Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([NH:15][C:16]([C:18]3[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[CH:19]=3)=[O:17])[CH:14]=2)=[CH:4][CH:3]=1.[N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]=[S:28].CS(C)=O>O>[CH3:23][N:22]1[C:18]([C:16]([NH:15][C:13]2[CH:14]=[C:9]([CH:10]=[CH:11][C:12]=2[CH3:25])[O:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:29](=[O:30])[O:31][CH2:32][CH3:33])=[S:28])=[N:7][CH:6]=2)=[O:17])=[CH:19][C:20]([CH3:24])=[N:21]1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc(N)nc3)ccc2C)n(C)n1
Reactant: CCOC(=O)N=C=S
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2ccc(C)c(NC(=O)c3cc(C)nn3C)c2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.3 %

Procedure:
A mixture of N-{5-[(6-aminopyridin-3-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (214 mg, 0.634 mmol), ethyl isothiocyanatoformate (108 mg, 0.824 mmol) and DMSO (5 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give ethyl ({[5-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl) carbonyl]amino}-4-methylphenoxy)pyridin-2-yl]amino}carbonothioyl)carbamate (280 mg, 94%) as a white solid. A mixture of ethyl ({[5-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-4-methylphenoxy)pyridin-2-yl]amino}carbonothioyl)carbamate (270 mg, 0.576 mmol) thus-obtained, hydroxylammonium chloride (280 mg, 4.03 mmol), N,N-diisopropylethylamine (502 μL, 2.88 mmol), ethanol (10 mL) and methanol (10 mL) was stirred at 80° C. for 8 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (164 mg, 75%) as a white solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH2:11]([C:13]1[CH:26]=[CH:25][C:16]([O:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[NH2:20])=[C:15]([O:27][CH3:28])[CH:14]=1)[CH3:12]>C1COCC1>[CH2:11]([C:13]1[CH:26]=[CH:25][C:16]([O:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[NH:20][CH:1]=[O:3])=[C:15]([O:27][CH3:28])[CH:14]=1)[CH3:12]
Reactant: CCc1ccc(Oc2ccccc2N)c(OC)c1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: C1CCOC1
Product: CCc1ccc(Oc2ccccc2NC=O)c(OC)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 126.4 %

Procedure:
To acetic anhydride (0.53 mmol; 51 μL) under argon, at 0° C., was added formic acid (0.66 mmol; 25 μL). The reaction was stirred 2 hours at 60° C. After cooling to 0° C., the mixture was diluted with 1 mL of dry THF, followed by a solution of 2-(4-ethyl-2-methoxyphenoxy)aniline (0.21 mmol; 50 mg) in dry THE (1 mL). The reaction was stirred 2 hours at room temperature. The mixture was concentrated in vacuo to give the title compound (72 mg; quantitative) as a brown oil, used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[C:8]([C:15]([OH:17])=O)=[CH:9][N:10]([CH3:14])[C:11](=[O:13])[CH:12]=2)=[C:4]([F:20])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:33][CH2:34][CH2:35][CH2:36][OH:37]>C1COCC1.CN(C=O)C>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[C:8]([C:15]([NH:33][CH2:34][CH2:35][CH2:36][OH:37])=[O:17])=[CH:9][N:10]([CH3:14])[C:11](=[O:13])[CH:12]=2)=[C:4]([F:20])[CH:3]=1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)cc1=O
Reactant: NCCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1cc(C(=O)NCCCO)c(Nc2ccc(Br)cc2F)cc1=O
Yield: 71 %

