Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1.[C:15](OCC)(=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>C(O)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH2:13][C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][CH:7]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(F)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.6 %

Procedure:
To a solution of sodium ethoxide (351 mL, 21% in ethanol, 1629 mmol) was added 1-(4-fluorophenyl) ethanone (150 g, 1086 mmol) in ethanol (100 mL) at 0° C. under a nitrogen atmosphere and the resulting reaction mixture was stirred at RT for 10 min Diethyl oxalate (156 mL, 1140 mmol) in ethanol (100 mL) was added and reaction was allowed to stir at RT for 12 h. Reaction mixture was cooled to 0° C. and acidified with 1.5 N HCl and the solid was filtered and the filtrate was diluted with water and extracted with DCM (3×750 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to afford Intermediate 1A (180 g, 70%) which was taken to next step without further purification. MS(ES): m/z=237 [M−H]+; 1H NMR (300 MHz, CDCl3) δ ppm 15.2 (bs, 1H), 8.00-8.09 (m, 2H), 7.15-7.25 (m, 2H), 7.05 (s, 1H), 4.42 (q, J=7.15 Hz, 2H), 1.43 (t, J=7.15 Hz, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:9]1[N:10]=[CH:11][S:12][C:13]=1[C:14](OCC)=[O:15])[CH3:8]>C1COCC1>[CH2:7]([C:9]1[N:10]=[CH:11][S:12][C:13]=1[CH2:14][OH:15])[CH3:8]
Reactant: CCOC(=O)c1scnc1CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1ncsc1CO
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 71.2 %

Procedure:
To a 0° C. mixture of lithium aluminum hydride (800 mg, 21.0 mmol) in anhydrous THF (30 mL) was slowly added a solution of ethyl 4-ethyl-1,3-thiazole-5-carboxylate (1.91 g, 10.3 mmol) in anhydrous THF (50 mL). The reaction mixture was stirred at 0° C. for 1.5 hours. The reaction was quenched with 5 N NaOH. Water (150 mL) and EtOAc (150 mL) were added. The mixture was stirred for 30 minutes. The solid material was removed by filtration. The organic layer was recovered. The aqueous layer was extracted with EtOAc (1×100 mL). The combined organic extracts were back extracted with brine (2×200 mL), dried over MgSO4, filtered, evaporated, and dried in vacuo, affording (4-ethyl-1,3-thiazol-5-yl)methanol (1.05 g, 71% yield). The product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[Cl:11].[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[Cl:11][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[Cl:1])[NH:8][C:9]([NH:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:31])[CH3:32])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1)=[O:10]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)Nc3ccc(Cl)c(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure P and Scheme AB using 1,2-dichloro-4-isocyanatobenzene and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 493.2 (M+H)+.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@@H:9]([CH3:38])[C:10]([NH:12][C@@H:13]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[C:14]([NH:16][C@@H:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]([C@:20]1([CH3:23])[CH2:22][O:21]1)=[O:19])=[O:15])=[O:11].[O:39]1[CH2:44][CH2:43][N:42]([CH2:45][C:46](O)=[O:47])[CH2:41][CH2:40]1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][C@:20]1([C:18](=[O:19])[C@@H:17]([NH:16][C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:46](=[O:47])[CH2:45][N:42]2[CH2:43][CH2:44][O:39][CH2:40][CH2:41]2)[CH3:38])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:22][O:21]1
Reactant: C[C@H](N)C(=O)N[C@@H](Cc1ccccn1)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@]1(C)CO1
Reactant: O=C(O)CN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccccn1)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@]1(C)CO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
To (S)-2-((S)-2-aminopropanamido)-N-((S)-1-((S)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)-3-(pyridin-2-yl)propanamide TFA salt (0.601 mmol assumed) was added morpholinoacetic acid (174 mg, 1.20 mmol), HOBt (130 mg, 0.962 mmol), HBTU (365 mg, 0.962 mmol) and DMF (3 mL). The mixture was cooled to 0° C. and DIEA (0.627 mL, 3.61 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (3:1 DCM/ethyl acetate+0-15% methanol) provided (S)-N-((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)propanamido)-3-(pyridin-2-yl)propanamide (121 mg, 37%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 8.39 (ddd, J=4.9, 1.8, 0.9 Hz, 1H), 7.89 (d, J=6.7 Hz, 2H), 7.60 (ddt, J=7.7, 5.6, 1.8, 1.8 Hz, 2H), 7.25-7.09 (m, 5H), 7.09-6.99 (m, 2H), 4.88-4.65 (m, 2H), 4.47 (p, J=7.1, 7.1, 7.0, 7.0 Hz, 1H), 3.88-3.61 (m, 4H), 3.34-3.23 (m, 2H), 3.14 (dd, J=15.2, 6.3 Hz, 1H), 3.08-2.94 (m, 3H), 2.88 (d, J=5.0 Hz, 1H), 2.76 (dd, J=14.1, 7.9 Hz, 1H), 2.66-2.42 (m, 4H), 1.45 (s, 3H), 1.35 (d, J=7.1 Hz, 3H). MS (EI) for C29H37N5O6, found 552.4 (MH+).
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:8]=2[C:9]#[N:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][O:17][C:18]1[CH:32]=[CH:31][C:21]([CH2:22][N:23]2[C:27]([C:28](Cl)=[O:29])=[N:26][N:25]=[N:24]2)=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:9]([C:8]1[C:7]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:14][CH:13]=[CH:12][C:11]=1[NH:15][C:28]([C:27]1[N:23]([CH2:22][C:21]2[CH:31]=[CH:32][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[N:24]=[N:25][N:26]=1)=[O:29])#[N:10]
Reactant: COc1ccc(Cn2nnnc2C(=O)Cl)cc1
Reactant: N#Cc1c(N)cccc1N1CCCCC1
Solvent: c1ccncc1
Product: COc1ccc(Cn2nnnc2C(=O)Nc2cccc(N3CCCCC3)c2C#N)cc1

