Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:17][CH:18]=[CH2:19])[C:9](=[O:16])[N:10]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]2=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:29][C:28]=1B1OC(C)(C)C(C)(C)O1>C(P([Pd]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C.CN1C(=O)CCC1>[CH3:13][C:12]([CH3:15])([CH3:14])[CH2:11][N:10]1[C:5]2[C:6](=[N:7][C:2]([C:32]3[CH:31]=[C:30]([C:33]([OH:36])([CH3:34])[CH3:35])[CH:29]=[CH:28][C:27]=3[CH3:26])=[CH:3][CH:4]=2)[N:8]([CH2:17][CH:18]=[CH2:19])[C:9]1=[O:16]
Reactant: Cc1ccc(C(C)(C)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: C=CCn1c(=O)n(CC(C)(C)C)c2ccc(Cl)nc21
Agent: CC(C)(C)[PH]([Pd][PH](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: C=CCn1c(=O)n(CC(C)(C)C)c2ccc(-c3cc(C(C)(C)O)ccc3C)nc21
Temperature: 100 °C

Procedure:
5-Chloro-1-(2,2-dimethylpropyl)-3-(prop-2-en-1-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (71-5, 100 mg, 0.36 mmol, 1.0 equiv), Cs2CO3 (1.17 g, 3.57 mmol, 10.0 equiv), 2-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-ol (225 mg, 0.82 mmol, 2.3 equiv), and bis(tri-t-butyl-phosphino)palladium (18.3 mg, 0.04 mmol, 0.1 equiv) were added to anhydrous NMP (4 mL). The resulting suspension was warmed to 100° C. for 20 min in a microwave emitter. Following this duration, the reaction contents were filtered through Celite® and washed with EtOAc (5 mL). The filtrate was then diluted with saturated aqueous NaHCO3 (5 mL). The layers were separated and the aqueous layer was back-extracted with 3×5 mL EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated to give a brown semi-solid. Purification by reverse-phase HPLC afforded 1-(2,2-dimethylpropyl)-5-[5-(1-hydroxy-1-methylethyl)-2-methylphenyl]-3-prop-2-en-1-yl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (71-6) as a white solid. HRMS (M+H)+: observed=394.2490, calculated=394.2489.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:18]([OH:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[OH-].[Na+].[CH3:23]OS([O-])(=O)=O>C(O)C.O>[CH3:1][C@@:2]12[C@@H:18]([OH:19])[CH2:17][CH2:16][C@H:15]1[C@@H:14]1[CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([O:20][CH3:23])[CH:8]=[CH:7][C:6]=3[C@H:5]1[CH2:4][CH2:3]2
Reactant: COS(=O)(=O)[O-]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12

Procedure:
To a solution of estradiol (10.0 g, 36.7 mmol) in ethanol (100 ml) at reflux was added NaOH (100 mmol) in water (10 ml) followed by the dropwise addition of methylsulfate (Me2SO4) (100 mmol). Neutralization with 10% HCl, subsequent concentration of the mixture followed by filtration through silica gel with ethyl ether, afforded 3-methoxyestradiol as white needles. Dissolving metal reduction of 3-methoxyestradiol was carried out via the methods described by Wilds and affording the known dihydroestradiene derivative as a white solid. (See Feiser, L. F., Feiser, M. “Reagents for Organic Synthesis”, John Wiley and Sons, Inc., New York, 1967, pp. v, 583-4, 622-3.)
Reaction SMILES: O[CH2:2][CH2:3][C@H:4]1[C:13]([CH3:15])([CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:16])[CH:11]=2)[C:6]([CH3:18])([CH3:17])[CH2:5]1.N1C=CC=CC=1.S(Cl)([Cl:27])=O>C1(C)C=CC=CC=1>[Cl:27][CH2:2][CH2:3][C@H:4]1[C:13]([CH3:15])([CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:16])[CH:11]=2)[C:6]([CH3:18])([CH3:17])[CH2:5]1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc2c(c1)C(C)(C)[C@H](CCO)CC2(C)C
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)C(C)(C)[C@H](CCCl)CC2(C)C
Temperature: 0 °C
Yield: 61.3 %

