Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[H-].[Na+]>O1CCCC1>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][O:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH:10]2[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)=[CH:15][CH:16]=1)[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(O)cc2)C1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(OC2CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)phenol (2.14 g) in tetrahydrofuran (43 l) were added ethyl bromoacetate (1.1 ml) and 60% sodium hydride (368 mg) with ice-cooling, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, ice water was added and the mixture was extracted with ethyl acetate and washed with 10% aqueous citric acid solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) and dried under reduced pressure to give the title compound (2.605 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1.Cl[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][N:17]=1>>[CH:23]1([O:22][C:19]2[CH:20]=[CH:21][C:16]([O:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:7]=3)=[N:17][CH:18]=2)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CC(=O)NCCCc1ccc(O)cc1
Reactant: Clc1ccc(OC2CCCC2)cn1
Product: CC(=O)NCCCc1ccc(Oc2ccc(OC3CCCC3)cn2)cc1

Procedure:
N-[3-(4-Hydroxyphenyl)propyl]acetamide was reacted with 2-chloro-5-cyclopentyloxypyridine in analogy to example 2c. M+H+: 355.18.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:5]=1)([O-:3])=[O:2].CC([O-])(C)C.[K+]>CN(C=O)C.O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:9][CH:10]=1)[NH:8][C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:11]2)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1C#Cc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2[nH]c(-c3ccccn3)cc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To the solution of 4-nitro-2-(pyridin-2-ylethynyl)aniline (1.5 g, 6.3 mmol) in DMF (50 mL) was added t-BuOK (1.5 g, 13 mmol). The reaction mixture was stirred at 90° C. for 2 h. The mixture was diluted with water and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by chromatography on silica gel (5-10% ethyl acetate/petroleum ether) to afford 5-nitro-2-(pyridin-2-yl)-1H-indole (1.0 g, 67% yield). 1H NMR (300 MHz, d-DMSO) δ 12.40 (s, 1H), 8.66 (d, J=2.1 Hz, 1H), 8.58 (d, J=1.8 Hz, 1H), 8.07-7.91 (m, 3H), 7.59 (d, J=6.6 Hz, 1H), 7.42-7.37 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1.ClCCl>[O:12]=[C:8]1[CH2:7][CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][C:13](=[O:15])[CH3:14])[CH:11]=[CH:10][C:9]1=2
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)CCCC2=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)CCCC2=O
Reaction time: 1 h

Procedure:
To a solution of 6-amino-3,4-dihydro-2H-naphthalen-1-one (CAS#3470-53-9, 0.875 g, 5.44 mmol) in pyridine (5 mL) is added acetic anhydride (0.83 g, 8.16 mmol). After 1 hour, the solution is diluted with dichloromethane and washed with water and 1M aqueous HCl. The organic phase is dried over sodium sulfate, filtered, and concentrated to give N-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetamide; 1H NMR (400 MHz, CDCl3) δ ppm 2.09-2.16 (m, 2 H), 2.22 (s, 3 H), 2.59-2.67 (m, 2 H), 2.95 (t, J=6.1 Hz, 2 H), 7.21 (dd, J=8.3, 2.1 Hz, 1 H), 7.42 (br. s., 1 H), 7.70 (br. s., 1 H), 8.00 (d, J=8.3 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][C:3]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]3([CH2:25][CH2:24][CH2:23][CH2:22]3)[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1.[CH3:26]OC(OC)OC.O>C(O)(=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][CH:26]=[N:9][N:8]=2)=[CH:4][C:3]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]3([CH2:25][CH2:24][CH2:23][CH2:22]3)[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1
Reactant: COC(OC)OC
Reactant: Cc1ccc(C(=O)NN)cc1-c1ccc2c(c1)NC(=O)C21CCCC1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(-c2nnco2)cc1-c1ccc2c(c1)NC(=O)C21CCCC1
Temperature: 150 °C
Reaction time: 3 h
Yield: 60.3 %

