Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[C:11]([NH2:21])=[CH:10][N:9]=2)[CH:4]=[N:3]1.S(=O)(=O)(O)O.[N:27]([O-])=O.[Na+]>O>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:9]=[CH:10][C:11]3[N:21]=[N:27][N:14]([C:15]4[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=4)[C:12]=3[N:13]=2)[CH:4]=[N:3]1
Reactant: O=N[O-]
Reactant: Cn1cc(Nc2ncc(N)c(Nc3cnn(C)c3)n2)cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cn1cc(Nc2ncc3nnn(-c4cnn(C)c4)c3n2)cn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 80 mg (0.28 mmol) N2,N4-bis-(1-methyl-1H-pyrazol-4-yl)-pyrimidine-2,4,5-triamine in 23 ml water is treated with 4 ml concentrated sulfuric acid and then with 39 mg (0.56 mmol) sodium nitrite. The reaction mixture is stirred for 90 minutes at room temperature. The reaction mixture is partitioned between water and dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with methanol/dichloromethane as eluent giving “A21” as off-white crystals; HPLC/MS (A) 1.42 min, [M+H] 297;
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH:9]1[CH:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1.C(OCC)C>ClCCl>[C:1]([NH:8][CH:9]1[CH:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: NC1CN(C(=O)OCc2ccccc2)CC1O
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)NC1CN(C(=O)OCc2ccccc2)CC1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
3.24 g acetic anhydride was added to 7.1 g benzyl 3-amino-4-hydroxypyrrolidine-1-carboxylate in 100 mL dichlormethane at 0-5° C. The mixture was stirred 2 h at RT, 100 mL diethylether was added and the mixture was stirred for 15 min. The precipitate was filtered to give 7.6 g of the desired product.
Reaction SMILES: [CH:1]([N:4]([CH3:24])[C:5]1[C:6]([C:19]2[CH:20]=[N:21][NH:22][CH:23]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].O.[OH-].[Li+]>CO.O>[CH:1]([N:4]([CH3:24])[C:5]1[C:6]([C:19]2[CH:20]=[N:21][NH:22][CH:23]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3cn[nH]c3)c(N(C)C(C)C)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cn[nH]c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-2-(1H-pyrazol-4-yl)quinoxaline-6-carboxylate (130.0 mg, 0.40 mmol,) in methanol (20 mL) and water (1 mL) was added lithium hydroxide hydrate (50.0 mg, 1.12 mmol). The resulting solution was stirred overnight at room temperature and then concentrated under vacuum. The residue was diluted with water (10 mL) and adjusted to pH 5 with citric acid (1N). The product were collected by filtration to afford 3-(isopropyl(methyl)amino)-2-(1H-pyrazol-4-yl)quinoxaline-6-carboxylic acid as yellow solid (64.7 mg, 52%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][S:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>C(#N)C>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:13]2[CH2:18][CH2:17][S:16][CH2:15][CH2:14]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: C1CSCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCSCC2)ccc1[N+](=O)[O-]
Temperature: 85 °C

Procedure:
In a 50 mL round-bottomed flask was charged 4-fluoro-2-methoxy-1-nitrobenzene (1.05 g, 6.14 mmol), thiomorpholine (1.164 ml, 12.27 mmol), and Hunig's Base (1.072 ml, 6.14 mmol) in acetonitrile (20.45 ml). The reaction was heated at 85° C. for three days. The mixture was concentrated and the residue was placed on a silica gel column. The product was eluted from the column with dichloromethane to give the title compound. MS (DCI(+)) m/e 255.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[C:10](=[CH:15]N(C)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)O.[NH2:23][C:24]([NH2:26])=[NH:25].O.O.O.C([O-])(=O)C.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:25]=[C:24]([NH2:26])[N:23]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N=C(N)N
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: CC(=O)[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2nc(N)ncc2C1
Yield: 54.5 %