Procedure:
4-(4-Bromo-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and CDI were dissolved in a mixture of anhydrous THF and anhydrous DMF and treated with 3-amino-1-propanol as for example 34. After workup, the residue was further purified by flash chromatography on silica gel (5% MeOH/CH2Cl2) to give 4-(4-bromo-2-fluoroanilino)-N-(3-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (71%) as a cream solid; m.p. (EtOAc/Hexane) 167-170° C. 1H NMR [400 MHz, (CD3)2SO] δ 10.10 (br s, 1H), 8.40 (t, J=5.3 Hz, 1H), 8.24 (s, 1H), 7.69-7.64 (m, 1H), 7.48-7.40 (m, 2H), 5.56 (s, 1H), 4.48 (t, J=5.1 Hz, 1H), 3.47 (dd, J=11.5, 6.2 Hz, 2H), 3.37 (s, 3H), 3.27 (dd, J=12.7, 6.9 Hz, 2H), 1.67 (p, J=6.7 Hz, 2H). LCMS (ACPI−) 398 (85%), 396 (100%). Anal. Calcd for C16H17BrFN3O3: C, 48.3; H, 4.3; N, 10.6. Found C, 48.2; H, 4.2; N, 10.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11](Br)[C:12]([F:15])([F:14])[F:13].COC1C=CC(CC(F)(F)F)=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([F:13])([F:15])[F:14]
Reactant: COc1ccc(C(Br)C(F)(F)F)c(OC)c1
Agent: COc1ccc(CC(F)(F)F)cc1
Product: COc1ccc(CC(F)(F)F)c(OC)c1

Procedure:
This compound was prepared from Compound 83 in the same manner of Compound 45.
Reaction SMILES: [BH4-].[Na+].O[CH:4]([C@H:9]1[C:11]([CH3:13])([CH3:12])[C@H:10]1[C:14]([OH:16])=[O:15])[C:5]([Cl:8])([Cl:7])Cl.Cl>CN(C)C=O.O>[Cl:8][CH:5]([Cl:7])[CH:4]1[CH:9]2[CH:10]([C:11]2([CH3:12])[CH3:13])[C:14](=[O:15])[O:16]1
Reactant: CC1(C)[C@H](C(O)C(Cl)(Cl)Cl)[C@@H]1C(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C2C(=O)OC(C(Cl)Cl)C21
Temperature: 80 °C
Yield: 25 %

Procedure:
Sodium borohydride (0.12 mmol) was added to a solution of cis 2-(1-hydroxy-2,2,2-trichloroethyl)-3,3-dimethylcyclopropane carboxylic acid (0.12 mol) in dry dimethylformamide (0.4 ml), and the mixture was heated for 30 minutes at 80° C. An additional amount of 0.12 mmol sodium borohydride was then added and the mixture was heated for a further 15 minutes at 80° C. It was then diluted with water, acidified with concentrated HCl and extracted with deuterochloroform, CDCl3. The extract was washed with water and analysed by NMR, which showed a yield of 25% of the desired product, with 30% of unconverted starting material.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)(=[O:30])=[O:29])[CH2:23][CH2:22]3)[CH2:15][CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)#[N:2].C([O-])([O-])=[O:38].[K+].[K+].OO.O>CS(C)=O>[NH2:2][C:1]([C:3]1[CH:4]=[C:5]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)(=[O:30])=[O:29])[CH2:23][CH2:22]3)[CH2:17][CH2:18]2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)=[O:38]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(N2CCN(CC[C@H]3CC[C@H](NS(=O)(=O)c4cccnc4)CC3)CC2)cc(C(F)(F)F)c1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cc(N2CCN(CC[C@H]3CC[C@H](NS(=O)(=O)c4cccnc4)CC3)CC2)cc(C(F)(F)F)c1