Procedure:
A stirred mixture of 4-methyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzohydrazide (preparation 53, 0.16 g, 0.24 mmol) and trimethylorthoformate (0.24 mL, 1.44 mmol) in acetic acid (3 mL) were heated to 150° C. in a sealed tube. After 3 hours, the mixture was cooled, poured into water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried (MgSO4) and evaporated in vacuo. Purification of the residue by flash chromatography (1:1 hexanes/ethyl acetate) gave the title compound (0.05 g, 60%) as a white solid.
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]([CH3:64])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[N:53]=[N+]=[N-])[CH:46]([O:62][CH3:63])[CH2:45]2)[CH:7]([CH3:65])[CH:6]([O:66][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:74])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[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]([CH3:64])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[NH2:53])[CH:46]([O:62][CH3:63])[CH2:45]2)[CH:7]([CH3:65])[CH:6]([OH:66])[CH2:5][C:4]1=[O:74])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(N=[N+]=[N-])c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(N)c4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 60 °C
Yield: 38.5 %

Procedure:
To a solution of the product from Step A (27 mg) in wet benzene (0.5 ml) was added triphenyl phosphine (15 mg) and the reaction heated to 60° C. for 2 hours. The reaction mixture was concentrated, dissolved in THF (200 μl) and treated with hydrogen fluoride/pyridine for 24 hours at room temperature. The reaction was quenched with saturated aqueous sodium bicarbonate solution and extacted into ethyl acetate. The crude material was purified by preparative plate chromatography (20cm×20cm, 500 microns) eluting with 90% dichloromethane:10% methanol+1% ammonium hydroxide to give the title compound (9 mg).
Reaction SMILES: [Na].[C:2]([O:10]CC)(=O)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:27])/[CH:24]=[CH:25]/[CH3:26])=[CH:16][CH:15]=1>C(O)C.COCCOCCOC>[CH2:7]([O:6][C:4]([CH:3]1[CH:25]([CH3:26])[CH2:24][C:23](=[O:27])[N:22]([CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)[C:2]1=[O:10])=[O:5])[CH3:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C/C=C/C(=O)NCCc1ccc(F)cc1
Agent: [Na]
Solvent: COCCOCCOC
Solvent: CCO
Product: CCOC(=O)C1C(=O)N(CCc2ccc(F)cc2)C(=O)CC1C

