Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]1[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH:16]=1.[H][H]>[Pd].C(O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]1
Reactant: [H][H]
Reactant: COCOc1ccc(C2=CC(=O)CCC2)c(OCOC)c1
Agent: [Pd]
Solvent: CCO
Product: COCOc1ccc(C2CCCC(=O)C2)c(OCOC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A suspension of 3-[2,4-bis(methoxymethoxy)phenyl]-2-cyclohexen-1-one (300 m g) and palladium catalyst (50 mg, 10% palladium on carbon) in ethanol was stirred at ambient temperature under 1 atmosphere of hydrogen. After 16 hr, the mixture was filtered through celite and the filtrate was evaporated in vacuo. The product was dissolved in dichloromethane (15 ml). Celite and pyridinium chlorochromate (430 mg) were added and the mixture was stirred at room temperature. After 3 hr, the mixture was filtered through a pad of silica and eluted with petroleum ether/ethyl acetate (10:3, v/v), then purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate 4:1 v/v) to furnish the title compound as an oil (200 mg, 70%). δH(CDCl3) 1.7-1.9 (2H, overlapping m), 2.05 (1H, m), 2.15 (1H, m), 2.35-2.60 (4H, overlapping m), 3.37 (1H, m), 3.490 (3H, s), 3.492 (3H, s), 5.15 (2H, s), 5.20 (2H, s), 6.70 (1H, dd), 6.82 (1H, d), 7.09 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20](=[O:31])OC3C=CC([N+]([O-])=O)=CC=3)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH2:33]1[CH:38]2[CH2:39][CH:40]3[CH:42]([NH2:43])[C@@H:34]1[CH2:35][C:36]([OH:44])([CH2:41]3)[CH2:37]2>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20]([NH:43][CH:42]3[CH:34]4[CH2:33][CH:38]5[CH2:37][C:36]([OH:44])([CH2:41][CH:40]3[CH2:39]5)[CH2:35]4)=[O:31])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC1C2CC3C[C@H]1CC(O)(C3)C2
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)NC1C2CC3CC1CC(O)(C3)C2

Procedure:
1-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3-(5-hydroxy-adamantan-2-yl)-urea was prepared starting from intermediate M and trans-4-aminoadamantan-1-ol. MS calcd. for C27H29ClN3O3 [(M+H)+] 478.2, obsd. 478.0.
Reaction SMILES: [CH:1]1[C:6]([C:7]2[C:16](=[O:17])[C:15]3[C:14]([OH:18])=[CH:13][C:12]([O:19][C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)=[CH:11][C:10]=3[O:9][CH:8]=2)=[CH:5][CH:4]=[C:3]([OH:31])[CH:2]=1>Cl>[CH:5]1[C:6]([C:7]2[C:16](=[O:17])[C:15]3[C:14]([OH:18])=[CH:13][C:12]([OH:19])=[CH:11][C:10]=3[O:9][CH:8]=2)=[CH:1][CH:2]=[C:3]([OH:31])[CH:4]=1
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)cc(O)c12
Agent: Cl
Product: O=c1c(-c2ccc(O)cc2)coc2cc(O)cc(O)c12
Yield: 96.1 %

Procedure:
About 1578 mg of genistin were refluxed in 960 ml 4N HCl for five hours at 100°±5° C. About 948 mg genistein were obtained with about 96% recovery. 483.2 mg of genistein (99% purity) recovered from the hydrolysis step was dissolved in 450 ml methanol and crystallized in 20 ml methanol. About 373.8 mg of genistein crystal was obtained giving a 77% recovery and 99.5% purity. Genistein m.p. 298.4°-299.9° C. 1H NMR (400 MHz, DMSO-d6) 6.22 (1H, d, J=2 Hz, H-8), 6.38 (1H, d, J=2 Hz, H-6), 6.83 (2H, d, J=8 Hz, H-3'), 7.39 (2H, d, J=8 Hz, H-2'), 8.43 (1H, s, H-2), 9.61 (1H, s, 4'-OH), 10.90 (1H, s, 7-OH) 12.92 (1H, s, 5-OH). 13C NMR (100 MHz, DMSO-d6) 154.5, 122.8, 180.7, 162.5, 99.5, 164.8, 94.2, 157.9, 105.0, 121.7, 130.7, 115.6, 158.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:21]([O:25][C:26]([N:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:29]3[N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH:32]=[CH:31][CH:30]=3)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Product: COc1cc(Nc2cncc(-c3cccn3C(=O)OC(C)(C)C)n2)cc(OC)c1OC
Yield: 4.1 %