Procedure:
0.37 g (0.7 mmol) of trans-N-(4-{2-[4-(3-cyano-5-trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-pyridine-3-sulfonamide was dissolved in 2 ml dimethylsulfoxide, 80 mg K2CO3 was added and 0.15 ml of 30% H2O2 was dropped in while keeping the temperature at 20° C. After stirring for 2 h 20 ml of water was added, the precipitate filtered, washed with water giving the title compound, melting point:191° C. (0.2 g; 53%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([OH:18])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.C1C(=O)N([Br:26])C(=O)C1.O>C(#N)C>[Br:26][C:14]1[C:15]2[C:10](=[CH:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)=[CH:17][CH:16]=2)[CH:11]=[CH:12][C:13]=1[OH:18]
Reactant: Oc1ccc(-c2ccc3cc(O)ccc3c2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: Oc1ccc(-c2ccc3c(Br)c(O)ccc3c2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
To a solution of 6-(4-hydroxyphenyl)-2-naphthol (4.02 g, 17.0 mmol) in acetonitrile (150 mL) at 0° C. was added NBS (3.03 g, 17.0 mmol). The reaction was stirred at 0° C. for 3 hr and then poured into water (200 mL) and extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with water, dried over sodium sulfate, filtered, evaporation of the solvent, and purification by silica column chromatography (20% ethyl acetate—hexanes) yielded 5.33 g (100%) of the title compound as a tan solid. The title compound was further purified by reverse phase HPLC to yield a white solid: mp 208-210° C.; 1H NMR (DMSO-d6): δ 6.89 (2H, d, J=8.47 Hz), 7.28 (1H, d, J=8.80 Hz), 7.63 (2H, d, J=8.50 Hz), 7.85 (2H, d, J=8.84 Hz), 8.02-8.06 (2H, m), 9.60 (1H, s), 10.54 (1H, s); MS (ESI) m/z 313/315 (M−H)−.
Reaction SMILES: C([Li])CCC.[I-].[CH:7]([P+:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])[CH3:8]>CCCCCC.O1CCCC1>[C:23]1([P:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:7]([CH3:9])[CH3:8])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A solution of n-butyllithium in hexane was added to a suspension of isopropyltriphenylphosphonium iodide in tetrahydrofuran to obtain a solution of 12.5×10-3M of triphenylisopropylidene phosphorane in tetrahydrofuran and 20 ml of the solution were added to a solution of 1.35 g of the product of Step B in 25 ml of tetrahydrofuran. After stirring at 0° C. for one hour and then at room temperature for one hour, the mixture was diluted with 10 ml of water and was extracted with ether. The extract was dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica to obtain the expected product in a 50 to 60% yield which after crystallization from cyclohexane had a specific rotation of [α]D =-55.5° (c=20.25 in CHCl3).
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([N:17]([C:28](=[O:39])[CH2:29][CH2:30][C@H:31]([NH2:38])[CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:18][CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:40]([C:43]1[C:44]([CH:56]=O)=[CH:45][C:46]([O:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[N:47][CH:48]=1)([O-:42])=[O:41].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl.CCOC(C)=O>[CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([N:17]([CH2:18][CH2:19][O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:28](=[O:39])[CH2:29][CH2:30][C@H:31]([NH:38][CH2:56][C:44]2[C:43]([N+:40]([O-:42])=[O:41])=[CH:48][N:47]=[C:46]([O:49][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH:45]=2)[CH:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]