Procedure:
Sodium (1.5 g, 65.1 mmol) was dissolved in ethanol (50 mL) and the solution was concentrated under vacuum. The residue was suspended in toluene (50 mL) and bis(2-methoxyethyl)ether (30 mL). Diethyl malonate (4.0 mL, 26.5 mmol) was added, followed by a suspension of trans-2-butenoic acid [2-(4-fluoro-phenyl)ethyl]amide (5.00 g, 24.1 mmol) in bis(2-methoxyethyl)ether (20 mL). The mixture was heated at reflux for 6 hours. The cooled mixture was washed with 1.0 N aqueous hydrochloric acid, then with water, and dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography, eluting with 25% ethyl acetate in hexane, to provide a pale yellowish oil which slowly crystallized (5.81 g, 75%). This appeared to be a mixture of cis and trans isomers (approximately 15% cis). 1H NMR (300 MHz, CDCl3) δ7.20 (m, 2H), 6.99 (t, J=9 Hz, 2H), 4.28 (m, 2H), 4.00 (m, 2H), 3.66 (d, J=5 Hz, 0.15H), 3.27 (d, J=10 Hz, 0.85H), 2.82 (m, 3H), 2.53 (m, 1H), 2.33 (dd, J=17, 10 Hz, 1H), 1.34 (m, 3H), 1.09 (d, J=7 Hz, 3H). Mass spec (AP+) m/z 322.0 (M+H+, 100%).
Reaction SMILES: C[O:2]CCO[AlH2-]OCCOC.[Na+].[N:13]1[CH:18]=[CH:17][C:16]([CH2:19][S:20][CH:21]([CH3:27])[C:22](OCC)=O)=[CH:15][CH:14]=1>O1CCCC1>[OH:2][CH:19]([S:20][CH:21]([CH3:27])[CH3:22])[C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1
Reactant: COCCO[AlH2-]OCCOC
Reactant: CCOC(=O)C(C)SCc1ccncc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)SC(O)c1ccncc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Red-al [70% solution of sodium bis(2-methoxyethyl)- aluminum hydride in benzene, 1.2 g., 1.1 ml., 5.86 mmoles]was cooled under nitrogen in an ice bath. A solution of ethyl 2-(4-pyridylmethylthio)propionate in 10 ml. of dry tetrahydrofuran was added dropwise over 10 minutes. The mixture was then heated and gently refluxed for 1 hour and then stirred at room temperature for approximately 16 hours. The reaction mixture was poured into 40 ml. of ice cold 1N HCl and salts removed by filtration. The filtrate was made basic with sodium bicarbonate and the product extracted into ethyl acetate (four times with 50 ml. aliquots). The combined ethyl acetate extracts were dried (by wash with saturated sodium chloride and then over anhydrous sodium sulfate) and concentrated to yield 4-(1-hydroxy-2-propylthiomethyl)pyridine (oil; approximately 200 mg.; pnmr/CDCl3 /TMS/delta: 8.6 (d, 3H), 7.2 (s, broad, 1H), 6.3 (m, 5H), 2.7 (d, 2H), 1.5 (d, 2H); m/e calcd: 183; found: 183, 152, 118, 92, 65; ir (film): 3.1, 6.25, 7.1, 9.25, 12.25μ). To further purify the product, it was taken up in chloroform, treated with activated carbon and concentrated to an oil (194 mg.).
Reaction SMILES: [N:1]1([CH2:6][C:7]([O:9]CC)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1>Cl>[N:1]1([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CN1CCCC1
Agent: Cl
Product: O=C(O)CN1CCCC1
Yield: 54 %

Procedure:
The solution of ethyl 2-(pyrrolidin-1-yl)acetate (1.8 g, 11.95 mmol, 1.0 eq) in 8 N HCl was stirred at 95° C. for 16 h. The mixture was concentrated on vacuum pump and quenched and extracted as in Intermediate Example 15(b). The solvent was distilled off to afford the product in 54% yield (1.4 g). LC-MS (ESI): Calculated mass: 129.1; Observed mass 130.1 [M+H]+ (rt: 0.26 min).
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=O)[C:4]1=[O:14])[CH3:2].[N+:15]([CH2:17][C:18]1[N:22]=[C:21]([CH:23]2[CH2:25][CH2:24]2)[O:20][N:19]=1)#[C-:16]>>[CH:23]1([C:21]2[O:20][N:19]=[C:18]([C:17]3[N:15]=[CH:16][N:6]4[C:7]5[CH:12]=[CH:11][CH:10]=[N:9][C:8]=5[N:3]([CH2:1][CH3:2])[C:4](=[O:14])[C:5]=34)[N:22]=2)[CH2:25][CH2:24]1
Reactant: [C-]#[N+]Cc1noc(C2CC2)n1
Reactant: CCn1c(=O)c(=O)[nH]c2cccnc21
Product: CCn1c(=O)c2c(-c3noc(C4CC4)n3)ncn2c2cccnc21

Procedure:
3-(5-cyclopropYl-1,2,4-oxadiazol-3-yl)-5-ethyl-4,5-dihydro4-oxo-imidazo(1,5-a)pyrido(2,3-e)pyrazine was prepared from 4-ethyl-1,2,3,4-tetrahydro-2,3-dioxo-pyrido(2,3-e)pyrazine and 3-isocyanomethyl-5-cyclopropyl-1,2,4-oxadiazole. M.p. 254.3°-255.4° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14].CS(O)(=O)=O.[CH3:20][OH:21]>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:21][CH3:20])=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: CO
Reactant: COc1cc2cc[nH]c(=O)c2cc1F
Agent: CS(=O)(=O)O
Product: COc1cc2c(OC)c[nH]c(=O)c2cc1F
Yield: 91 %

