(CCO)SC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[C:40](=[O:41])[C:36]2[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)C(NC(=O)OC(C)(C)C)c2ccc(F)cc2)cc1
Reactant: O=Cc1cccnc1
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C(=O)c1cccnc1)c1ccc(F)cc1
Temperature: 35 °C
Reaction time: 0.17 h
Yield: 111.2 %

Procedure:
10.0 g (26.4 mmol) of tert-butyl [(4-fluorophenyl)(toluene-4-sulfonyl)methyl]carbamate, 665 mg (2.6 mmol) of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide, 55 ml (395 mmol) of triethylamine and 5.6 g (26.4 mmol) of 3-pyridinecarboxaldehyde were mixed in 230 ml of methylene chloride at room temperature and then heated at 35° C. for 3 h. After reaction of the aldehyde was complete, 100 ml of saturated ammonium chloride solution were added, and the reaction mixture was stirred for 10 minutes. After removal of the aqueous phase, the organic phase was washed with 0.5 M sodium hydroxide solution and saturated sodium chloride solution. 9.7 g of tert-butyl [1-(4-fluorophenyl)-2-oxo-2-pyridin-3-ylethyl]carbamate were obtained and were reacted further without purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].OS(O)(=O)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=O)=O.[Mg+2].[CH3:30][CH2:31]O>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:30][CH3:31])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CCO
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
A solution of 4-fluoro-3-nitrobenzoic acid (Alfa Aesar, 10.0 g, 54 mmol) and concentrated H2SO4 (0.2 ml, 4.1 mmol) in EtOH (200 ml) was refluxed for 40 h. The mixture was cooled to 0° C., solid NaHCO3 and MgSO4 was added, and the suspension was filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([NH:20][CH2:21][C:22]([OH:24])=O)[S:18][CH:19]=2)=[CH:11][CH:10]=1.Cl.[CH3:26][NH:27][CH3:28].C(N(CC)CC)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([NH:20][CH2:21][C:22]([N:27]([CH3:28])[CH3:26])=[O:24])[S:18][CH:19]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)CNc1nc(-c2ccc(F)cc2)cs1
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)CNc1nc(-c2ccc(F)cc2)cs1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid trifluoroacetic acid salt, 66.8 mg (0.81 mmol) of dimethylamine hydrochloride and 165.7 mg (1.64 mmol) of triethylamine. Yield: 52 mg.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10](OCC)=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cccnc1C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1ncccc1CO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The 2-isopropyl-3-carboethoxypyridine (400 mg, 2 mmol) in distilled THF (50 mL) under nitrogen was cooled to 0° C. and lithium aluminum hydride (1M in THF) (2.07 mL) was added dropwise. The reaction was stirred for 18 hours at room temperature then cooled to 0° C. and quenched with EtOAc (100 μL), then H2O (100 μL), then 15% NaOH (100 μL), followed by H2O (300 μL). The mixture was filtered and the solvent was removed under reduced pressure. Toluene was added and the solvent was removed under reduced pressure to give the desired 2-isopropyl-3-hydroxymethylpyridine.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:19])[CH2:6][N:7]([C:13](=[O:18])[CH:14]([CH3:17])[CH2:15][SH:16])[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:3].[CH2:20](I)[CH3:21]>C(O)C>[CH2:2]([O:4][C:5](=[O:19])[CH2:6][N:7]([C:13](=[O:18])[CH:14]([CH3:17])[CH2:15][S:16][CH2:20][CH3:21])[CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12]1)[CH3:3]
Reactant: CCOC(=O)CN(C(=O)C(C)CS)C1CCCC1
Reactant: CCI
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CN(C(=O)C(C)CSCC)C1CCCC1
Reaction time: 1 h

Procedure:
To a solution of 0.45 g (0.02M) of sodium in 50 ml ethanol was dropwise added a solution of 4.8 g of N-(3-mercapto-2-methyl propanoyl)-N-cyclopentyl glycine ethyl ester in 10 ml ethanol and stirring continued for 1 hour. Then, 3.04 g (0.02M) ethyl iodide in 5 ml ethanol was added and stirring continued for 4 hours. The solution was concentrated in vacuum, diluted with ether, washed with water, dried over MgSO4 and evaporated to dryness. The oily residue was chromatographed by HPLC using EtOAc-hexane (3:17) as eluent.
Reaction SMILES: Cl[C:2]1[N:26]=[CH:25][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.C(O)(=[O:29])C>>[CH3:19][C:17]1[N:18]=[C:14]([C:8]2[N:7]=[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([OH:29])[N:26]=[CH:25][C:5]=43)[CH:9]=2)[N:15]([CH2:20][C:21]([F:22])([F:23])[F:24])[N:16]=1
Reactant: CC(=O)O
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(Cl)cc2OCC3)n(CC(F)(F)F)n1
Product: Cc1nc(-c2cn3c(n2)-c2cnc(O)cc2OCC3)n(CC(F)(F)F)n1