Procedure:
Using Method C with 100 mg (0.34 mmol) 2a and 86 mg (0.41 mmol) 1-tert-butoxycarbonyl-2-pyrrolyl boronic acid, 6 mg pure title compound were obtained. The filtrate was submitted to purification by preparative HPLC (eluent:AcOEt) and a fraction of 52 mg of a product containing 25% (LC-MS) of the desired compound was obtained. A second purification using a semi-preparative Supelco discovery C18 column (250×10 mm) (eluent: acetonitrile:H2O 9:1) led to 6 mg (4.1%) of pure title compound. Reaction time: 18 hours. 1H-NMR (DMSO), δ (ppm), J (Hz): 1.25 (s, 9H, t-Bu), 3.60 (s, 3H, CH3O(4′)), 3.72 (s, 6H, CH3O(3′+5′)), 6.33 (t, 1H, Hpyr 4′, J=3.30), 6.58-6.60 (m, 1H, Hpyr 3′ or 5′), 7.16 (s, 2H, Harom(2+6)), 7.42-7.44 (m, 1H, Hpyr 5′ or 3′), 8.04 (s, 1H, HP5), 8.12 (s, 1H, HP3), 9.53 (s, 1H, NHamine); MS, (C22H16N4O5), m/z: 427 [M++1, 100].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=1.[B:17](OC)([O:20]C)[O:18]C>>[C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:3]1[C:2]([F:1])=[CH:7][CH:6]=[C:5]([B:17]([OH:20])[OH:18])[C:4]=1[F:8])#[N:16]
Reactant: COB(OC)OC
Reactant: N#Cc1ccccc1-c1c(F)cccc1F
Product: N#Cc1ccccc1-c1c(F)ccc(B(O)O)c1F

Procedure:
2′,6′-Difluorobiphenyl-2-carbonitrile was lithiated and reacted with trimethyl borate as described in Example 31 to give 2′-cyano-2,6-difluorobiphenyl-3-boronic acid as a white crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[C:19]2[O:26][N:25]=[C:24]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[C:20]=2[N:21]=[CH:22][N:23]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[C:19]3[O:26][N:25]=[C:24]([C:27]4[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=4)[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)c1ccc(-c2noc3c(Cl)ncnc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3c(-c4ccc(S(C)(=O)=O)cc4)noc23)CC1
Reaction time: 0.17 h
Yield: 60.2 %