Procedure:
The N-[2-cyano-3-(1-piperidinyl)phenyl]-1-(4-methoxyphenylmethyl)-1H-tetrazole-5-carboxamide was prepared in the usual manner as illustrated in Example I from 2-(1-piperidinyl)-6-aminobenzonitrile and 1-p-methoxybenzyl-5-tetrazolecarbonylchloride in the presence of pyridine. The product was recrystallized from acetonitrile, m.p. 166°-168° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][CH2:29][S:30]([C:33]1[CH:34]=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36])(=[O:32])=[O:31]>>[OH:27][CH2:28][CH2:29][S:30]([C:33]1[CH:34]=[C:35]([NH:36][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:37]=[CH:38][CH:39]=1)(=[O:31])=[O:32]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)CCO)c1
Product: O=C(Nc1cccc(S(=O)(=O)CCO)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-(2-hydroxy-ethanesulfonyl)-aniline [commercially available] according to general procedure II. Yellow solid. MS (ISP) 559.4 [(M+H)+]; mp 237° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:20]([Si:22]([CH3:25])([CH3:24])[CH3:23])#[CH:21]>[Cu](I)I.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:12][C:9]1[CH:10]=[CH:11][C:2]([C:21]#[C:20][Si:22]([CH3:25])([CH3:24])[CH3:23])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1cc(Cl)ccc1Br
Agent: I[Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Cl)ccc1C#C[Si](C)(C)C
Temperature: 50 °C
Reaction time: 20 h
Yield: 102.9 %