Procedure:
(S)-3-(2-Hydroxyethyl)-1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene ([α]546 -8.1° (C=0.62 in ethanol)) (70.5 g; 0.287 mol) was dissolved in toluene (700 g), and pyridine (25.0 g; 0.316 mol) was added thereto. The resulting mixture was cooled to 0° C., and thionyl chloride (41.0 g; 0.345 mol) was added dropwise thereto. After the addition was completed, the resultant mixture was heated at 60° C. for 5 hours. The reaction mixture was cooled, washed with dilute hydrochloric acid, saturated sodium carbonate solution and saturated sodium chloride solution in order, dried over anhydrous sodium sulfate and concentrated to give (S)-3-(2-chloroethyl)-1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene (46.5 g; 0.176 mol; 61%). B.P., 106°-107° C./0.13 mmHg. [α]546 -33.4° (C=1.2 in ethanol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1.Cl>[CH2:22]([O:21][C:19]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH2:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)=[O:20])[CH3:23]
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)n1ccc2cc(N)ccc21
Temperature: 0 °C
Yield: 112.2 %

Procedure:
To a solution of 4.27 gm (32.3 mMol) 5-amino-1H-indole in 50 mL tetrahydrofuran were added 5.4 ML (38.8 mMol) triethylamine and the reaction mixture was then cooled to 0° C. To this solution were then added dropwise 3.4 mL (35.5 mMol) ethyl chloroformate. After 4 hours the reaction mixture was diluted with 1N HCl and was then extracted with ethyl acetate. The organic phase was washed sequentially with 1N HCl, water and saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure to give 7.4 gm of a dark oil. This oil was purified by flash chromatography, eluting with a gradient of dichloromethane containing 0-2.5% methanol, to give 4.95 gm (75%) of the title compound as a tan solid.
Reaction SMILES: [CH:1](=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(O)(=O)C.[C-:20]#[N:21].[K+]>C(OCC)C>[OH:15][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:20]#[N:21]
Reactant: CCCCCCCCCCCCCC=O
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCC(O)C#N
Temperature: 25 °C
Reaction time: 72 h
Yield: 22 %

Procedure:
To an ice-cooled solution of tetradecanal (18.75 g) in diethyl ether (100 ml) was added acetic acid (5.66 ml) and potassium cyanide (6.64 g). The mixture was warmed to room temperature and stirred for 72 hours. The resulting solution was washed with water, and the aqueous phase was extracted with diethyl ether (50 ml). The combined organic phase was dried, and concentrated to dryness. The residue was purified by silica gel chromatography and triturated in diisopropyl ether (10 ml) to give 2-hydroxypentadecanenitrile (4.66 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17](O)=[N:18]3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[NH2:21][C:22]1[CH:23]=[C:24]([CH:28]2[N:33]([CH3:34])[CH2:32][CH2:31][N:30]([CH3:35])[C:29]2=[O:36])[CH:25]=[CH:26][CH:27]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17]([NH:21][C:22]4[CH:23]=[C:24]([CH:28]5[N:33]([CH3:34])[CH2:32][CH2:31][N:30]([CH3:35])[C:29]5=[O:36])[CH:25]=[CH:26][CH:27]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CN1CCN(C)C(c2cccc(N)c2)C1=O
Reactant: CS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Product: CN1CCN(C)C(c2cccc(Nc3ncc4ccc(-c5cccc(S(C)(=O)=O)c5)n4n3)c2)C1=O