Procedure:
4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.49 mmol) was dissolved in anhydrous THF (5 mL) and treated with NaH, 60% oil dispersion (20 mg, 0.49 mmol) at ambient temperature. After stirring for 10 min, 7-chloro-3-(4-methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidine (0.15 g, 0.49 mmol) was added. The reaction was stirred for 3 h and concentrated under vacuum. The residue was purified by column chromatography using ethyl acetate and hexane (1/1) to afford 4-[3-(4-methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.14 g, 61%). 1H NMR (400Mz, DMSO-d6) δ 8.51 (s, 1H), 8.42 (d, J=7.1, 2H), 8.34 (d, J=7.1, 2H), 4.11˜3.83 (m, 4H), 3.52 (m, 1H), 3.26 (s, 3H), 1.41˜1.22 (m, 4H). LCMS 475.3[M+H].
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@H:21]([C@@:39]([OH:47])([CH2:43]C(O)=O)[C:40]([OH:42])=[O:41])/[CH:22]=[CH:23]/[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]>C(O)=O>[C:14]([O:16][CH2:17][CH2:43][C@:39]([OH:47])([C@@H:21]([C:19](=[O:20])[NH:18][C@H:13]([C:14]([O:16][CH3:17])=[O:15])[CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:11][CH:10]=1)/[CH:22]=[CH:23]/[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:40]([OH:42])=[O:41])(=[O:15])[CH3:13]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CC(=O)O)C(=O)O)C(=O)OC)cc1
Solvent: O=CO
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCOC(C)=O)C(=O)O)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
No. 5318799 (Compound R; 11.4 g, 15.4 mmol) was dissolved in formic acid (229 mL), and then the solution was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and then dissolved in ethyl acetate (250 mL). After washing twice with a 6:1 mixture (250 mL) of an aqueous solution of 1% sodium bicarbonate and a saturated aqueous solution of sodium chloride, the solution was washed with a 6:1 mixture (220 mL) of an aqueous solution of 10% ammonium chloride and a saturated aqueous solution of sodium chloride, and finally with a saturated aqueous solution of sodium chloride (100 mL), dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure. The residue was purified on Biotage (silica gel, dichloromethane/methanol) to obtain 10.5 g (15.3 mmol, 99% yield) of No. 5214354 (Compound S).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C:20]1[CH:24]=[C:23]([C:25]2[S:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[O:22][N:21]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][C:6]1[N:7]=[CH:8][N:9]([CH2:19][C:20]2[CH:24]=[C:23]([C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[O:22][N:21]=2)[CH:10]=1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: COC(=O)CCc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1cn(Cc2cc(-c3ccc(Cl)s3)on2)cn1
Temperature: 70 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
To a solution of 190 mg of 3-(1H-Imidazol-4-yl)-propionic acid methyl ester (hydrochloride salt) in DMF (5 mL) was added K2CO3 (414 mg) and 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole (278 mg). The mixture was stirred for 2 h at 70° C. After removal of the solvent in vacuo the residue was taken up in ethyl acetate. The mixture was washed with water and brine. The organic phase was dried over anhydrous MgSO4 and concentrated under reduced pressure to give crude 3-{1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-imidazol-4-yl}-propionic acid methyl ester (174 mg) as a brown solid which was used in the next step without further purification.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([C:16](=O)/[CH:17]=[CH:18]/[N:19](C)C)=[N:12][CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.Cl.[NH:24]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])N.Cl>CCO>[OH:8][CH2:9][C:10]1[C:11]([C:16]2[N:24]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:19]=[CH:18][CH:17]=2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CN(C)/C=C/C(=O)c1ncccc1CO[Si](C)(C)C(C)(C)C
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cn1nccc1-c1ncccc1CO
Temperature: 80 °C
Yield: 74.4 %