Procedure:
To a stirred solution of methyl 2-bromo-5-chlorobenzoate (14.8 g, 59 mmol) in triethylamine (124 ml, 890 mmol) was added copper iodide (339 mg, 1.8 mmol) and triphenylphosphine (778 mg, 3.0 mmol) at room temperature, under nitrogen. This mixture was purged with nitrogen before the addition of ethynyl(trimethyl)silane (12.5 ml, 89 mmol) and Pd(OAc)2 (266 mg, 1.2 mmol). The reaction mixture was stirred at 50° C. for 20 hours and concentrated in-vacuo. The residue was dissolved in deionized water (50 ml) and EtOAc (50 ml) and filtered through Celite. The filter cake was washed with EtOAc (50 ml) before the phases were separated and the aqueous layer was extracted with EtOAc (2×50 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (10 g Silica Isolute cartridge, 1-15% EtOAc:Heptanes) to give the title compound (16.2 g, 93%) as an orange solid. LC-MS 91%, m/z=267.4, 268.9; 1H NMR (500 MHz, Chloroform-d) δ ppm 7.90 (d, J=2.21 Hz, 1H) 7.52 (d, J=8.35 Hz, 1H) 7.42 (dd, J=8.28, 2.29 Hz, 1H) 3.93 (s, 3H) 0.28 (s, 9H).
Reaction SMILES: [OH:1][C@@:2]([C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21](Cl)=[O:22])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8].[N:24]([CH2:27][C@@H:28]([NH2:36])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N+:25]=[N-:26].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:24]([CH2:27][C@@H:28]([NH:36][C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@@H:15]([C@:2]([OH:1])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8])[CH2:16]1)=[O:22])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N+:25]=[N-:26]
Reactant: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=O)Cl)C1
Reactant: [N-]=[N+]=NC[C@@H](N)Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=O)N[C@H](CN=[N+]=[N-])Cc2ccccc2)C1
Reaction time: 12 h
Yield: 109.8 %

Procedure:
A solution of (R)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbonyl chloride (135 mg, 0.4 mmol) in CH2Cl2 (10 mL) was added to a solution of (S)-1-azido-3-phenylpropan-2-amine (156.3 mg, 0.73 mmol), triethylamine (0.6 mL, 4.3 mmol), and DMAP (16.6 mg, 0.13 mmol) in CH2Cl2. After stirring for 12 h, the reaction was taken up in CH2Cl2 (50 mL), washed with satd aq NaHCO3 (3×10 mL), and brine (3×10 mL), dried (Na2SO4), decanted, and stripped to afford (3R)-N-((S)-3-azido-1-phenylpropan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide (210.7 mg) as a brown residue (theoretical yield: 192.0 mg). MS ESI +ve m/z 502 (M+Na).
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[C:14]1([CH3:26])[CH:19]=[CH:18][C:17]([S:20]([CH2:23][CH2:24]O)(=[O:22])=[O:21])=[CH:16][CH:15]=1>O=S(Cl)Cl>[C:14]1([CH3:26])[CH:19]=[CH:18][C:17]([S:20]([CH2:23][CH2:24][O:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:5]([S:2]([Cl:1])(=[O:4])=[O:3])[CH:6]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: Cc1ccc(S(=O)(=O)CCO)cc1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(S(=O)(=O)CCOC(=O)c2cccc(S(=O)(=O)Cl)c2)cc1
Yield: 100.9 %

Procedure:
A heterogeneous mixture of 3-chlorosulfonyl-benzoic acid (11.0 g, 50.0 mmol) in 18 mL of SOCl2 was refluxed for 3 h. Thereafter the excess of SOCl2 was removed, the residual brown oil was dissolved in 60 mL of CH3CN, and then 2-(p-tolylsulfonyl)ethanol (9.4 g, 47.0 mmol, 0.95 eq.) was added. The mixture was heated to reflux temperature for 20 h. Thereafter the most of CH3CN was removed, the resulting oil was purified by short column chromatography (silica gel, CH2Cl2) to give light brown oil, which was dried further under vacuum to yield 19.1 g (95%) of a light brown solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[C:15]([NH:19][NH2:20])(=O)[CH2:16][CH3:17]>C(O)CCC>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([C:15]([CH2:16][CH3:17])=[N:19][N:20]=3)[N:4]=2)=[CH:9][CH:10]=1
Reactant: Clc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: CCC(=O)NN
Solvent: CCCCO
Product: CCc1nnc2ccc(-c3ccc(Cl)cc3)nn12