Procedure:
3-{3-[7-(3-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-1,4-dimethyl-piperazin-2-one was prepared from 7-(3-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 3-(3-amino-phenyl)-1,4-dimethyl-piperazin-2-one in an analogous manner to Example 1052a. Product isolated as an orange foam (69 mg, 46%). LCMS (m/e) 491 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.75 (s, 1H), 8.59 (d, 1H, J=8.0 Hz), 8.52 (s, 1H), 7.91 (d, 1H, J=7.8 Hz), 7.84 (d, 1H, J=8.1 Hz), 7.75-7.66 (m, 1H), 7.41-7.33 (m, 1H), 7.10 (s, 1H), 7.12-7.04 (m, 2H), 6.89-6.81 (m, 2H) 3.76-3.66 (m, 2H), 3.27-3.18 (m, 1H), 3.09 (s, 3H), 3.06-2.96 (m, 1H), 2.98 (s, 3H), 2.74-2.62 (m, 1H), 2.19 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:25])[CH2:12][CH2:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][C:16]=2[CH3:24])[CH2:7][CH2:6]1.[CH:28]1[C:33]2[NH:34][CH2:35][CH2:36][CH2:37][O:38][C:32]=2[CH:31]=[CH:30][CH:29]=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH:28]1[C:33]2[N:34]([C:19]([C:18]3[CH:22]=[CH:23][C:15]([CH2:14][CH2:13][CH2:12][C:11]([N:8]4[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][C:2]([CH3:1])([CH3:26])[CH3:27])[CH2:10][CH2:9]4)=[O:25])=[C:16]([CH3:24])[CH:17]=3)=[O:21])[CH2:35][CH2:36][CH2:37][O:38][C:32]=2[CH:31]=[CH:30][CH:29]=1
Reactant: c1ccc2c(c1)NCCCO2
Reactant: Cc1cc(C(=O)O)ccc1CCCC(=O)N1CCN(CCC(C)(C)C)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCCOc3ccccc32)ccc1CCCC(=O)N1CCN(CCC(C)(C)C)CC1
Yield: 10 %

Procedure:
WSCD (58 mg, 0.30 mmol) and DMAP (18 mg, 0.15 mmol) were added to a solution of 4-{4-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-4-oxo-butyl}-3-methyl-benzoic acid from Example E43 (55 mg, 0.15 mmol) and 6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (44 mg, 0.30 mmol) in di-chloromethane (3 ml) and DIEA (0.052 ml, 0.30 mmol). The mixture was heated at reflux for 5 days, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloro-methane) to give a white solid identified as the title compound (6 mg, 10%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:20])[NH:9][CH:10]([C:12]1[CH:13]=[N:14][C:15]([F:19])=[CH:16][C:17]=1[I:18])[CH3:11])([CH3:6])([CH3:5])[CH3:4].[F:21][CH2:22][CH2:23]I>C(Cl)(Cl)Cl.C(O)(C)C>[F:19][C:15]1[N:14]=[CH:13][C:12]([CH:10]([N:9]([CH2:23][CH2:22][F:21])[C:8](=[O:20])[O:7][C:3]([CH3:4])([CH3:5])[CH3:6])[CH3:11])=[C:17]([I:18])[CH:16]=1
Reactant: FCCI
Reactant: CC(NC(=O)OC(C)(C)C)c1cnc(F)cc1I
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: CC(c1cnc(F)cc1I)N(CCF)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 41.5 %

Procedure:
Add sodium hydride (58.9 mg, 2.46 mmol) to a solution of [1-(6-fluoro-4-iodo-pyridin-3-yl)-ethyl]-carbamic acid tert-butyl ester (300 mg, 819 μmol) at 0° C. Stir the mixture at 0° C. to RT for 1 h. Add 1-fluoro-2-iodo-ethane (570 mg, 3.28 mmol). Stir the mixture at RT for 4 h and then at 50° C. overnight. Dilute the mixture with chloroform/IPA (3/1, 100 mL) and wash with water/aqueous saturated sodium chloride. Dry the organic phase over sodium sulfate and concentrate in vacuo to give the crude product. Purify the crude product by FCC (20% ethyl acetate in hexane) to give 140 mg of the title compound (41%). MS (ES) m/z 413 [M+1]+.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(N(CC)CC)C.[Br:12][C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])O.[Na+]>C1COCC1>[Br:12][C:13]1[CH:14]=[C:15]([S:19]([N:3]([CH3:4])[CH3:2])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
In THF (10 mL), dimethylamine hydrochloride (2.04 g, 25.0 mmol) and triethylamine (3.48 mL, 25.0 mmol) were dissolved, and 3-bromobenzenesulfonyl chloride (0.721 mL, 5.00 mmol) was added thereto at 0° C., and then, the mixture was stirred at room temperature for 1 hour. To the mixture, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-bromo-N,N-dimethylbenzenesulfonamide (1.23 g, 4.66 mmol, yield: 93%).
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)([O-:13])=[O:12]>>[N+:11]([C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:6][C:5]2[CH:7]=[CH:8][C:9]3[O:10][CH2:1][O:2][C:3]=3[CH:4]=2)=[O:19])=[CH:21][CH:22]=1)([O-:13])=[O:12]
Reactant: Nc1ccc2c(c1)OCO2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: O=C(Nc1ccc2c(c1)OCO2)c1ccc([N+](=O)[O-])cc1
Yield: 87 %