Procedure:
A solution of 8-chloro-2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene (4 g, 10.4 mmol) in acetic acid (100 mL) was heated to 150° C. for 65 hours. The reaction was cooled, concentrated in vacuo and loaded onto an Isolute SCX-2 cartridge, washing with methanol and eluting with 2M ammonia in methanol. Basic fractions were combined and concentrated in vacuo, the resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 2-[5-Methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol. LCMS: RT=2.25 min, [M+H]+=367.33. 1H NMR 300 MHz (DMSO-d): δ 8.40 (1H, br, s), 7.94 (1H, s), 5.85 (1H, s), 5.77 (1H, s), 5.73 (2H, m), 4.56 (2H, m), 4.49 (2H, m), 2.29 (3H, s)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.ON1C2C=CC=CC=2N=N1.[NH2:25][CH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1.CCCCCC.C(OCC)(=O)C>CN(C=O)C.C(OCC)(=O)C>[CH:26]1([NH:25][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[N:7][CH:6]=3)[N:1]=2)=[O:13])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1
Reactant: NC1CCc2ccccc21
Reactant: O=C(O)c1ccc2cnccc2n1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(NC1CCc2ccccc21)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (6.3 mL) at room temperature was added sequentially 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 1-aminoindan (56.0 μL, 0.431 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum and the resulting residue was re-dissolved in CH2Cl2 (50 mL). The organic layer was washed with aqueous NaHCO3, dried over anhydrous Na2SO4, and concentrated to give the crude mixture. Flash column chromatography of the crude (50% hexane/ethyl acetate to 100% ethyl acetate) afforded the desired product as a white solid (80.1 mg, 96%): m.p. 156-157° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][N:8]=1)[NH2:6].N1C=CC=CC=1.O>O1CCCC1>[N+:13]([C:10]1[CH:11]=[CH:12][C:7]([NH:5][NH:6][C:1](=[O:3])[CH3:2])=[N:8][CH:9]=1)([O-:15])=[O:14]
Reactant: CC(=O)Cl
Reactant: NNc1ccc([N+](=O)[O-])cn1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NNc1ccc([N+](=O)[O-])cn1
Reaction time: 0.5 h

Procedure:
Acetyl chloride (0.51 g, 6.5 mmole) was added dropwise to a stirred solution of 2-hydrazino-5-nitropyridine (1.0 g, 6.5 mmole) in tetrahydrofuran (20 ml). Pyridine (0.51 g, 6.5 mmole) was added, the mixture stirred for 0.5 h, and then poured into water (200 ml). The aqueous solution was extracted with ethyl actate, the extract dried (MgSO4) and the solvent removed under reduced pressure. Recrystallisation of the residue from 1,2-dichloroethane afforded the pure product, 1.1 g, 86%, as a cream coloured solid, m.p. 226°-227° C.
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=O)[O:11][C:9](=[O:10])[C:8]2=[CH:14][CH:15]=1>C(O)C>[Br:4][C:5]1[CH:6]=[C:7]2[C:8](=[CH:14][CH:15]=1)[C:9](=[O:10])[N:3]=[N:2][C:12]2=[O:11]
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C1N=NC(=O)c2cc(Br)ccc21

Procedure:
96.9 ml hydrazine monohydrate was added to a mixture of 20 g 4-bromophthalic anhydride and 400 ml ethanol, and the mixture was heated under reflex for 8 hr. After cooling, the resulting precipitates were collected by filtration to give 28 g of 6-bromo-1,4-phthalazinedione.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.O>CN(C)C=O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCCCCCBr
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c(CCCCCBr)cccc21
Reaction time: 2 h
Yield: 281.4 %