Procedure:
To (E)-1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one (crude, 350 mg, 1.09 mmol, 1 eq.) in EtOH (10 mL) was added ethyl 2-hydrazinylacetate hydrochloride (338 mg, 2.18 mmol, 2.0 eq.). The mixture was heated at 80° C. for 2 h, cooled to rt, added HCl (6 N, 0.5 mL), and stirred O/N. The mixture was concentrated, and diluted with a mixture of EtOAc (50 mL) and NaHCO3(sat) (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using EtOAc as eluent to give ethyl 2-(5-(3-(hydroxymethyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetate (212 mg, 74%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.61 (dd, J=4.7, 1.6 Hz, 1H), 7.97 (dd, J=7.8, 1.4 Hz, 1H), 7.64 (d, J=1.9 Hz, 1H), 7.36 (dd, J=7.8, 4.8 Hz, 1H), 6.56 (d, J=1.9 Hz, 1H), 5.21 (s, 2H), 4.79 (d, J=5.8 Hz, 2H), 4.09 (q, J=7.1 Hz, 2H), 2.54 (t, J=6.0 Hz, 1H), 1.18 (t, J=7.1 Hz, 31-1). LRMS m/z 262.1
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Br)=[CH:6][CH:7]=1.[CH3:9][S:10]C.[Na]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([S:10][CH3:9])=[CH:6][CH:7]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CSC
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: CSc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3,6-dibromopyridine (1.0 eq.) in DMSO (0.3M) was added sodium methylsulfide (1.1 eq.). The mixture was stirred for 2 d at rt then poured in water. The resulting precipitate was filtered to afford the title compound as white solid.
Reaction SMILES: CN1C[CH2:5][CH2:4][C:3]1=O.[C:8]([OH:21])(=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].O.[Cl-].[NH4+].CC#C.C=C=C>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Zn+2]>[C:8]([O:21][C:4]([CH3:5])=[CH2:3])(=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)CCCCCCCCC(=O)O
Reactant: CN1CCCC1=O
Agent: C#CC
Agent: C=C=C
Agent: CC(=O)/C=C(/C)[O-]
Solvent: O
Product: C=C(C)OC(=O)CCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A 1-liter pressure vessel equipped with a magnetic stirrer, a thermocouple, a thermocontroller, a methyl acetylene reservoir tank, a pressure burette, a gas line, and a control valve, was flushed free of air with nitrogen and charged with 100 ml (1.04 moles) of N-methyl-2-pyrrolidone; 10.0 gm (0.0038 moles) of zinc acetylacetonate; 25.0 gm. (0.12 moles) sebacic acid; 11.0 gms (0.61 moles) water; 5.0 gm (0.093 moles) ammonium chloride; and 135 ml of MAPP gas (65 mole percent methyl acetylene and allene), and heated to 155° C. at a maximum pressure of 550 psi with stirring for about 14 hours. The reaction vessel was allowed to cool at room temperature and an aliquot removed. The aliquot was shaken with diethyl ether and water and the ether layer dried with magnesium sulphate and evaporated to dryness. An infrared spectrum of the dried product in carbon disulphide solution showed quantitative conversion to isopropenyl hydrogen sebacate. The IR spectrum was identical to that of a pure reference sample.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:24](=[S:26])[NH2:25])[N:6]2[CH2:21][O:22][CH3:23].Br[CH2:28][CH:29](OCC)OCC.CN(C)C(=O)C>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])=[O:14])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:24]1[S:26][CH:28]=[CH:29][N:25]=1)[N:6]2[CH2:21][O:22][CH3:23]
Reactant: COCn1c(C(N)=S)cc2c(F)ccc(N(C)S(=O)(=O)c3cccs3)c21
Reactant: CCOC(CBr)OCC
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COCn1c(-c2nccs2)cc2c(F)ccc(N(C)S(=O)(=O)c3cccs3)c21
Yield: 62 %

Procedure:
A mixed solution of 4-fluoro-1-(methoxymethyl)-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.25 g), 1-bromo-2,2-diethoxyethane (0.24 mL) and N,N-dimethylacetamide (10 ml) was stirred at 90° C. for 7 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=15:85-30:70) to give the title compound (165 mg, yield 62%) as colorless needle crystals.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][NH:5][C:4]1=[S:8])[CH3:2].[N:9]([O-])=[O:10].[Na+].Cl>ClCCl>[CH2:1]([N:3]1[CH2:7][CH2:6][N:5]([N:9]=[O:10])[C:4]1=[S:8])[CH3:2]
Reactant: O=N[O-]
Reactant: CCN1CCNC1=S
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CCN(N=O)C1=S
Temperature: 0 °C