Procedure:
Using 3,4-methylenedioxyaniline (1.44 g, 10.5 mmol) and 4-nitrobenzoyl chloride (1.86 g, 10.0 mmol), the procedure of Reference Example 11 was repeated to obtain 2.49 g (87.2%) of the title compound in the form of yellow crystals.
Reaction SMILES: [C:1]([CH:4]=[CH:5][C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[CH2:9][NH:10][C:11]1[N:15]([C@@H:16]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]2[OH:18])[C:14]2[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=2[N:12]=1)([OH:3])=O.[NH2:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.C(N(CC)CC)C>[OH:35][CH2:34][CH:33]([NH:32][C:1]([CH:4]=[CH:5][C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[CH2:9][NH:10][C:11]1[N:15]([C@@H:16]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]2[OH:18])[C:14]2[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=2[N:12]=1)=[O:3])[CH2:36][OH:37]
Reactant: NC(CO)CO
Reactant: O=C(O)C=Cc1cccc(CNc2nc3ccccc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(C=Cc1cccc(CNc2nc3ccccc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1)NC(CO)CO
Reaction time: 17 h
Yield: 88.8 %

Procedure:
2-[3-(2-Carboxyvinyl)benzylamino]-1-(β-D-ribofuranosyl)-1H-benzimidazole (50 mg), 2-amino-1,3-propanediol (21 mg), 1-hydroxybenzotriazole (36 mg) and triethylamine (41 μL) were suspended in tetrahydrofuran (2 mL). To the mixture was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (45 mg), and the mixture was stirred for 17 hours. The solvent was removed under reduced pressure, and the obtained residue was purified by preparative reverse phase column chromatography (Shiseido CAPSELL PAC C18UG80, 5 μm, 20×50 mm, flow rate 30 mL/minutes linear gradient, water/methanol=70/30-10/90) to give the title compound (52 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.O>[CH2:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(OCc2ccccc2)cn1
Temperature: 23 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
2-Chloro-5-hydroxypyridine (2.6 g, 20 mmol) and cesium carbonate (7.2 g, 22 mmol) in 8 mL of DMF were treated with benzyl bromide (2.6 mL). After stirring at 23° C. for 6 hours, the reaction mixture was diluted with water, adjusted to pH 7 with saturated aqueous NaH2PO4, and extracted with dichloromethane. The organic extract was dried over Na2SO4 filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with CH2Cl2) to provide the title compound as a white solid (3.44 g, 79%). mp<50° C.; Rf=0.4 (CH2Cl2); MS 220 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.20 (d, 1H, J=2.7 Hz), 7.55 (dd, 1H, J=9, 2.7 Hz), 7.3-7.5 (m, 6H), 5.19 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[C:3]1=[O:12]>CO.C1COCC1.[Pd]>[NH2:8][C:6]1[CH:5]=[C:4]([CH3:11])[C:3](=[O:12])[N:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])cn(C)c1=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(N)cn(C)c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.7 %

