Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:14]=[C:13]([CH2:15]B2OCC(C)(C)CO2)[O:12][C:11]=1[CH3:24])(C)C)(C)(C)C.BrC1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[N:27]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:33][O:32][C:28]1[N:27]=[C:15]([C:13]2[O:12][C:11]([CH3:24])=[C:10]([CH2:9][OH:8])[CH:14]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: COc1cccc(Br)n1
Reactant: Cc1oc(CB2OCC(C)(C)CO2)cc1CO[Si](C)(C)C(C)(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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(-c2cc(CO)c(C)o2)n1
Reaction time: 8 h
Yield: 100.4 %

Procedure:
A mixture of tert-butyl({5-[(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)methyl]-2-methylfuran-3-yl}methoxy)dimethylsilane (2.4 g), 2-bromo-6-methoxypyridine (1.9 g), tetrakis(triphenylphosphine)palladium(0) (0.4 g), 2N aqueous sodium carbonate solution (7 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), 1N tetrabutylammonium fluoride in tetrahydrofuran (10 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 100% ethyl acetate/hexane) to give the title compound (1.5 g, 95%) as an oil.
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:7]=[CH:6][N:5]=1>N1C=CC=CC=1>[NH:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:7]=[CH:6][N:5]=1)[NH2:2]
Reactant: COCCOc1ccnc(Cl)c1
Reactant: NN
Solvent: c1ccncc1
Product: COCCOc1ccnc(NN)c1
Yield: 32.8 %

Procedure:
Hydrazine (10 mL, 318.6 mmol) was added to a solution of 2-chloro-4-(2-methoxyethoxy)pyridine (1.00 g, 5.330 mmol) in pyridine (25 mL). The reaction was heated to reflux. After 18 hours the reaction mixture was partitioned between H2O and DCM and the aqueous phase was extracted with DCM. The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified via flash column chromatography (40:1 DCM/MeOH followed by 20:1 DCM/MeOH) to provide 320 mg (33%) of desired product as a white solid.
Reaction SMILES: [C:1]1([CH2:13][CH2:14][C:15]([NH2:17])=[O:16])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.C[O:19][C:20](=O)[C:21]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=O.CC(C)([O-])C.[K+].Cl>O1CCCC1.C(OCC)(=O)C>[C:1]1([CH2:13][C:14]2[C:15](=[O:16])[NH:17][C:20](=[O:19])[C:21]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][CH:24]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: COC(=O)C(=O)c1c[nH]c2ccccc12
Reactant: NC(=O)CCc1cn2c3c(cccc13)CCC2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1Cc1cn2c3c(cccc13)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
To a solution of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-propionamide (249 mg, 1.1 mmol) and (1H-indol-3-yl)-oxo-acetic acid methyl ester (244 mg, 1.2 mmol) in anhydrous tetrahydrofuran (10 ml) at 0° C. was added potassium tert-butoxide (4.36 ml, 4.36 mmol; 1M in tetrahydrofuran). The mixture was allowed to warm to room temperature for 2 hours. Concentrated hydrochloric acid (4 ml) was added and the mixture stirred at room temperature for a further 30 minutes. The mixture was poured into ethyl acetate (250 ml), washed with water (750 ml) and purified by flash column chromatography (SiO2, 30 to 40% EtOAc in hexanes) to afford 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-ylmethyl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione as an orange foam (226 mg). 400 MHz 1H NMR (CDCl3) δ: 8.54 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.53 (d, J=3.2 Hz, 1H), 7.42 (m, 1H), 7.3-7.25 (m, 1H), 7.21-7.17 (m, 1H), 7.09 (dd, J=1.6 and 7.2 Hz, 1H), 6.92-6.86 (m, 2H), 4.15-4.04 (m, 4H), 2.95 (t, J=6.4 Hz, 2H), 2.22-2.16 (m, 2H); LCMS: 382 [M+H].
Reaction SMILES: [Br-:1].[CH2:2]([C:4]1[CH:5]=[CH:6][C:7]([CH3:13])=[N+:8]([CH2:10][CH2:11][CH3:12])[CH:9]=1)[CH3:3].[CH3:14][N:15]([CH3:24])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.N1CCCCC1.CCOCC>CO>[Br-:1].[CH3:14][N:15]([CH3:24])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH:13][C:7]2[CH:6]=[CH:5][C:4]([CH2:2][CH3:3])=[CH:9][N+:8]=2[CH2:10][CH2:11][CH3:12])=[CH:18][CH:17]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CCC[n+]1cc(CC)ccc1C
Agent: [Br-]
Solvent: C1CCNCC1
Solvent: CCOCC
Solvent: CO
Product: CCC[n+]1cc(CC)ccc1C=Cc1ccc(N(C)C)cc1
Yield: 62.2 %