Procedure:
A mixture of 9.0 g. of 3-chloro-6-(p-chlorophenyl)pyridazine (prepared as in Example 12), 7.4 g. of propionic acid hydrazide and 60 ml. of butyl alcohol is stirred at reflux temperature for 48 hours. The mixture is chilled, filtered and the solid is washed with petroleum ether and with water. The material is recrystallized from 50 ml. of ethyl alcohol to afford the product of the example as crystals, m.p. 197°-199° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17].CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[CH:33]=[C:32]([NH:37][C:38]([C:40]2[CH:44]=[CH:43][S:42][CH:41]=2)=[O:39])[CH:31]=[CH:30]3)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(Cl)Cl.O>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][CH2:13][NH:12][C:7]1[C:8]2[C:3](=[C:2]([C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][CH:36]=3)[CH:33]=[C:32]([NH:37][C:38]([C:40]3[CH:44]=[CH:43][S:42][CH:41]=3)=[O:39])[CH:31]=[CH:30]4)[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Reactant: CN(C)CCCNc1nccc2c(Br)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CN(C)CCCNc1nccc2c(-c3ccc4cc(NC(=O)c5ccsc5)ccc4c3)cccc12
Reaction time: 0.17 h
Yield: 40 %

Procedure:
To a microwave vial containing 5-bromo-N-(3(dimethylamino)propyl) isoquinolin-1-amine (Step 5, 0.055 g, 0.2 mmol) in 1,4-Dioxane (2 mL), was added N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (0.100 g, 0.3 mmol), Fibrecat catalyst (0.005 g, 5% by wt.), along with 2 M Potassium Carbonate (0.5 mL, 1 mmol). The reaction mixture was placed into CEM Microwave for 10 minutes at 80° C., while supplying 60 Watts of energy via power-max. The mixture was diluted with DCM and H2O, and extracted with DCM (3×10 mL). Then dried organics (over sodium sulfate), was filtered, and concentrated in-vacuo. The crude was purified on reverse-phase HPLC. This gave an off-white amorphous solid after drying, which was titled product (0.023 g, 0.08 mmol). MS (ESI pos. ion) m/z: 481 (M+H). Calc'd Exact Mass for C29H28N4OS: 480
Reaction SMILES: [F:1][S:2]([F:9])=[C:3]([OH:8])[C:4]([F:7])([F:6])[F:5].[N+:10]([C:13]([N+:20]([O-:22])=[O:21])([N+:17]([O-:19])=[O:18])[CH2:14][CH2:15]O)([O-:12])=[O:11].S(=O)(=O)(O)O>ClCCCl>[F:1][S:2]([F:9])=[C:3]([O:8][CH2:15][CH2:14][C:13]([N+:17]([O-:19])=[O:18])([N+:10]([O-:12])=[O:11])[N+:20]([O-:22])=[O:21])[C:4]([F:7])([F:6])[F:5]
Reactant: OC(=S(F)F)C(F)(F)F
Reactant: O=[N+]([O-])C(CCO)([N+](=O)[O-])[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: O=[N+]([O-])C(CCOC(=S(F)F)C(F)(F)F)([N+](=O)[O-])[N+](=O)[O-]
Yield: 95.6 %