Procedure:
To a solution of 7-fluoro-6-methoxyisoquinolin-1(2H)-one (6.3 g, 32.6 mmol) in methanol (70 ml) was added iodozobenzenediacetate (10.5 g, 32.6 mmol) followed by methane sulphonic acid (3.76 g, 39.1 mmol) at room temperature. The reaction mass was heated at reflux for 3 h. The solvent was evaporated and the residue was diluted with cold water. The precipitated solid was filtered, washed with water to get crude compound (6.6 g, 91%) as a light red colored solid. MS: MS m/z 224.0 (M++1).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9](/[CH:12]=[N:13]/[OH:14])[C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[OH:14][N:13]=[C:12]([Cl:19])[C:9]1[C:8]([C:15]([F:17])([F:18])[F:16])=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][N:10]=1
Reactant: O/N=C/c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: ON=C(Cl)c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (E)-5-phenyl-4-(trifluoromethyl)isoxazole-3-carbaldehyde oxime (step C, 0.360 g, 1.41 mmol) in N,N-dimethylformamide (1.0 mL) at room temperature was added N-chlorosuccinimide (0.281 g, 2.11 mmol) in one portion. The resulting green, homogeneous reaction mixture was stirred at room temperature for 30 min. An additional 220 mg of NCS was added, and the reaction mixture was stirred for an additional 30 min. The reaction mixture was diluted with ethyl acetate (35 mL), washed with a 10% aqueous solution of lithium chloride (2×), and brine. The combined aqueous layers were extracted with ethyl acetate (35 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave a pale green solid which was triturated with ether and filtered. The white solid was rinsed with ether, and the filtrate was concentrated under reduced pressure and dried under reduced pressure overnight to give a quantitative yield of N-hydroxy-5-phenyl-4-(trifluoromethyl)isoxazole-3-carbimidoyl chloride as a green solid. The compound had an HPLC ret. time=2.72 min. (condition A); LC/MS M+1=291.0. 1H NMR (400 MHz, CDCl3) δ ppm 7.51-7.58 (m, 2H), 7.58-7.64 (m, 1H), 7.70 (d, J=7.48 Hz, 2H), 8.04 (s, 1H), and 9.69 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].[CH2:11](Br)[CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.CCOC(C)=O>[CH2:13]([O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[Br:1])[CH:12]=[CH2:11]
Reactant: N#Cc1ccc(O)c(Br)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: C=CCOc1ccc(C#N)cc1Br
Temperature: 25 °C

Procedure:
Mix 3-bromo-4-hydroxy-benzonitrile (1.520 g, 8.0 mmol), allyl bromide (1.161g, 9.6 mmol), potassium carbonate (3.317 g, 24 mmol) and potassium iodide (133 mg, 0.1 mmol) in acetone (80 mL). Heat the mixture to reflux for 12 h. Cool to ambient temperature, add EtOAc, wash the organic layer with water, and extract the aqueous layer twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate. Purify by chromatography on silica gel eluting with EtOAc/hexane (1:8) to obtain the desired intermediate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][NH2:11])[CH:8]=1)([O-:3])=[O:2].CN1C(=O)CCC1.Cl[C:20]1[N:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[N:21]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:29][O:28][C:22]1[CH:23]=[C:24]([O:26][CH3:27])[N:25]=[C:20]([NH:11][CH2:10][CH2:9][N:7]2[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[N:6]2)[N:21]=1
Reactant: NCCn1cc([N+](=O)[O-])cn1
Reactant: COc1cc(OC)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: COc1cc(OC)nc(NCCn2cc([N+](=O)[O-])cn2)n1
Temperature: 150 °C