Procedure:
5-Ethyl-2-methyl-1-propylpyridinium bromide (8.1 g, 0.033 mole) and 4-dimethylaminobenzaldehyde (6.0 g, 0.04 mole) were refluxed in methanol (50 ml) in the presence of piperidine (1.5 ml) under nitrogen for four hours. Ether was added to the cool solution and, on scratching, a red solid crystallised which was collected and washed with a little isopropanol to give 2-[4-(dimethylamino)-styryl]-5-ethyl-1-propylpyridinium bromide (7.7 g). Melting point 236°-237° (decomposition).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C:9]2([CH2:11][CH2:10]2)[O:8][C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31]CC)=[CH:27][CH:26]=3)[CH:18]=2)[C@@H:6]1[O:34][C:35](=[O:37])[CH3:36])(=[O:3])[CH3:2].B(Br)(Br)Br>ClCCl.C(OCC)C.O>[C:1]([O:4][C@H:5]1[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C:9]2([CH2:10][CH2:11]2)[O:8][C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=3)[CH:18]=2)[C@@H:6]1[O:34][C:35](=[O:37])[CH3:36])(=[O:3])[CH3:2]
Reactant: CCOc1ccc(Cc2cc([C@@H]3OC4(CC4)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)C2(CC2)O[C@H]1c1ccc(Cl)c(Cc2ccc(O)cc2)c1
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a stirred solution of acetic acid (5S,6S,7R,8S)-7,8-diacetoxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-4-oxa-spiro[2.5]oct-6-yl ester (300 mg, 0.56 mmol) in dry dichloromethane (5 mL) was added BBr3 (0.54 mL, 5.6 mmol) at −78° C. After stirring for 1 h, reaction mixture was diluted with diethyl ether (5.0 mL), stirred for 30 min. and further diluted with water and extracted with DCM to furnish 280 mg of acetic acid (5S,6S,7R,8S)-7,8-diacetoxy-5-[4-chloro-3-(4-hydroxy-benzyl)-phenyl]-4-oxa-spiro[2.5]oct-6-yl ester.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[S:5][CH2:4][CH2:3]1.Cl.[CH3:16][NH:17][CH3:18].[CH2:19]=O>C(O)(=O)C>[CH3:16][N:17]([CH2:19][CH:3]1[CH2:4][S:5][C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]1=[O:1])=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH3:18]
Reactant: CNC
Reactant: C=O
Reactant: O=C1CCSc2[nH]c3ccccc3c21
Agent: Cl
Solvent: CC(=O)O
Product: CN(C)CC1CSc2[nH]c3ccccc3c2C1=O
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
A mixture of 4.10 g (0.2 mol) of 4-oxo-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole, 3.26 g (0.04 mol) of dimethylamine hydrochloride and 1 g of paraformaldehyde in 50 ml of acetic acid is stirred vigorously at 100° C. under a nitrogen atmosphere and for 45 minutes. After the mixture is cooled, the solvent is evaporated off, the residue is dissolved in 80 ml of water and the aqueous phase is washed with ethyl acetate and alkalinized with concentrated ammonia solution. The precipitate is extracted with methylene chloride and the solution is washed with water saturated with sodium chloride and then concentrated. The residue is dissolved in 50 ml of hot ethanol and the solution is treated at 40° C. with 7 ml of an ethanolic solution of hydrochloric acid. After dilution with ethyl ether, the precipitate is drained, washed with ethyl ether, dried and recrystallized in ethanol.
Reaction SMILES: [CH2:1]([C@H:8]([NH:29][C:30](=[O:40])[O:31][C@@H:32]1[C@H:39]2[C@H:35]([O:36][CH2:37][CH2:38]2)[O:34][CH2:33]1)[C@@H:9]([OH:28])[CH:10]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1)(=[O:20])=[O:19])OC1CCCC1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:42][C:43]([N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1)=[O:44].[C:51](=[O:54])([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([C@H:8]([NH:29][C:30](=[O:40])[O:31][C@@H:32]1[C@H:39]2[C@H:35]([O:36][CH2:37][CH2:38]2)[O:34][CH2:33]1)[C@H:9]([OH:28])[CH2:10][N:17]([O:54][CH:51]1[CH2:3][CH2:2][CH2:1][CH2:8]1)[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:42][C:43]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[O:44])[CH:22]=1)(=[O:19])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@@H](O)C(NS(=O)(=O)c1cccc(O)c1)OC1CCCC1)O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: O=C([O-])[O-]
Reactant: O=C(CBr)N1CCOCC1
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCC1)S(=O)(=O)c1cccc(OCC(=O)N2CCOCC2)c1)O[C@H]1CO[C@H]2OCC[C@H]21
Yield: 129.5 %