Procedure:
A solution of 1-t-Butoxycarbonyl-3-(dimethylamino)methylene-4-piperidone (7.64 g, 30.04 mmol) in methanol (190 mL) was treated with guanidine carbonate (21.65 g, 120.16 mmol), followed by sodium acetate trihydrate (32.70 g, 240.32 mmol). The reaction mixture was heated at reflux for 17 hours and the solvent was removed in vacuo. The residue was diluted with water and the mixture was swirled for a few minutes. The undissolved white solid was collected and washed with water, followed by a small amount of cold ethyl acetate to give the title compound (4.10 g, 55%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[O:12][C:13]3[C:18]([C:19](=O)[CH:20]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:2]=1.Cl.[C:23]([O:27][NH2:28])([CH3:26])([CH3:25])[CH3:24]>CO>[C:23]([O:27][N:28]=[C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12][C:11]([C:3]2[N:2]=[CH:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:20]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=c1cc(-c2cc3ccccc3cn2)oc2ccccc12
Reactant: CC(C)(C)ON
Agent: Cl
Solvent: CO
Product: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccccc12
Temperature: 130 °C
Yield: 67.3 %

Procedure:
To a suspension of 2-isoquinolin-3-yl-chromen-4-one (459 mg, 1.67 mmol) in methanol (11 ml) was added O-tert-butyl hydroxylamine hydrochloride (421 mg, 3.35 mml). The mixture was heated to 130° C. under microwave irradiation for 30 min. The volatiles were removed by vacuum distillation and the residue was purified by flash chromatography (cyclohexane/ethyl acetate 95/5) to yield 2-isoquinolin-3-yl-chromen-4-one O-tert-butyl-oxime (387 mg, 67%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[CH:4]=[CH:5][C:6]=1[CH:7]=[O:8].[Br:18]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:18][C:4]1[N:3]([S:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:11])[C:2]([CH3:1])=[C:6]([CH:7]=[O:8])[CH:5]=1
Reactant: Cc1c(C=O)ccn1S(=O)(=O)c1cccnc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C=O)cc(Br)n1S(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
To a solution of 2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (974 mg) in N,N-dimethylformamide (10 mL) was added N-bromosuccinimide (1.17 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give the title compound as white crystals (yield 675 mg, 53%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:19][C:20]([O:23][C:24]([NH:26][C@H:27]([C:34](O)=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])([CH3:22])[CH3:21].Cl.CN(C)CCCN=C=NCC>ClCCl>[C:20]([O:23][C:24](=[O:25])[NH:26][C@H:27]([C:34](=[O:35])[N:9]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:22])([CH3:19])[CH3:21]
Reactant: Cc1ccc(CCNc2ccc(C)c(C)c2)nc1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(CCN(C(=O)[C@@H](NC(=O)OC(C)(C)C)c2ccccc2)c2ccc(C)c(C)c2)nc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
To a 0° C. solution of 35 mg (0.15 mmol) (3,4-dimethyl-phenyl)-[2-(5-methyl-pyridin-2-yl)-ethyl]-amine and 40.4 mg (0.16 mmol) Boc-L-alpha-phenylglycine in 540 uL dichloromethane under argon, was added 31.4 mg (0.16 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The mixture was stirred at 0° C. for 3 hours then at ambient temperature overnight. The solution was washed once with a sat. NaHCO3 solution (3 mL) and once with water (3 mL). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was purified with flash column chromatography on silica eluting with a gradient formed from heptane and ethylacetate to provide 0.052 g (75%) of the title compound as an oil. MS (m/e): 474.