Procedure:
A mixture of 1,3-dimethyl-5-nitropyridin-2(1H)-one (8.315 g, 49.4 mmol) and Pd/C 10% (1 g) in MeOH (100 mL) and THF (100 mL) was stirred under an atmospheric pressure of H2 at RT for 1.5 hr, filtered through celite, and concentrated. The residue was triturated in Et2O to afford the title compound (6.12 g, 90% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.94 (s, 3 H) 3.31 (s, 3 H covered by water signal) 4.15 (br s, 2 H) 6.70 (s, 1 H) 6.95 (s, 1 H).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]2[C:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:15][O:16][CH:17]=2)=[CH:7][N:6]=1)=[O:4].COC(C1C=NC(NCC2C(C3C=CC=CC=3)=NOC=2C)=CN=1)=O.[F:49][C:50]([F:54])([F:53])[CH2:51][NH2:52]>>[F:49][C:50]([F:54])([F:53])[CH2:51][NH:52][C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]2[C:14]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[N:15][O:16][CH:17]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1cnc(OCc2conc2-c2ccc(F)cc2)cn1
Agent: COC(=O)c1cnc(NCc2c(-c3ccccc3)noc2C)cn1
Product: O=C(NCC(F)(F)F)c1cnc(OCc2conc2-c2ccc(F)cc2)cn1
Yield: 71 %

Procedure:
As described for example 9b, 5-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-pyrazine-2-carboxylic acid methyl ester (75 mg, 0.23 mmol), instead of 5-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-pyrazine-2-carboxylic acid methyl ester, was converted, using 2,2,2-trifluoroethylamine instead of isopropylamine, to the title compound (64 mg, 71%) which was obtained as a light yellow solid. MS: m/e=397.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH:6]([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:5]2.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>ClCCl>[C:22]([O:11][CH:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH2:5][CH:6]1[S:12]([CH3:15])(=[O:14])=[O:13])(=[O:24])[CH3:23]
Reactant: CS(=O)(=O)C1Cc2cc(Cl)ccc2C1O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC1c2ccc(Cl)cc2CC1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
0.247 g (1 mmol) of 5-chloro-2-methylsulfonylindan-1-ol is dissolved in 5 ml of dichloromethane. 1 ml of pyridine and 1 ml of acetic anhydride are added to the solution, and the reaction mixture is then stirred at room temperature for 2 days. The reaction solution is evaporated completely and the residue is taken up in dichloromethane and extracted with dilute citric acid. The organic phase is separated off, concentrated and purified chromatographically (silica gel; dichloromethane/methanol 20/1). This gives 1-acetoxy-5-chloro-2-methylsulfonylindane of melting point 136° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:32])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][CH3:31])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:32])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][CH3:31])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:33]([F:34])([F:36])[F:35]
Reactant: CCOc1ccccc1C(=O)c1ncc(Cl)cc1N(COC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCOc1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
4-Chloro-N-[5-chloro-2-(2-ethoxy-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide was hydrolyzed using 4 M HCl in dioxane (12 mL) and water (4 mL) at 100° C. to provide 4-chloro-N-[5-chloro-2-(2-ethoxy-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide. Product was purified by HPLC. MS m/z 519.1 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3][CH2:4][CH2:5][CH:6](Br)[CH3:7].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>O1CCCC1>[CH3:7][CH:6]([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)[CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: c1c[nH]cn1
Reactant: CC(C)CCCC(C)CCCC(C)Br
Solvent: C1CCOC1
Product: CC(C)CCCC(C)CCCC(C)n1ccnc1
Temperature: 160 °C
Yield: 83 %