Procedure:
A mixture of 0.57 g (0.003 mole) of pentafluorothioacetic acid, 1.2 g (0.006 mole) of 3,3,3-trinitropropanol and 0.3 ml of concentrated sulfuric acid in 10 ml of 1,2-dichloroethane was stirred at reflux temperature for 24 hr in a flask with a reverse Dean Stark trap attached. The reaction mixture was cooled and the organic layer was decanted from the insoluble sulfuric acid. After the removal of volatiles from the organic layer, the residue (oil) was chromatographed on silica gel 40 using methylene chloride as eluent to give 0.99 g (89%) of product, mp 32° C.;
Reaction SMILES: [CH2:1]1[CH:13]2[N:4]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:12]2)[CH2:3][CH2:2]1.[N+:14]([O-])([O-:16])=[O:15].[K+].[OH-].[NH4+].[ClH:21]>S(=O)(=O)(O)O.C(O)(C)C.C(O)C>[ClH:21].[N+:14]([C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][CH:13]3[CH2:1][CH2:2][CH2:3][N:4]3[CH2:5][C:6]=2[CH:7]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: c1ccc2c(c1)CC1CCCN1C2
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc2c(c1)CN1CCCC1C2
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of 1,2,3,5,10,10a-hexahydropyrrolo[1,2-b]isoquinoline (4.12 g, 23.8 mmol) in concentrated sulfuric acid (100 ml) at -10° C. was added, in portions over 1 h, potassium nitrate (2.40 g, 23.7 mmol). After addition was complete, the reaction mixture was stirred for 1 h before it was poured over ice. The aqueous solution was made basic with concentrated ammonium hydroxide and the product was extracted into dichloromethane (twice). The dried (magnesium sulfate) organic phase was concentrated to give a red oil that solidified on standing. This solid was taken up in isopropanol (100 ml) and hydrogen chloride in ethanol was added until acidic. The solid was collected, washed with isopropanol and dried to give the crude product (3.39 g, 56%). This solid was recrystalized from ethanol to give the title compound (2.16 g, 36%) as an off-white solid, m.p. 231-3° C. (dec.)
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[N+:9]([C:12]1[CH:13]=[C:14]([C:21](Cl)=[O:22])[C:15](=[CH:19][CH:20]=1)[C:16](Cl)=[O:17])([O-:11])=[O:10]>CCO>[N+:9]([C:12]1[CH:13]=[C:14]2[C:15](=[CH:19][CH:20]=1)[C:16](=[O:17])[C:8]1[C:1]([OH:2])=[CH:3][CH:4]=[C:5]([OH:6])[C:7]=1[C:21]2=[O:22])([O-:11])=[O:10]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1C(=O)Cl
Reactant: Oc1ccc(O)cc1
Solvent: CCO
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)c2c(O)ccc(O)c21
Yield: 75 %

Procedure:
The method was similar to that in Example 1 but using 11.0 g (0.1 mols) of hydroquinone and 24.7 g (0.1 mols) of 4-nitrophthalic acid dichloride. The product was 21.4 g (75% yield) of 6-nitro-1,4-dihydroxy-9,10-anthraquinone (5), m.p.=226°-228° C. (EtOH). The compound had the following characteristics:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[C:19](Br)[C:18]([CH:22]=O)=[C:17]([CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]2)[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:38][NH2:39]>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[C:19]2[NH:38][N:39]=[CH:22][C:18]2=[C:17]([CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:25]2)[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc(Br)c2C=O)C1
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc3[nH]ncc23)C1
Temperature: 90 °C
Reaction time: 15 h
Yield: 23 %