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:14]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)[CH2:21][CH2:22]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: c1cncc(CN2CCNCC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 5-bromo-4-chloro-3-nitro-pyridin-2-ylamine (0.126 g, 0.50 mmol) and isopropanol (9 ml) was added 1-[(3-pyridyl)-methyl]-piperazine (0.097 g, 0.55 mmol) followed by diisopropylethylamine (0.10 ml, 0.57 mmol). The reaction mixture was heated at 45° C. for 18 h, then allowed to cool to room temperature. The precipitate was collected by filtration and washed with isopropanol and diethyl ether. The title compound was thus obtained as a yellow solid (0.160 g, 82%); 1H-NMR (500 MHz, DMSO-d6) 3.05 (br s, 4H, piperazine N(CH2)2), 3.56 (s, 2H, NCH2), 7.02 (s, 2H, NH2), 7.36 (dd, J=7.80, 4.75 Hz, 1H, pyridyl 5-H), 7.74 (dt, J=7.80, 1.70 Hz, 1H, pyridyl 4-H), 8.16 (s, 1H, 6-H), 8.47 (dd, J=4.75, 1.60 Hz, 1H, pyridyl 6-H), 8.50 (d, J=1.65 Hz, 1H, pyridyl 2-H);
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:31]O.Cl>CO.O>[CH3:27][S:24]([C:21]1[CH:22]=[CH:23][C:18]([C@H:10]2[CH2:9][C@H:8]([C:6]3[O:7][NH:31][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])=[CH:19][CH:20]=1)(=[O:26])=[O:25]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccc(S(C)(=O)=O)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(S(C)(=O)=O)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 64.3 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(methylsulfonyl)phenyl)piperidine-1-carboxylate (505 mg, 1.23 mmol) (from example 38, step 1) was suspended in MeOH (5 mL) and cooled to −40° C. 3.8 M sodium hydroxide (0.323 mL, 1.23 mmol) in water was added. After 20 min, hydroxylamine (50% in water, 0.075 mL, 1.23 mmol) was added and stirring continued at −40° C. for 3 h. The reaction mixture was then added to a prewarmed 80° C. solution of 6 M hydrogen chloride (6.14 mL, 36.82 mmol) and stirred for 20 min. The solvent was evaporated in vacuo. DCM (50 mL) and water (50 mL) were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated in vacuo. The residue was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 15-40% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer, over 25 minutes with a flow of 19 mL/min. Trans-methyl 2-(4-(methylsulfonyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (301 mg, 64.5%) was isolated. 1H NMR (600 MHz, cdcl3) δ 1.61-1.73 (m, 1H), 1.91-1.99 (m, 1H), 2.05-2.14 (m, 1H), 2.66-2.82 (m, 2H), 2.91 (t, 1H), 3.05 (s, 3H), 3.77 (s, 3H), 4.12-4.46 (m, 1H), 5.60-5.80 (m, 2H), 7.44 (d, 2H), 7.95 (d, 2H). MS m/z 381 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[C:12]([OH:22])[C:13]([N+:19]([O-:21])=[O:20])=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:23][O:24][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br>>[CH3:23][O:24][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:22][C:12]1[C:13]([N+:19]([O-:21])=[O:20])=[CH:14][C:15]([N+:16]([O-:18])=[O:17])=[C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)[CH:11]=1
Reactant: COC(=O)CCCCCBr
Reactant: Cc1ccc(Nc2cc(O)c([N+](=O)[O-])cc2[N+](=O)[O-])cc1C
Product: COC(=O)CCCCCOc1cc(Nc2ccc(C)c(C)c2)c([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
5 g of 3-[(3,4-dimethylphenyl)amino]-4,6-dinitrophenol was O-alkylated with 6-bromohexanoic acid methyl ester at 70° C. analogously to general operating instructions 8.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.[F-].[K+].[CH2:29]([N:32]=[C:33]=[O:34])[CH:30]=[CH2:31].O>C1C=CC=CC=1>[CH2:29]([NH:32][C:33]([N:12]1[C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][C:4]=3[C:5]=2[N:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([C:22]#[N:23])([CH3:24])[CH3:25])=[CH:17][CH:16]=2)[C:13]1=[O:26])=[O:34])[CH:30]=[CH2:31]
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: C=CCN=C=O
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: C=CCNC(=O)n1c(=O)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(Br)ccc3ncc21