Procedure:
52.6 parts by weight of 6,10-dimethylundec-2-yl bromide and 27.2 parts by weight of imidazole are dissolved in 80 parts by weight of tetrahydrofuran and the solution is placed in a 250 ml autoclave and heated for 15 hours at 160° C. The reaction product is then filtered and the solvent is removed from the filtrate at atmospheric pressure. Distillation in vacuo of the residue obtained gives 41.5 parts by weight (83% of theory) of 1-(1,5,9-trimethyldecyl)-imidazole; b.p.: 185° C.
Reaction SMILES: [N+:1]([CH:4]([N+:6]([O-:8])=[O:7])[CH3:5])([O-:3])=[O:2].C(N(CC)CC)C.[CH2:16]=[C:17]([C:22]([O:24][CH3:25])=[O:23])[C:18]([O:20][CH3:21])=[O:19]>CCOCC>[N+:1]([C:4]([N+:6]([O-:8])=[O:7])([CH3:5])[CH2:16][CH:17]([C:22]([O:24][CH3:25])=[O:23])[C:18]([O:20][CH3:21])=[O:19])([O-:3])=[O:2]
Reactant: CC([N+](=O)[O-])[N+](=O)[O-]
Reactant: C=C(C(=O)OC)C(=O)OC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)C(CC(C)([N+](=O)[O-])[N+](=O)[O-])C(=O)OC
Yield: 72 %

Procedure:
Carefully controlled reaction conditions are required because the addition of a nucleophile (nitro- or halonitroalkyl ion) to a methylenemalonate ester gives the salt of an alkylmalonate which is itself capable of undergoing further nucleophilic reactions. Nitroform, a strong acid, reacts with diethyl methylenemalonate in aqueous methanol at ambient temperature, without a base as catalyst, to produce diethyl 2,2,2-trinitroethylmalonate. The same conditions may also be used to produce dimethyl 2,2,2-trinitroethylmalonate. The reaction of 1,1-dinitroethane with methylenemalonates does not take place under these conditions, presumably because the nitro compound is not sufficiently ionized. However, the addition of triethylamine to an ether solution of 1,1-dinitroethane and dimethyl methlenemalonate at 0° C. resulted in a 72% yield of dimethyl 2,2-dinitropropylmalonate. In the same manner, diethyl 2,2-dinitropropylmalonate may be prepared. Finally, the addition fluorodinitromethane to methylenemalonates in ether solution in the presence of catalytic amounts of pyridine produces good yields of dimethyl and diethyl 2-fluoro-2,2-dinitroethylmalonates.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(N(CC)CC)C.[CH2:12]([S:16](Cl)(=[O:18])=[O:17])[CH2:13][CH2:14][CH3:15]>C(Cl)Cl>[CH2:12]([S:16]([NH:4][CH2:1][CH2:2][CH3:3])(=[O:18])=[O:17])[CH2:13][CH2:14][CH3:15]
Reactant: CCCN
Reactant: CCCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCS(=O)(=O)NCCC
Reaction time: 20 h

Procedure:
6.9 ml of n-propylamine (4.9 g, 84 mmol) and 11.6 ml of triethylamine (8.5 g, 84 mmol) were dissolved at room temperature in 85 ml of methylene chloride. Likewise at room temperature 10.9 ml of n-butanesulfonyl chloride (13.1 g, 84 mmol) were added dropwise to this solution over the course of 1 h. After 20 h of stirring the reaction mixture was washed twice with 50 ml of water. The organic phase was dried over magnesium sulphate, the methylene chloride was distilled off and the oily residue which remained was dried in vacuo. This gave 13.5 g of the target compound, whose constitution was verified by NMR spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10](OCC)=[O:11])=[C:6]([O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[CH:5]=[CH:4][N:3]=1.CO.[H][H]>[C].[Pd].O1CCCC1>[O:11]=[C:10]1[NH:1][C:2]2[N:3]=[CH:4][CH:5]=[C:6]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[C:7]=2[CH2:8][CH2:9]1
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1c(Oc2ccc([N+](=O)[O-])cc2)ccnc1N
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ccnc3c2CCC(=O)N3)cc1
Yield: 16.8 %

Procedure:
Ethyl (E)-3-[2-amino-4-(4-nitrophenoxy)-3-pyridyl]-2-propenoate (330 mg), palladium-carbon (10%, aqueous, 100 mg), methanol (5 ml) and tetrahydrofuran (5 ml) were stirred overnight at under a hydrogen atomsphere at 1 atmosphere. The palladium-carbon was filtered off, the filtrate was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography (ethyl acetate, followed by ethyl acetate:methanol=5:1) to obtain 43 mg of a white solid.