Reactant: N[C@@H](CCC(=O)N(CCOCc1ccccc1)[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1)C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C(CC[C@H](NCc1cc(Oc2ccccc2)ncc1[N+](=O)[O-])C1CCOCC1)N(CCOCc1ccccc1)[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-[[4-amino-4-(S)-(tetrahydro-pyran-4-yl)-butyryl]-(2-benzyloxy-ethyl)-amino]-cis-cyclohexanecarboxylic acid benzyl ester (1.9 g, 3.5 mmol) and 5-nitro-2-phenoxy-pyridine-4-carboxaldehyde (0.86 g, 3.53 mmol) in 1,2 dichloroethane (100 mL) was stirred at room temperature for 4 hours, and then NaBH(OAc)3 (1.4 g, 6.6 mmol) was added. The resulting mixture was stirred at room temperature overnight. Then 1N NaOH was added, and the reaction mixture was then poured into EtOAc (200 mL). The organic layer washed with aq. NaCl, dried with MgSO4, filtered, and evaporated to yield a residue. The residue was purified by column chromatography (1:1 heptane/EtOAc) to yield 4-{(2-benzyloxy-ethyl)-[4-[(5-nitro-2-phenoxy-pyridin-4-ylmethyl)-amino]-4-(S)-(tetrahydro-pyran-4-yl)-butyryl]-amino}-cis-cyclohexanecarboxylic acid benzyl ester as an oil.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH3:10][C:11]1[CH:18]=[C:17]([C:19]2[S:20][C:21]3[C:26]([N:27]=2)=[CH:25][CH:24]=[C:23]([C:28]2([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:30][CH2:29]2)[N:22]=3)[CH:16]=[CH:15][C:12]=1[C:13]#N.C(C(C(C([O-])=O)O)O)([O-])=[O:38]>C(Cl)Cl>[CH3:10][C:11]1[CH:18]=[C:17]([C:19]2[S:20][C:21]3[C:26]([N:27]=2)=[CH:25][CH:24]=[C:23]([C:28]2([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:30][CH2:29]2)[N:22]=3)[CH:16]=[CH:15][C:12]=1[CH:13]=[O:38]
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Reactant: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)ccc1C#N
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)ccc1C=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
DIBAL-H (1.0M in hexanes; 0.132 mL, 0.132 mmol) was added to a solution of 2-methyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzonitrile (44.2 mg, 0.120 mmol) in CH2Cl2 (2.0 mL) at 25° C., and the resulting solution was stirred at 25° C. for 45 min. Saturated aqueous Na/K tartrate solution (2.0 mL) was then added, and the resulting mixture was stirred for 15 min, then partitioned between CH2Cl2 (20 mL) and water (10 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 15% EtOAc/hexanes) provided 2-methyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzaldehyde as a light yellow solid. MS (ESI) m/z: Calculated: 370.1; Observed: 371.2 (M++1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:40]=[C:39]([CH2:41]Cl)[CH:38]=[C:37]([CH3:43])[N:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:34][C:35]1[CH:40]=[C:39]([CH2:41][N:32]2[CH:31]=[CH:30][N:29]=[C:28]2[CH:8]([NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9][C:10]2[CH:18]=[C:17]([CH3:19])[C:16]3[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=3)[CH:11]=2)[CH:38]=[C:37]([CH3:43])[N:36]=1
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: Cc1cc(CCl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(Cn2ccnc2C(Cc2cc(C)c3nn(COCC[Si](C)(C)C)cc3c2)NC(=O)OC(C)(C)C)cc(Cl)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl-1-(1H-imidazol-2-yl)-2-(7-methyl-2-[{2-[trimethylsilyl]ethoxy}methyl]-2H-indazol-5-yl)ethylcarbamate (0.1 g, 0.212 mmol), 2-chloro-4-(chloromethyl)-6-methylpyridine (39.0 mg, 0.222 mmol, 1.05 equiv), and cesium carbonate (0.21 g, 0.64 mmol) were combined in dimethylformamide (2.0 mL). After stirring at room temperature for 16 h, the solvents were removed and the residue purified by column chromatography to afford 0.1 g (77%). Mass spec.: 611.21 (MH)+.
Reaction SMILES: [Br:1]Br.[C:3]([N:7]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[NH:10][C:9](=[O:19])[CH2:8]1)([CH3:6])([CH3:5])[CH3:4].C([O-])(=O)C.[Na+].C(OCC)(=O)C>C(O)(=O)C>[Br:1][C:16]1[CH:17]=[CH:18][C:11]2[NH:10][C:9](=[O:19])[CH2:8][N:7]([C:3]([CH3:6])([CH3:4])[CH3:5])[C:13](=[O:14])[C:12]=2[CH:15]=1
Reactant: BrBr
Reactant: CC(C)(C)N1CC(=O)Nc2ccccc2C1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)N1CC(=O)Nc2ccc(Br)cc2C1=O
Temperature: 25 °C
Reaction time: 29 h
Yield: 64.3 %