Procedure:
To a suspension of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 0.040 g, 0.10 mmol) and potassium fluoride (0.009 g, 0.147 mmol) in dry benzene (6 ml) was added allylisocyanate (0.010 g, 0.10 mmol) at RT. The reaction was stirred at reflux temperature for 6 hours. The reaction mixture was cooled and poured into cold water, extracted with ethyl acetate (2×20 ml). Organic layer was washed with water dried over sodium sulfate and concentrated. The crude product was triturated with ethyl acetate, filtered and filtrate was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 0.020 g (41%); 1H NMR (DMSO-d6, 300 MHz): δ 9.653 (s, 1H), 8.723-8.761 (t, 1H), 7.971-8.001 (d, 1H, J=9 Hz), 7.874-7.903 (d, 2H, J=8.7 Hz), 7.769-7.798 (d, 2H, J=8.7 Hz), 7.723-7.761 (dd, 1H, J=9, 2.1 Hz), 6.808-6.814 (d, 1H, J=1.8 Hz), 5.904-5.996 (m, 1H), 5.234-5.296 (dd, 1H, J=17.1, 1.2 Hz), 5.134-5.173 (dd, 1H, J=10.5, 1.2 Hz), 4.010-4.045 (t, 2H), 1.806 (s, 6H); MS: m/z 492 (M+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22](=O)[CH3:23])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.Cl.[NH2:26][O:27][CH2:28][CH2:29][OH:30].C(N(CC)CC)C>CO>[OH:30][CH2:29][CH2:28][O:27]/[N:26]=[C:22](/[C:19]1[CH:20]=[CH:21][C:16]2[N:17]([C:13]([CH2:12][C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][C:2]=3[F:1])[N:8]([CH3:11])[N:7]=[CH:6]4)=[CH:14][N:15]=2)[N:18]=1)\[CH3:23]
Reactant: NOCCO
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cnn(C)c4cc3F)n2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C/C(=N\OCCO)c1ccc2ncc(Cc3cc4cnn(C)c4cc3F)n2n1
Temperature: 30 °C
Reaction time: 20 h
Yield: 72.5 %

Procedure:
To a solution of 1-(3-((6-fluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (50 mg, 0.155 mmol) in methanol (7 mL) was added 2-(aminooxy)ethanol hydrochloride (17.6 mg, 0.155 mmol). Triethyl amine was added dropwise to adjust the pH to 5-6. The reaction mixture was stirred at 30° C. for 20 h. The solvent was removed in vacuo and the residue was dissolved in DCM, washed with NaHCO3 (aq) and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the crude product which was purified by column chromatography to afford 43 mg (70%) of the title compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.05 (d, 1H), 7.97 (s, 1H), 7.70 (d, 1H), 7.63 (d, 1H), 7.62 (s, 1H), 7.53 (d, 1H), 4.75 (t, 1H), 4.43 (s, 1H), 4.23 (t, 2H), 3.97 (s, 3H), 3.68 (q, 2H), 2.28 (s, 3H). LCMS (method B): [MH]+=383, tR=2.45 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.S1C=CC=C1[Li].[C:19](OCC)(=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1COCC1.CCCCCC>[CH2:23]([O:22][C:20](=[O:21])[C:19]([C:5]1[S:4][C:3]([O:2][CH3:1])=[CH:7][CH:6]=1)=[O:25])[CH3:24]
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1cccs1
Agent: [Li]CCCC
Agent: [Li]c1cccs1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1ccc(OC)s1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-Methoxythiophene (15.4 g) is dissolved in 100 ml anhydrous THF and butyl lithium (0.135 moles) in hexane is added dropwise. The solution is stirred at room temperature 15 hr and then heated at reflux for 1 hr. After cooling, the clear solution is transferred to a dropping funnel by means of a siphon. The solution of thienyl lithium is added dropwise to a solution of diethyl oxalate (19.7 g) in 150 ml THF at -78° C. After stirring 2 hr at -78° C, the mixture is brought to -10° C and treated with saturated NH4C1 solution. The aqueous fraction is separated and extracted several times with ether. The combined ether extracts are washed with water and brine, dried (MgSO4) and concentrated. Chromatography on silica gel (eluant = benzene) gives 5-methoxy-2-thiopheneglyoxylic acid ethyl ester (2; X1 = CH3O, X2 and X3 = H and R10 = C 2 H5); mp 136 -137° C after recrystallization from benzene-hexane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ncc(Br)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
To a solution of 5-bromo-2-(methyloxy)-3-nitropyridine (45 g, 193 mmol) in ethyl acetate (1 L) was added tin(II) chloride dihydrate (174 g, 772 mmol). The reaction mixture was heated at reflux for 4 h. LC/MS indicated some starting material remained, so added 20 mol % tin (II) chloride dihydrate and continued to heat at reflux. After 2 h, the reaction was allowed to cool to ambient temperature and concentrated in vacuo. The residue was treated with 2 N sodium hydroxide and the mixture stirred for 1 h. The mixture was then with methylene chloride (1 L), filtered through Celite, and washed with methylene chloride (500 mL). The layers were separated and the organics dried over magnesium sulfate and concentrated to give 5-bromo-2-(methyloxy)-3-pyridinamine (23 g, 113 mmol, 58.7% yield). The product was used crude in subsequent reactions. MS (ES)+ m/e 201.9, 203.9 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(C)C=CC=CC=1>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:15]=[CH:16][C:2]([C:24]#[C:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:3][CH:4]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: C#Cc1ccccc1
Reactant: O=C(c1ccc(F)cc1)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(c1ccc(F)cc1)c1ccc(C#Cc2ccccc2)cc1
Temperature: 70 °C