Procedure:
A microwave tube was charged with 2-(4-nitro-1H-pyrazol-1-yl)ethanamine (1.92 g, 5.52 mmol), NMP. (15 mL), 2-chloro-4,6-dimethoxypyrimidine (1.16 g, 6.62 mmol) and K2CO3 (4.19 g, 30.34 mmol). The resulting mixture was heated to 150° C. for 20 min in the microwave (no cooling). The reaction mixture was diluted with DCM and washed with water. The org. layer was separated and the aq. layer was extracted with DCM (2×) The combined organic layers were washed with brine, dried (MgSO4), filtered and the solvent was removed under reduced pressure. Purification was performed by FC (EtOAc/hept 6:4) to obtain 4,6-dimethoxy-N-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidin-2-amine. LC-MS conditions A: tR=0.33 min, [M+H]+=no ionization.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([NH2:19])[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].CN(C)[CH:22]=[O:23].C(OC(=O)C)(=O)C>C(O)=O>[CH3:9][N:8]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:6]=[C:7]1[C:10]1[N:14]2[N:15]=[C:16]([NH:19][CH:22]=[O:23])[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1
Reactant: CN(C)C=O
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N)nn12
Solvent: O=CO
Solvent: CC(=O)OC(C)=O
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(NC=O)nn12

Procedure:
100 mg. 3-(5-nitro-1-methyl-2-imidazolyl)-6-amino-s-triazolo [4,3-b]pyridazine were suspended in 1.3 ml. dimethyl formamide and, after the addition of 1.5 ml. of the mixed anhydride obtainable from formic acid and acetic anhydride, stirred at ambient temperature until no more starting material could be detected by thin layer chromatography. The almost clear solution thus obtained was, after filtration, evaporated in a vacuum and the residue brought to crystallization with ether. There were thus obtained 72 mg. (65 percent of theory) 3-(1-methyl-5-nitro-2-imidazolyl)-6-formylamino-s-triazolo[4,3-b]pyridazine in the form of yellowish crystals which melt, with decomposition, at 200° - 204° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:10][CH2:11][CH:12]1[O:14][CH2:13]1.O.[OH-].[Li+]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:13][CH:12]([OH:14])[CH2:11][CH3:10])#[N:2]
Reactant: N#Cc1cccc(O)c1
Reactant: CCC1CO1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCC(O)COc1cccc(C#N)c1

Procedure:
is obtained analogously to Example H1 by using 20.7 g of 3-cyanophenol, 13.8 g of α-butylene oxide and 0.5 g of lithium hydroxide monohydrate in a yield of 25.9 g in the form of an oil; b.p. 116°-118° C./0.04 torr.
Reaction SMILES: CI.[C:3]([O-])(O)=O.[Na+].Cl.[Cl:9][C:10]1[CH:11]=[C:12]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]1[CH:17]([C:23]3([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][CH2:24]3)[NH:16][CH2:15][CH2:14][C:13]2=1>C(O)C>[ClH:9].[Cl:9][C:10]1[CH:11]=[C:12]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]1[CH:17]([C:23]3([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:25][CH2:26]3)[N:16]([CH3:3])[CH2:15][CH2:14][C:13]2=1
Reactant: CCOC(=O)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: CCOC(=O)C1(C2c3[nH]c4ccc(Cl)cc4c3CCN2C)CCC1