Procedure:
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(3-hydroxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate (0.09 mmol, 50 mg) was combined with 2-bromo-1-morpholino-1-ethanone (0.09 mmol, 18 mg) and potassium carbonate (0.26 mmol, 36 mg), and stirred in anhydrous DMF (1 mL) under nitrogen for 15 hours at room temperature. The reaction was concentrated to a residue, dissolved in ethyl acetate, washed in distilled water and brine, and dried over magnesium sulfate. The dried solution was then concentrated and purified by silica gel flash chromatography (1:1 hexanes/ethyl acetate) to provide 41 mg (67%) of a white solid. Rf=0.1 (1: 1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ7.47 (2H,m), 7.38 (1H,m), 7.32-7.14 (7H,m), 5.64 (1H,s), 5.03 (2H,m), 4.91-4.76 (1H,m), 4.78 (2H,s), 3.98-3.89 (2H,m), 3.89-3.77 (2H,m), 3.74-3.63 (8H,m), 3.63-3.52 (2H,m), 3.15 (1H,br.s), 3.08-2.98 (2H,m), 2.98-2.84 (3H,m), 2.84-2.74 (1H,m), 1.89-1.71 (4H,m), 1.71-1.49 (4H,m). MS (ESI): M+H=704.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:34][N:35]([CH3:40])[CH2:36][C:37](O)=[O:38].[F:41][C:42]1[CH:47]=[CH:46][C:45]([NH:48][C:49]2[C:50]3[C:57]4[CH2:58][CH2:59][NH:60][CH2:61][C:56]=4[S:55][C:51]=3[N:52]=[CH:53][N:54]=2)=[C:44]([O:62][CH:63]2[CH2:68][CH2:67][O:66][CH2:65][CH2:64]2)[CH:43]=1>CN(C=O)C.O>[CH3:34][N:35]([CH3:40])[CH2:36][C:37]([N:60]1[CH2:59][CH2:58][C:57]2[C:50]3[C:49]([NH:48][C:45]4[CH:46]=[CH:47][C:42]([F:41])=[CH:43][C:44]=4[O:62][CH:63]4[CH2:68][CH2:67][O:66][CH2:65][CH2:64]4)=[N:54][CH:53]=[N:52][C:51]=3[S:55][C:56]=2[CH2:61]1)=[O:38]
Reactant: Fc1ccc(Nc2ncnc3sc4c(c23)CCNC4)c(OC2CCOCC2)c1
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)cc4OC4CCOCC4)c23)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40.4 %

Procedure:
HATU (0.285 g, 0.75 mmol) was added into a stirred solution of Hünig's base (0.13 mL, 0.75 mmol) and N,N-dimethylglycine (0.077 g, 0.75 mmol) in DMF (1.0 mL) and the mixture stirred for 20 minutes at ambient temperature. [4-Fluoro-2-(tetrahydro-2H-pyran-4-yloxy)-phenyl]-(5,6,7,8-tetrahydro-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-yl)-amine (0.10 g, 0.25 mmol) was added and the mixture stirred for 18 hours. Water (5 mL) was added and the mixture stirred for 20 minutes. The precipitated solid was collect by filtration, washed with water (10 mL), diethyl ether (10 mL), and dried under vacuum to give a colourless solid (0.049 g, 40%).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:10][C:9]2=[O:23])=[CH:4][C:3]=1[NH:24][CH3:25].[Cl:26][C:27]([Cl:33])([Cl:32])[C:28](=[NH:31])OC.O>CC(O)=O>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:31]=[C:28]([C:27]([Cl:26])([Cl:32])[Cl:33])[N:24]([CH3:25])[C:3]=4[CH:4]=3)[C:9](=[O:23])[CH:10]=2)=[CH:21][CH:20]=1
Reactant: CNc1cc(-n2ccc(OCc3ccc(F)cc3)cc2=O)ccc1N
Reactant: COC(=N)C(Cl)(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(C(Cl)(Cl)Cl)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (270 mg) in AcOH (3 ml) was added methyl 2,2,2-trichloroacetimidate (0.196 ml) dropwise at 0° C. The mixture was stirred at room temperature for 2 h. Water was added to the mixture. The resulting precipitate was collected by filtration and dried to give the title compound (220 mg) as an ivory solid.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[C:13]([Cl:19])[CH:12]=1)[CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][O:7]1.[OH-].[Li+]>CO>[Cl:19][C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][C@H:6]2[CH2:10][CH2:9][CH2:8][O:7]2)[C:3]([OH:20])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17][CH3:18]
Reactant: COC(=O)C(C[C@H]1CCCO1)c1ccc(SC)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CSc1ccc(C(C[C@H]2CCCO2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
A solution of 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid methyl ester (0.519 g, 1.65 mmol) in methanol (7 mL) was treated with a 0.8M aqueous lithium hydroxide solution (40.7 mL, 33.0 mmol). The reaction mixture was stirred at 25° C. for 1.5 h and then concentrated in vacuo to remove methanol. The remaining aqueous layer was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford pure 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid (0.495 g, 95.8%) as a light yellow oil that crystallized upon standing: mp 93–96° C.; [α]23589=−23.70° (c=0.46, chloroform); EI-HRMS m/e calcd for C14H17ClO3S (M+) 300.0587, found 300.0579.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[N:10]=[C:9](S(C)(=O)=O)[N:8]=[C:7]([NH:15][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH3:17])[C:6]=1[C:22]1[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=1[F:30]>CN(C=O)C.CC(OC)(C)C>[Cl:4][C:5]1[N:10]=[C:9]([O:2][CH3:1])[N:8]=[C:7]([NH:15][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH3:17])[C:6]=1[C:22]1[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=1[F:30]
Reactant: C[C@H](Nc1nc(S(C)(=O)=O)nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: COc1nc(Cl)c(-c2c(F)cc(F)cc2F)c(N[C@@H](C)C(F)(F)F)n1
Temperature: 22.5 °C
Reaction time: 16 h
Yield: 55.8 %

