Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@@H:10]2[CH2:23][O:24][CH2:25][C:26](N2CCOCC2)=[O:27])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH2:34].[OH-].[Li+].[Cl-].[NH4+]>C1COCC1.CO.O>[C:19]([O:18][C:16]([N:12]1[CH2:11][C@H:10]([CH2:23][O:24][CH2:25][C:26]([OH:34])=[O:27])[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:15][CH2:14][CH2:13]1)=[O:17])([CH3:21])([CH3:20])[CH3:22]
Reactant: O
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@@H](COCC(=O)N2CCOCC2)C1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@@H](COCC(=O)O)C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of tert-butyl (6R*,7R*)-7-(3,4-dichlorophenyl)-6-{[2-(morpholin-4-yl)-2-oxoethoxy]methyl}-1,4-oxazepane-4-carboxylate (649 mg) in THF (2.5 mL) and methanol (2.5 mL) was added a solution of lithium hydroxide monohydrate (108 mg) in distilled water (1.5 mL), and the mixture was stirred at 70° C. for 2 hr. Furthermore, a solution of lithium hydroxide monohydrate (108 mg) in distilled water (1.5 mL) was added, the mixture was stirred at 70° C. overnight, and neutralized with aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (381 mg).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:16])[CH2:4][CH2:5][C:6](=[O:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+].[BH4-].[Na+]>CO.O.O>[CH3:16][N:3]([CH3:2])[CH2:4][CH2:5][CH:6]([OH:15])[CH:7]=[CH:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(C)CCC(=O)C=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: O
Solvent: CO
Product: CN(C)CCC(O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
5-(Dimethylamino)-1-phenyl-1-penten-3-one, hydrochloride (1:1) (18.6 g, 0.078 mole) is dissolved in 200 ml 1:1 methanol-water. Sodium bicarbonate (2.0 g) is added, followed by the portionwise addition of NaBH4 (3.0 g) at 35° C. After addition, the reaction mixture is stirred for 2 hours at room temperature. This solution is diluted with 200 ml of water and organics are extracted with ether. The ether is dried with MgSO4, filtered and concentrated in vacuo to yield 14.3 g of product. IR consistent.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.F[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(C)C(N)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: O=Cc1ccc(O)cc1
Agent: CC(C)C(N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: N#Cc1ccc(Oc2ccc(C=O)cc2)c2ccccc12
Temperature: 120 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
4-Hydroxybenzaldehyde (300 mg, 2.46 mmol) was dissolved in dimethylacetoamide (8.0 mL), and 4-fluoro-naphthalene-1-carbonitrile (463 mg, 0.420 mmol) and cesium carbonate (1.20 g, 3.69 mmol) were sequentially added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 120° C. for 2 hours. After the temperature of the reaction solution was returned to room temperature, water was added thereto, and the organic matter was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, then dried over anhydrous sodium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=95:5 to 70:30 (v/v)), whereby the objective title compound was obtained (515 mg, yield: 77%).
Reaction SMILES: O1CCCC1.[O:6]([CH2:13][C:14]1[N:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[N:22][OH:23])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:25]([C:27]1[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[O:6]([CH2:13][C:14]1[N:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:26]=[C:25]([C:27]3[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=3)[O:23][N:22]=2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(COc2ccccc2)nc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(COc3ccccc3)nc2)no1
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 6.6 %

Procedure:
To a tetrahydrofuran (3.00 mL) solution of (6-phenoxymethyl-pyridin-3-yl)-acetohydroximoyl chloride (80.0 mg, 0.289 mmol) described in Manufacturing Example 54-1-6 and 3-ethynyl-pyridin-2-ylamine (20.0 mg, 0.169 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (70.7 μL, 0.507 mmol) at room temperature, which was stirred for 4.5 hours at 60° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1→3:1) to obtain the title compound (4.00 mg, 6.60%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([NH:1][C:2]1[C:10]2[O:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12
Product: CC(=O)Nc1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12

Procedure:
Using the method of Example 12, 7-amino-2-nitro-3-phenylbenzofuran is reacted with acetic anhydride to provide yellow solid 7-acetamido-2-nitro-3-phenylbenzofuran, m.p. 224°-226° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:4]([O:14][C:15]2[CH:22]=[CH:21][C:18](C=O)=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.OO.C([O-])(O)=[O:32].[Na+]>CO.OS(O)(=O)=O.CCOC(C)=O>[CH3:1][C:2]1[C:3]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:4]([O:14][C:15]2[CH:16]=[CH:17][C:18]([OH:32])=[CH:21][CH:22]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccccc3)c(C)cc2c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc2c(Oc3ccc(O)cc3)c(-c3ccccc3)c(C)cc2c1
Yield: 80 %