Procedure:
Bromine (1.72 g, 10.8 mmol) is added to a mixture of 4-tert-butyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (1.0 g, 4.3 mmol) and sodium acetate (0.39 g, 4.8 mmol) in acetic acid. The reaction mixture is stirred at room temperature for 29 hours, concentrated in vacuo, diluted with ethyl acetate, washed sequentially with 0.1N sodium hydroxide solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue. Chromatography of the residue using silica gel and 20% to 25% ethyl acetate in hexanes solutions gives the title product as a white solid (0.86 g, mp 205°-208° C.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([N:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10]2)=[O:8])[CH2:3][CH2:2]1.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:27]([C:23]1[CH:22]=[C:21]([CH2:20][N:1]2[CH2:6][CH2:5][CH:4]([C:7]([N:9]3[CH2:18][CH2:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH2:10]3)=[O:8])[CH2:3][CH2:2]2)[CH:26]=[CH:25][CH:24]=1)([O-:29])=[O:28]
Reactant: O=C(C1CCNCC1)N1CCc2ccccc2C1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(C1CCN(Cc2cccc([N+](=O)[O-])c2)CC1)N1CCc2ccccc2C1
Reaction time: 15 h
Yield: 119.8 %

Procedure:
A mixture of 7 g (28.6 mmol) of 2-[(4-piperidyl)carbonyl]-1,2,3,4-tetrahydroisoquinoline, 6.8 g (31.5 mmol) of α-bromo-3-nitrotoluene and 6 g (43 mmol) of potassium carbonate in 140 ml of acetone is stirred for 15 h. The solvent is evaporated off, water and dichloromethane are added and the organic phase is separated off, neutralized, dried and evaporated. 13 g of a yellow oil are obtained, and this is purified by chromatography on a silica column, eluting with a 98:2 dichloromethane/methanol mixture. After recrystallization in ether, 9.6 g of product are obtained, this being used without further purification in the following stage.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[N:4]=[C:5]2[C:14]3[C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19](OC)=[O:20])=[CH:12][C:11]([O:23][CH3:24])=[CH:10][C:9]=3[NH:8][C:7](=[O:25])[C:6]=12.[NH3:33]>CO>[NH2:1][C:2]1[N:3]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[N:4]=[C:5]2[C:14]3[C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]([NH2:33])=[O:20])=[CH:12][C:11]([O:23][CH3:24])=[CH:10][C:9]=3[NH:8][C:7](=[O:25])[C:6]=12
Reactant: COC(=O)CCCOc1cc(OC)cc2[nH]c(=O)c3c(N)n(-c4ccccc4C)nc3c12
Reactant: N
Solvent: CO
Product: COc1cc(OCCCC(N)=O)c2c(c1)[nH]c(=O)c1c(N)n(-c3ccccc3C)nc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of methyl 4-{[3-amino-7-methoxy-2-(2-methylphenyl)-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-9-yl]oxy}butanoate (60 mg) and 2N solution of ammonia in methanol was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified with column chromatography to obtain the target compound (37 mg).
Reaction SMILES: [H-].[Na+].[OH:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.I[CH3:18].O>CN(C=O)C>[CH3:18][O:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCN(O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.2 %

Procedure:
A 57% oil dispersion containing 0.6 g (0.025 mole) NaH was added in one portion to a solution of 4.7 g (0.023 mole) 1-hydroxy-4-(1,1-dimethylethoxycarbonyl)piperazine in 100 ml DMF under a dry N2 atmosphere. The mixture was stirred for 2 hours at room temperature and then 6.5 g (0.046 mole) iodomethane was added over 1 minute. After stirring for an additional 15 minutes, the mixture was poured into 100 ml H2O, stirred briefly, and extracted thoroughly with low boiling (35°-65° C.) petroleum ether. The extracts were dried (MgSO4), filtered and evaporated in vacuo to give 1.8 g of an oil. The oil was dissolved in ethyl ether, washed with dilute aqueous HCl, dried (MgSO4), filtered, and evaporated in vacuo to yield 1.3 g yellow oil. Short path distillation (Kugelrohr) returned 0.8 g colorless distillate, b.p.* 55°-65° C./0.15 mm. Calc. for C10H 20 N2O3 (216.28): C, 55.53; H, 9.32; N, 12.95; O, 22.19. Found: C, 55.61; H, 9.13; N, 12.96; O, 22.33.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][N:13]=[CH:12]2)=[CH:7][N:6]=1)(=[O:4])=[O:3].[Cl:22]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.O1CCCC1>[Cl:22][C:14]1[N:13]=[CH:12][N:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6][CH:7]=2)[C:15]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CS(=O)(=O)c1ccc(-n2cncc2-c2ccccc2)cn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-n2cnc(Cl)c2-c2ccccc2)cn1
Yield: 60.7 %