Procedure:
In an inert atmosphere glovebox, 4-bromo-4′-fluorobenzophenone (10 g, 35.8 mmol), PdCl2(PPh3)2 (250 mg), CuI (680 mg), phenylacetylene (4.02 g, 1.1 eq), triethylamine (3.6 g, 1 eq), and toluene (25 mL) were combined. The flask was closed and heated to 70° C. for 24 h. The mixture was poured over ice and extracted with methylene chloride, which was separated and evaporated. The residue was recrystallized twice from hot ethanol using decolorizing charcoal to give the title product as white crystals.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1>CC(C)=O.O>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:1]=[N+:2]=[N-:3])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
Sodium azide (2.7 g, 42 mmol) was added to a cold (0-4° C.) stirred solution of (4-methyl-benzenesulfonyl chloride (8 g, 42 mmol) in acetone:water (1:1, 240 mL) and continued stirring at 0° C. for 2 hr. Concentrated the reaction mixture to get the residue. The residue was extracted with diethyl ether and the organic phase was dried Na2SO4 and concentrated under reduced pressure to afford 7.3 g (88.2% yield) of 4-methyl-benzenesulfonyl azide.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([CH2:14]O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH2:1]([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([CH2:14][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CN(Cc2ccccc2)CC1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CC1CN(Cc2ccccc2)CC1O
Yield: 93.9 %

Procedure:
1-Benzyl-3-hydroxymethyl-4-hydroxypyrrolidine (66.2 g) and triethylamine (38.8 g) are added to dry dichloromethane (700 ml) and the mixture is cooled till a temperature of from -5° to -10° C. At this temperature, methanesulfonyl chloride (36.6 g) is added dropwise to the mixture with stirring. After the addition, the mixture is stirred for 30 minutes, and then washed with an aqueous sodium hydrogen carbonate and subsequently with water. Thereafter, the dichloromethane layer is separated, dried and concentrated to give 1-benzyl-4-hydroxy-3-methanesulfonylmethylpyrrolidine (80.8 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:10][CH3:11])[C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].[Cl:12][C:13]1[C:14]([CH3:23])=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>>[Cl:12][C:13]1[C:14]([CH3:23])=[C:15]([S:19]([NH:9][C:5]2[C:4]([O:10][CH3:11])=[N:3][C:2]([Cl:1])=[C:7]([Cl:8])[N:6]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: COc1nc(Cl)c(Cl)nc1N
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: COc1nc(Cl)c(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1C

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5,6-dichloro-3-methoxy-2-pyrazinamine (0.1 g) and 3-chloro-2-methylbenzenesulphonyl chloride (0.14 g). Yield 0.13 g.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[C:15]([NH:18][NH2:19])(=O)[CH3:16]>C(O)CCC>[CH3:16][C:15]1[N:3]2[N:4]=[C:5]([C:8]3[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=3)[CH:6]=[CH:7][C:2]2=[N:19][N:18]=1
Reactant: CC(=O)NN
Reactant: Cc1cccc(-c2ccc(Cl)nn2)c1
Solvent: CCCCO
Product: Cc1cccc(-c2ccc3nnc(C)n3n2)c1

Procedure:
As in Example 36, a mixture of 6.0 g. of 3-chloro-6-(m-tolyl)pyridazine and 4.34 g of acetylhydrazine in 100 ml. of n-butanol is refluxed for 48 hr. to give 2.0 g. of cream colored crystals, m.p. 160°-162° C.