Procedure:
294 mg (1.30 mmol) of sodium methoxide (90% in methanol) were added to a solution of 282 mg (0.65 mmol) of sulfone 1 in 4 ml of anhydrous DMF. The mixture was stirred at 20-25° C. for 16 hours and then diluted with MTBE, washed with water and dried. Distillative removal of the solvent and chromatography on silica gel gave 0.14 g of the title compound of m.p. 121-129° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:5]=1[C:6](N(OC)C)=[O:7])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].CCCCCC.C(OC(=O)C)C>C1COCC1>[CH2:1]([NH:3][C:4]1[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:5]=1[CH:6]=[O:7])[CH3:2]
Reactant: CCNc1cc(C(F)(F)F)ccc1C(=O)N(C)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCNc1cc(C(F)(F)F)ccc1C=O
Yield: 29.5 %

Procedure:
2-Ethylamino-N-methoxy-N-methyl-4-trifluoromethyl-benzamide (95 mg, 0.343 mmol) was reacted with LAH in THF at −40° C. for 1.5 hrs as described above to yield title compound (22 mg, 29%) after column chromatography (hexane/ethylacetate=20/1).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:10]=[C:9]([CH3:11])[NH:8][C:7]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)(O)[O-].[Na+]>>[CH3:5][C:6]1[C:10]([N+:1]([O-:4])=[O:2])=[C:9]([CH3:11])[NH:8][C:7]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1[nH]c(C)c([N+](=O)[O-])c1C
Temperature: 0 °C
Yield: 14 %

Procedure:
Nitric acid (70 w/w %, 5 mL) was added to ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (1.0 g, 6.0 mmol) cooled to 0° C. The reaction mixture was stirred and allowed to warm to RT over 1 h. The reaction mixture was poured into an ice bath with sat. sodium bicarbonate (25 mL) and extracted with EtOAc (3×50 mL), the organic layers combined, dried over sodium sulfate, filtered and evaporated. Purification by column chromatography afforded ethyl 3,5-dimethyl-4-nitro-1H-pyrrole-2-carboxylate (0.185 g, 14%) as a white solid. 1H NMR (400 MHz, DMSO-d5): δ ppm 12.49 (br. s., 1H) 4.26 (q, 2H) 2.51 (s, 3H) 2.50 (s, 3H) 1.28 (t, 3H). MS: m/z 213.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>O1CCOCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][N:9]2[C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:20]=2[Cl:19])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: O=C1CCNc2cc(Cl)ccc21
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: O=C1CCN(C(=O)c2ccc(Cl)cc2Cl)c2cc(Cl)ccc21
Yield: 88.1 %