Procedure:
0.3 ml of methyl iodide and 0.8 g of NaHCO3 are added to a solution of 1 g of the compound of Example 1 in 25 ml of ethanol. After reaction for 24 hours at ambient temperature, the reaction mixture is concentrated under reduced pressure and then the residue is taken up in a mixture of water and dichloromethane. After extraction, drying and filtration, the organic phase is concentrated under reduced pressure. Crystallisation from a solution of ethanol and ethereal hydrogen chloride enables the expected product to be obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:7][S:8][C:9]23[CH:18]=[CH:17][CH:16]=[CH:15][C:10]2=[N:11][CH:12]=[CH:13][C:14]=13)=O)C.[NH2:19][NH2:20].C(N(CC)CC)C>CO>[S:8]1[C:9]23[CH:18]=[CH:17][CH:16]=[CH:15][C:10]2=[N:11][CH:12]=[CH:13][C:14]3=[C:6]([C:4]([NH:19][NH2:20])=[O:3])[CH2:7]1
Reactant: CCOC(=O)C1=C2C=CN=C3C=CC=CC32SC1
Reactant: NN
Solvent: CCN(CC)CC
Solvent: CO
Product: NNC(=O)C1=C2C=CN=C3C=CC=CC32SC1
Yield: 34.7 %

Procedure:
In 20 ml of desiccated methanol was dissolved 515 mg of benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid ethyl ester and after adding thereto 252 mg of hydrazine.di-chloride and 700 μl of triethylamine, the mixture was stirred for 2 days. Then, after refluxing the mixture for 2 hours, the temperature was allowed to lower to room temperature and crystals thus deposited were collected by filtration to provide 169 mg (yield of 0%) of benzo[b]thieno[2,3-c]pyridine-3-carbohydrazide.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([F:13])[C:6]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)=O)C.C(=O)(O)O.[NH2:19][C:20]([NH2:22])=[NH:21].Cl>C(O)C.O>[NH2:21][C:20]1[NH:22][C:4](=[O:3])[C:5]([F:13])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:19]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C(F)C(=O)c1ccco1
Agent: Cl
Agent: O=C(O)O
Solvent: O
Solvent: CCO
Product: Nc1nc(-c2ccco2)c(F)c(=O)[nH]1
Temperature: 100 °C
Yield: 71.8 %

Procedure:
Following the method of Skulnick and Wierenga (Patent WO 86/04583), a mixture of 8.72 g (43.6 mmol) (RS)-2-fluoro-3-furan-2-yl-3-oxo-propionic acid ethyl ester and 8.89 g (49.3 mmol) guanidine carbonate in 30 ml ethanol was heated at 100° C. for 16 hours. The reaction mixture was then cooled to 0° C. and diluted with 100 ml water. 1M hydrochloric acid was added dropwise until the mixture was ca pH 3, whereupon the resulting crystals were collected by filtration and washed sequentially with water and with ether to afford 6.11 g (72%) 2-amino-5-fluoro-6-furan-2-yl-3H-pyrimidin-4-one as a brown crystalline solid. EI-MS m/e (%): 95 (M+, 100), 154 ([M—MeCN]+, 24).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22](O)[CH:21]=2)=[CH:5][CH:4]=1.[Br:27][CH2:28][CH2:29][CH2:30][CH2:31]Br.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:31][CH2:30][CH2:29][CH2:28][Br:27])[CH:21]=2)=[CH:5][CH:4]=1
Reactant: BrCCCCBr
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2-c2cccc(O)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2-c2cccc(CCCCBr)c2)cc1

Procedure:
A slurry of 4.04 g (11 mmol) of 2-(4-Methoxyphenyl)-3-(3-hydroxyphenyl)-6-methoxybenzo[b]thiophene, 1,4-dibromobutane 26.3 mL (220 mmol), and 3.5 g (25.3 mmol) of K2CO3 in 200 mL of 2-butanone was preapared. The reaction mixture was heated to reflux for two hours, then filtered, and evaporated to dryness. The resulting oil was chromatographed on a silica gel column eluted with a linear gradient begining with EtOAc-hexane (1:9) (v/v) and ending with EtOAc-hexane (1:4) (v/v). The desired fractions were combined and evaporated to a yellow oil. This yielded 5 g of the title compound.