Procedure:
To a stirred solution of tert-butyl 3-{6-[2-(benzyloxy)phenyl]-2-bromo-3-formyl-4-pyridinyl}-1-piperidinecarboxylate (0.150 g, 0.272 mmol) in 1,4-dioxane (1 mL) was added hydrazine monohydrate (0.5 mL). The reaction mixture was stirred at 90° C. for 15 hrs. After cooled to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from diethyl ether to give tert-butyl 3-{6-[2-(benzyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}-1-piperidinecarboxylate as a white solid (0.030 g, 23%). Then tert-butyl 3-{6-[2-(benzyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridin-4-yl}-1-piperidine-carboxylate was treated in a similar manner as that of the step (2) of Example 1-1 and then the step (3) of Example 1-1 to obtain 2-(4-Piperidin-3-yl-1H-pyrazolo[3,4-b]pyridin-6-yl)-phenol hydrochloride.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:14]([OH:17])[CH:15]=[CH2:16].[H-].[Na+]>CN(C)P(=O)(N(C)C)N(C)C>[CH2:14]([O:17][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1)[CH:15]=[CH2:16]
Reactant: C=CCO
Reactant: Clc1nccnc1N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCOc1nccnc1N1CCOCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
120 g of 2-chloro-3-morpholinyl-pyrazine and 70 g of allyl alcohol are dissolved in 640 ml of hexamethylphosphoric acid triamide. 28.8 g of sodium hydride are introduced into this solution over the course of 30 minutes at 0° C. The mixture is then stirred for a further hour at 0° C. and thereafter for 1 hour at 30° C. and 15 hours at room temperature, until the reaction has subsided. The reaction mixture is then poured out onto 2 liters of ice water. After the excess sodium hydride present has been decomposed, the mixture is extracted by shaking with ether. The ether extracts are washed with water until neutral, dried over sodium sulphate and evaporated in a waterpump vacuum. The residue is distilled in a high vacuum. 2-Allyloxy-3-morpholinyl-pyrazine, boiling point 105°-106° C./0.03 mm Hg, is thus obtained.
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[N+:13]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[CH2:1][CH2:2][CH3:3])[C:8]([OH:10])=[O:9])([O-:15])=[O:14]
Reactant: CCCc1ccc(C(=O)O)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
9.44 g (57.5 mmol, 1.0 equiv.) of 4-propylbenzoic acid were partially dissolved in 50 mL conc. H2SO4 and chilled in an ice bath. A solution of 4.7 mL (74.7 mmol, 1.3 equiv) conc. HNO3 in 10 mL conc. H2SO4 was added dropwise over 1-2 min. After stirring 1 hour at 0° C., the reaction mixture was poured into a 1 L beaker half full with ice. After stirring 10 minutes, the white solid which formed was filtered, washed 1×H2O, and dried to give 12.01 g (100%) of the title compound: mp 106-109° C.; IR (KBr) 3200-3400, 2966, 2875, 2667, 2554, 1706, 1618, 1537, 1299, 921 cm−1; 1H NMR (300 MHz, DMSO-d6) d 0.90 (t, 3H, J=7.4 Hz), 1.59 (m, 2H), 2.82 (m, 2H), 7.63 (d, 1H, J=8.0 Hz), 8.12 (dd, 1H, J=1.7, 8.0 Hz), 8.33 (d, 1H, J=1.7 Hz); 13C NMR (75.5 MHz, DMSO-d6) d 14.2, 23.7, 34.2, 125.4, 130.5, 132.9, 133.6, 141.4, 149.5, 165.9; Anal. calcd for C10H11NO4.1/4H2O: C, 56.20; H, 5.42; N, 6.55. Found: C, 56.12; H, 5.31; N, 6.81.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][OH:11].[C:12](Cl)(=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15].C1(C2C3C(=C(Cl)C=CC=3)CCN=2)C=CC=CC=1>>[C:12]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][OH:11])(=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CC(=O)Cl
Reactant: NCCc1ccccc1CO
Agent: Clc1cccc2c1CCN=C2c1ccccc1
Product: CC(C)CC(=O)NCCc1ccccc1CO

Procedure:
1-Amino-2-(2-hydroxymethylphenyl)ethane and isovaleryl chloride were successively reacted in the same way as in steps (b) and (c) of Example 12 to afford 1-isovalerylamino-2-(2-hydroxymethylphenyl)ethane. The product was successively reacted in the same way as in steps (d), (e), (f), and (g) of Example 12 to afford 1-isobutylisoquinoline-5-acetonitrile as an oil.