Procedure:
To a mixture of 7-chloro-2,3-dihydro-4(1H)-quinolinone (25 g), pyridine (32 g) and dioxane (200 ml) was added 2,4-dichlorobenzoylchloride (37 g) dropwise under cooling at 0° C. to 5° C. with stirring. The mixture was allowed to react at room temperature for additional 3 hours. The reaction mixture was subjected to the procedure described in example 2, and 43 g of 7-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4-(1H)-quinolinone was obtained as white crystal.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH:29][CH2:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[CH:33][C:32]=1[CH2:41][C:42]([N:44]1[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]1)=[O:43]>ClCCl>[CH2:8]([NH:26][C:27](=[O:28])[O:29][CH2:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[CH:33][C:32]=1[CH2:41][C:42]([N:44]1[CH2:45][CH2:46][N:47]([CH3:50])[CH2:48][CH2:49]1)=[O:43])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: COc1cc(CO)c(CC(=O)N2CCN(C)CC2)cc1OC
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCc1cc(OC)c(OC)cc1CC(=O)N1CCN(C)CC1
Reaction time: 15 h

Procedure:
Triethylamine (0.41 ml) and octadecyl isocyanate (0.91 ml) were added to a solution of 2-[2-(hydroxymethyl)-4,5-dimethoxyphenyl]-1-(4-methylpiperazinyl)-1-ethanone (0.82 g) in dichloromethane (8.5 ml) at room temperature. After being stirred for 15 hours, resulting insoluble materials were filtrated out under a vacuum and washed with chloroform. A mixture of the filtrate and chloroform used for washing was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated. The residue was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=50:1-30:1), thereby yielding 0.83 g of the aimed compound as light brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:12][CH2:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][C:6]=2[CH:17]=1.[CH2:18]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29](OB(O)O)=[CH:28][CH:27]=1)[CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O>[CH2:18]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([C:2]2[CH:3]=[CH:4][C:5]3[NH:12][CH2:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][C:6]=3[CH:17]=2)=[CH:30][CH:31]=1)[CH2:19][CH2:20][CH3:21]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2NCCC1
Reactant: CCCCOCCOc1ccc(OB(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCCN3)cc1
Reaction time: 1 h
Yield: 40.1 %

Procedure:
A suspension of methyl 8-bromo-1,2,3,4-terahydro-1-benzoazocine-5-carboxylate (6.0 g), 4-(2-butoxyethoxy)phenyl boric acid (6.26 g) and potassium carbonate (7.28 g) in toluene (100 ml), ethanol (10 ml) and water (10 ml) was stirred under argon atmosphere for 1 hour, after which tetrakis(triphenylphosphin)palladium (1.17 g) was added, and the mixture was refluxed for 6 hours. After returning to room temperature, water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 hexane:ethyl acetate=4:1), and recrystallized from hexane-ethyl acetate to give methyl 8-(4-(2-butoxyethoxy)phenyl)-1,2,3,4-terahydro-1-benzoazocine-5-carboxylate (3.33 g) as a yellow solid.
Reaction SMILES: N1C=CC=C(N[N:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])C=1.[NH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.C(#N)CC#N.O.[NH2:27][NH2:28]>C(O)C>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([NH:14][N:8]=[C:9]2[C:10]([NH2:11])=[N:28][N:27]=[C:12]2[NH2:13])[CH:16]=1
Reactant: Nc1cccnc1
Reactant: N#CC(C#N)=NNc1cccnc1
Reactant: NN
Solvent: CCO
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1cccnc1
Temperature: 25 °C

Procedure:
4-(pyridin-3-ylhydrazono)-4H-pyrazole-3,5-diamine was prepared using 2-[(pyridin-3-yl)hydrazono]malononitrile (342 mg, 2 mmol), which was derived from 3-aminopyridine (940 mg, 10 mmol)) and malononitrile (858 mg, 13 mmol), and hydrazine hydrate (110 mg, 2.2 mmol) in ethanol. Solids had not formed after heating the reaction at 80° C. for 40 minutes, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to ambient temperature and the solvent was evaporated. The product was obtained after upon re-crystallization from ethanol as a yellow solid (150 mg); 1H NMR (ppm, DMSO-d6): 6.18 (br., s, 4H), 7.20 (dd, 1H), 8.00 (dd, 1H), 8.38 (d, 1H), 8.85 (s, 1H), 10.77 (br., s, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][NH:16][CH3:17].[H-].[Na+].O>O1CCCC1>[CH3:15][N:16]([CH3:17])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: CNC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
To a solution of 1-floro-4-nitro-2-trifluoromethylbenzene (2.0 g) in tetrahydrofuran (20 mL) were added dimethyamine (0.64 g) and sodium hydride (0.34 g) at room temperature, and this mixture was stirred at 50° C. for 16 hours. This reaction mixture was poured into water, and this mixture was extracted with ethyl acetate. This organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.94 g).