Procedure:
2-(methylsulfonyl)-5-(5-phenyl-1H-imidazol-1-yl)pyridine (83 mg, 0.28 mmol), N-chlorosuccinimide (39 mg, 0.29 mmol), azobisisobutyronitrile (2 mg) and tetrahydrofuran (10 mL) were added into a 25 mL round bottom flask, and stirred to conduct reflux reaction for 18 hours. After the reaction, the solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate=20:1) to yield white solid target compound (56 mg, 0.17 mmol). 1H-NMR (300 MHz, CDCl3): δ 3.26 (3H, s), 7.19-7.22 (2H, m), 7.38-7.40 (3H, m), 7.66 (1H, dd), 7.71 (1H, s), 8.11 (1H, dd), 8.58 (1H, dd); LC-MS m/z: 335 [M++1]; purity (HPLC)>95%.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[OH:9].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:1][CH2:2][C@H:3]2[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]2[OH:9])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1CCCC[C@@H]1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCC[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of (1S,2R)-2-(hydroxymethyl)cyclohexanol (0.44 g, 3.85 mmol) and N,N-dimethylaminopyridine (DMAP) (0.485 g, 3.97 mmol) in anhydrous CH2Cl2 (10 mL) was added a solution of p-toluenesulfonyl chloride (0.767 g, 4.02 mmol) in anhydrous CH2Cl2 (5 mL) under argon at room temperature. The reaction mixture was stirred at room temperature for 22 hrs and triethylamine (0.5 mL) was added. The mixture was stirred for additional 100 min, concentrated under reduced pressure, water was added and the product was extracted with EtOAc twice. Combined organic layers were washed with brine, concentrated under reduced pressure and purified by flash chromatography (20% to 70% EtOAc/hexanes gradient) to give ((1R,2S)-2-hydroxycyclohexyl)methyl 4-methylbenzenesulfonate as a colorless oil. Yield (0.732 g, 71%). 1H NMR (400 MHz, DMSO-d6) δ 7.72-7.76 (m, 2H), 7.42-7.47 (m, 2H), 4.60 (d, J=5.5 Hz, 1H), 4.12 (dd, J=3.1, 9.2 Hz, 1H), 3.90 (dd, J=7.2, 9.2 Hz, 1H), 3.00-3.10 (m, 1H), 2.40 (s, 3H), 1.73-1.80 (m, 1H), 1.46-1.65 (m, 3H), 1.34-1.42 (m, 1H), 0.85-1.16 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7](=O)[CH3:8].C(O)C.Cl.[NH2:17][OH:18]>O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7](=[N:17][OH:18])[CH3:8]
Reactant: CC(=O)COc1cccc(C)c1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(COc1cccc(C)c1)=NO

Procedure:
1-(3-Methylphenoxy)propan-2-one (24.9 g.) and ethanol (100 ml.) were added to a solution of hydroxylamine hydrochloride (25 g.) and fused sodium acetate (25 g.) in water (110 ml.). The resulting solution was refluxed for 31/2 hours and evaporated to near dryness under reduced pressure. The residue was partitioned between water and ether. The ether extract was washed with water, dried over anhydrous potassium carbonate and evaporated. The residue was distilled to give a fraction, b.p. 159°-163°/12 mm. Redistillation gave 1-(3-methylphenoxy)propan-2-one oxime, b.p. 165°-167°/13 mm.