Procedure:
Potassium phthalimide (5.4 mmoles) was added to a solution of 1.5-dibromopentane (3.72 g; 16.2 mmoles) in dimethylformamide (8 ml) and heated to 80° C. approx. under stirring. After 2 hours, water was added and the solution was repeatedly extracted with ether. The collected organic phases were washed with water, dried on Na2SO4 and evaporated under reduced pressure to give a solid (4.50 g), which was purified by chromatography on silica gel (Etp/Et2O 8:2) yielding 2.38 g of a white solid. Yield 68%.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][N:11]([CH2:21][CH2:22][OH:23])[C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:10][N:11]([CH2:21][CH2:22][O:23][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: CN(CCO)c1nc2ccccc2s1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN(CCOc1ccc(C=O)cc1)c1nc2ccccc2s1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of 4-fluorobenzaldehyde (1.5 g) and 2-[N-methyl-N-(2-benzothiazolyl)amino]ethanol (2.4 g) in dimethyl sulphoxide (50 ml) containing anhydrous potassium carbonate (2 g) was stirred at 100° C. for 24 hours. The mixture was cooled to room temperature and added to water (300 ml). The aqueous solution was extracted with diethyl ether (2×300 ml). The organic extracts were washed with brine (1×300 ml), dried (MgSO4), filtered and evaporated to dryness. The title compound was obtained as a waxy solid following chromatography on silica-gel in 1% methanol in dichloromethane.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([OH:10])[CH:8]=[CH:7][S:6]1)=[O:4].S(Cl)(Cl)(=O)=O.C(N(CC)CC)C.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[OH:10])=[O:4]
Reactant: COC(=O)C1SC=CC1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1sccc1O
Reaction time: 2 h
Yield: 82 %

Procedure:
80 parts of 3-hydroxy-dihydrothiophene-2-carboxylic acid methyl ester are dissolved in 250 parts by volume of methylene chloride. 67.5 parts of sulfuryl chloride in 100 parts by volume of methylene chloride are added in the course of one hour at from 0° to 5° C., whilst passing nitrogen into the mixture. The mixture is then stirred for 2 hours at from 0° to 5° C. 50 parts of triethylamine are then added at from 0° to 5° C. and the pH is brought to 7.5 with more triethylamine. The mixture is stirred for 2 hours at 0° C. and is then brought to pH 5 by means of 10 percent strength by weight hydrochloric acid. The mixture is separated into its phases and the organic phase is washed with twice 100 parts by volume of saturated sodium chloride solution, dried, concentrated and distilled. 65 parts (82% of theory) of 3-hydroxy-thiophene-2-carboxylic acid methyl ester of boiling point 68°-73° C./0.4 mbar and melting point 42°-43° C. are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]1[C:8](=[O:18])[O:9][C:10]2[C:15]([C:16]=1[OH:17])=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:2].[Li+].CC([N-]C(C)C)C.[CH:28]1[CH:33]=[CH:32][C:31]([CH2:34]Br)=[CH:30][CH:29]=1>C1COCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([CH2:34][C:31]1[CH:32]=[CH:33][CH:28]=[CH:29][CH:30]=1)[CH2:6][C:7]1[C:8](=[O:18])[O:9][C:10]2[C:15]([C:16]=1[OH:17])=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CCc1c(O)c2ccccc2oc1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccccc1)Cc1c(O)c2ccccc2oc1=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester in THF at −78° C. was added LDA (1.5M, 3.05 mL) dropwise. A yellow precipitate was formed during the addition. The reaction was stirred at −78° C. for 15 min and allowed to warmed to 0° C. and stirred for 30 min, after which BnBr (0.24 mL in THF) was added dropwise. The reaction was warmed to room temperature, stirred for 12 hours, cooled to 0° C. and quenched with saturated ammonium chloride and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and conc. in vacuo to a crude colorless oil, which was purified by column chromatography to provide 2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester as a colorless oil (250 mg). MS: 351[M−H].
Reaction SMILES: C([N:3](CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([CH2:15][CH:16]([OH:35])/[CH:17]=[CH:18]/[C@H:19]2[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[N:20]2[CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][C:32](O)=[O:33])[CH:12]=[CH:13][CH:14]=1.ClC(OCC)=O.N.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([CH2:15][CH:16]([OH:35])/[CH:17]=[CH:18]/[C@H:19]2[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[N:20]2[CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][C:32]([NH2:3])=[O:33])[CH:12]=[CH:13][CH:14]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1cccc(Cl)c1
Agent: CCOC(=O)Cl
Agent: N
Agent: O=C([O-])O
Solvent: ClCCl
Product: NC(=O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 10.6 %

Procedure:
Triethylamine (8.8 μL, 0.063 mmol) was added to a solution of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-hydroxy-but-1-enyl]-6-oxo-piperidin-1-yl}-butoxy)-acetic acid (12.4 mg, 0.030 mmol) in CH2Cl2 (0.2 mL). After cooling to 0° C., the reaction mixture was treated with ethyl chloroformate (3.2 μL, 0.033 mmol). After 1 h at 0° C., ammonia (0.5 M in 1,4-dioxane, 0.32 mL, 0.16 mmol) was added and the reaction mixture was allowed to warm to rt. After 18 h at rt, the reaction mixture was treated with saturated aqueous NaHCO3 (5 mL) and extracted with CH2Cl2 (3×5 mL). The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (5%→20% MeOH/CH2Cl2, gradient) afforded 1.3 mg (11%) of the title compound.