Procedure:
To an ice-cooled mixture of 6.81 g of 1-ethyl-imidazolidine-2-thion and 3.6 g of NaNO2 in 440 ml of dichloromethane 63 ml of 1 M HCl are added dropwise and the mixture obtained is stirred for ca 10 minutes. A two phase system is obtained and the phases are separated. The organic phase is washed with H2O, dried over Na2SO4 and the solvent is evaporated off. Solid 1-ethyl-3-nitrosoimidazolidine-2-thion is obtained.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[CH3:41][C:42]1[O:46][C:45]([C:47]2[CH:48]=[C:49]([S:53](Cl)(=[O:55])=[O:54])[CH:50]=[CH:51][CH:52]=2)=[N:44][N:43]=1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:53]([C:49]2[CH:50]=[CH:51][CH:52]=[C:47]([C:45]3[O:46][C:42]([CH3:41])=[N:43][N:44]=3)[CH:48]=2)(=[O:55])=[O:54])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1nnc(-c2cccc(S(=O)(=O)Cl)c2)o1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nnc(-c2cccc(S(=O)(=O)n3cc(CN(C)C(=O)OC(C)(C)C)c(F)c3-c3cccnc3F)c2)o1
Reaction time: 2 h
Yield: 51.9 %

Procedure:
To a suspension of sodium hydride (60% in oil, 18 mg) in tetrahydrofuran (0.5 mL) were added dropwise a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (97 mg) in tetrahydrofuran (0.5 mL), 15-crown-5 (100 mg) and 3-(5-methyl-1,3,4-oxadiazol-2-yl)benzenesulfonyl chloride (85 mg) under ice-cooling and the mixture was stirred for 2 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1) to give the title compound as a pale-yellow oil (yield 85 mg, 52%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[O:9]1[CH2:14][CH2:13][CH:12](O)[CH2:11][CH2:10]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH:12]2[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: OC1CCOCC1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnn(C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 175.5 %

Procedure:
4-nitro-1H-pyrazole (0.15 g, 1.3 mmol), tetrahydro-2H-pyran-4-ol (0.14 g, 1.3 mmol), DIPAD (0.35 g, 1.7 mmol), PPh3 (0.42 g, 1.6 mmol) were dissolved in THF (5 mL) and the resulting mixture was stirred at 25° C. for 3 hours. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/petroleum ether=6/1) to give 4-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (0.45 g). 1H NMR (500 MHz, CDCl3): δ 8.19 (s, 1H), 8.10 (s, 1H), 4.38 (m, 1H), 4.16-4.12 (m, 2H), 3.57-3.53 (m, 2H), 2.17-2.05 (m, 4H).
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([C:15]#[C:16][C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)=[CH:10][N:9]=1.[Cl-].[NH4+].O>CN1C(=O)CCC1.CN1C(=O)CCC1.O>[Br:7][C:8]1[N:9]=[CH:10][C:11]2[CH:15]=[C:16]([C:17]3[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=3)[NH:14][C:12]=2[CH:13]=1
Reactant: Cn1cc(C#Cc2cnc(Br)cc2N)cn1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Temperature: 50 °C
Yield: 92.8 %

Procedure:
Potassium t-butoxide (315 mg 2.81 mmole) was dissolved in NMP (3 mL) and 2-bromo-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-amine (24) (375 mg 1.35 mmole) was added to the stirred solution. The reaction was placed under nitrogen and warmed at 50° C. for 3 hours. The reaction was cooled and 10% ammonium chloride (3 mL) added. Water (21 mL) was heated to about 60° C. and the product solution in NMP/water was added to the water; a solid immediately crashes out. The suspension was allowed to cool to r.t., filtered and the solid washed with water. Drying in a vac desiccator over KOH for 3 days gave product (347 mg) which was azeotroped with ethanol (2×15 mL) and toluene (2×15 mL) to give the title compound (315 mg, 84%). 1H-NMR (d6-DMSO, 500 MHz): δ 3.90 (s, 3H), 6.69 (d, J=0.95 Hz, 1H), 7.47 (t, J=0.95 Hz, 1H), 7.94 (d, J=0.63 Hz, 1H), 8.18 (s, 1H), 8.50 (d, J=0.95 Hz, 1H), 11.92 (br s, 1H, NH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]([O:17]CC)=[O:16])[C:9]2=[O:20])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]([OH:17])=[O:16])[C:9]2=[O:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(C)cn(-c2ccc(F)cc2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
To a solution of ethyl 1-(4-fluorophenyl)-5-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (1.2 g, 4.36 mmol) in methanol (12 mL) was added 1N aqueous sodium hydroxide solution (10 mL, 10 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the obtained residue was diluted with ethyl acetate and water and extracted with water. The aqueous layer was treated with 1N hydrochloric acid (20 mL, 20 mmol), and the precipitate was collected by filtration to give a white solid. The white solid was washed with water to give the title compound (730 mg, 68%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]([OH:18])=[O:17])=[CH:10][NH:11][C:12]2=[O:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:19][NH:20][CH3:21].Cl>>[CH3:19][N:20]([CH3:21])[S:2]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]([OH:18])=[O:17])=[CH:10][NH:11][C:12]2=[O:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=C(O)c1c[nH]c(=O)c2cc(S(=O)(=O)Cl)ccc12
Reactant: CNC
Agent: Cl
Product: CN(C)S(=O)(=O)c1ccc2c(C(=O)O)c[nH]c(=O)c2c1
Reaction time: 18 h

Procedure:
7-(Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (0.8 g) was added to dimethylamine (15 ml) and the mixture was stirred for 18 h. The mixture was acidified with concentrated hydrochloric acid and then filtered to yield 7-[(dimethylamino)sulfonyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid as a white solid.
Reaction SMILES: C(O[C:4]([C:6]12[CH2:13][CH2:12][C:9]([C:14]([OH:16])=[O:15])([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)=O)C.Cl.[NH2:18][C:19]1[C:20](=[O:33])[N:21]([CH2:30][CH2:31][CH3:32])[C:22](=[O:29])[N:23]([CH2:26][CH2:27][CH3:28])[C:24]=1[NH2:25].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[K+]>O.CC(O)C.C(#N)C>[O:29]=[C:22]1[N:23]([CH2:26][CH2:27][CH3:28])[C:24]2[N:25]=[C:4]([C:6]34[CH2:7][CH2:8][C:9]([C:14]([OH:16])=[O:15])([CH2:10][CH2:11]3)[CH2:12][CH2:13]4)[NH:18][C:19]=2[C:20](=[O:33])[N:21]1[CH2:30][CH2:31][CH3:32]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: CCOC(=O)C12CCC(C(=O)O)(CC1)CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To a stirred mixture of 2.00 g (8.84 mmol) of bicyclo[2.2.2]octane-1,4-dicarboxylic acid monoethyl ester, 2.60 g (9.89 mmol) of 5,6-diamino-1,3-dipropyl 1H-pyrimidine-2,4-dione hydrochloride, 5.32 ml (38.1 mmol) of NEt3, and 30 ml anhydrous acetonitrile was added 3.76 g (9.89 mmol) of HATU. The reaction solution was stirred at rt for 1 h. The reaction mixture was concentrated in vacuo and combined with 40 ml EtOAc and 40 ml of 10% citric acid. The aqueous layer was separated and washed twice with 40-ml portions of EtOAc. The combined organic fractions were washed with 20-ml portions of sat'd NaHCO3 and brine and conc'd in vacuo. The resultant solid was combined, in a 200-ml round-bottom flask equipped with a condenser, with a mixture of 35 ml of i-PrOH and 35 ml of 1 N KOH (35 mmol) and heated to reflux. After heating for 1 hour, the reaction solution was conc'd in vacuo, taken up in 40 ml of water, and washed twice with 30-ml portions of CH2Cl2. The aqueous layer was acidified with conc'd HCl and the resultant precipitate collected by suction filtration to give 3.00 g (87% yield) of an off-white solid. (MH+=389.25)