Procedure:
To a solution of 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzaldehyde (8) (0.740 g, 2 mmol) in MeOH (20 mL) were added an aqueous solution of 30-40%, by weight, H2O2 (0.60 mL) and 2-3 drops of conc. H2SO4. The resultant mixture was stirred for over night. The reaction mixture was neutralized with sat. NaHCO3 and then diluted with EtOAc (100 mL). The organic layer was washed with water, brine, dried (Na2SO4) and concentrated under reduced pressure to afford the crude product. The product was purified by SiO2 column chromatography using hexanes:EtOAc (9:1 to 4:1) as an eluent to give 0.570 g (80%) of the title compound (233) as a white foam. IR (film) 3415, 1633, 1599, 1503, 1198 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J=9.2 Hz, 1H), 7.53 (s, 1H), 7.29-7.22 (m, 3H), 7.14-7.11 (m, 3H), 7.08 and 7.03 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 6.53-6.50 (m, 2H), 6.45-6.42 (m, 2H), 3.93 (s, 3H), 2.23 (s, 3H). LCMS (ES) m/z 357.01 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]3([CH3:15])[CH2:12][CH2:11][NH:10][C:9](=O)[CH:8]3[O:14][C:5]=2[CH:4]=1.[AlH4-].[Li+].Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]3([CH3:15])[CH2:12][CH2:11][N:10]=[CH:9][CH:8]3[O:14][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)OC1C(=O)NCCC21C
Agent: Cl
Agent: [AlH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)OC1C=NCCC21C
Reaction time: 2 h

Procedure:
To a solution of 7-methoxy-4a-methyl-3,4,4a,9a-tetrahydro-2Hbenzo[4,5]furo[2,3-c]pyridine-1-one (1.0 g, 4.30 mmol) in tetrahydrofuran (3 mL) was slowly added 1.0 M of lithium tetrahydroaluminate in tetrahydrofuran (2 mL). After 30 min stirring another portion of 1.0 M of lithium tetrahydroaluminate in tetrahydrofuran (1 mL) was added and the reaction was stirred for 2 h. The reaction was transferred into ice, 6N aqueous HCl was added followed by ethyl acetate. The aqueous layer was basified by adding NaOH and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated to provide a colorless oil. The product was used in the next reaction step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][S:5][C:6]1[CH:11]=[N:10][C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=2[Cl:23])(=[O:15])=[O:14])=[C:8]([O:24][CH3:25])[N:7]=1.[OH-].[Li+]>CO.O>[Cl:23][C:17]1[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:16]=1[S:13]([NH:12][C:9]1[N:10]=[CH:11][C:6]([S:5][CH2:4][C:3]([OH:26])=[O:2])=[N:7][C:8]=1[O:24][CH3:25])(=[O:15])=[O:14]
Reactant: COC(=O)CSc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OC)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1nc(SCC(=O)O)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl
Reaction time: 2 h

Procedure:
[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinylsulphanyl]acetic acid methyl ester (Example 82) (0.1 g) and lithium hydroxide (0.04 g) in methanol (5 mL) and water (1 mL) was stirred at room temperature. After 2 h, the mixture was evaporated and saturated aqueous citric acid (5 mL) added. The white solid was collected, washed with water and dried. Yield 0.07 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]=[N:10][S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Br:12]Br.C([O-])(O)=O.[Na+].ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:12][C:6]1[C:7]2[S:11][N:10]=[CH:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: BrBr
Reactant: COc1cccc2sncc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Br)c2sncc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 66.4 %

Procedure:
To a solution of 4-methoxy-benzo[d]isothiazole (prepared as described above) (1.0 g, 6.05 mmol) in carbon tetrachloride (20 mL) at 0° C. was added bromine (310 μL, 6.05 mmol) in carbon tetrachloride (10 mL). The reaction was allowed to stir at 0° C. for 3 h and was then warmed to rt. Saturated aqueous NaHCO3 and dichloromethane were added and the organic phase was separated. The aqueous phase was extracted with 2×20 mL dichloromethane. The combined organic phases were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with EtOAc:hexane [0:100 to 1:20] to yield the title compound (980 mg, 66%): δH (300 MHz, CDCl3): 9.09 (1H, s), 7.52 (1H, d, J=8.1 Hz), 6.67 (1H, d, J=8.4 Hz), 4.00 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[N:6][CH:7]=1.Cl.[NH2:15][C@@H:16]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:17]([N:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1)=[O:18].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].CN1CCOCC1>C(O)C>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C@H:16]([NH:15][C:11]([C:9]2[NH:8][C:5]3=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:13])[C:17]([N:19]2[CH2:20][CH2:21][CH:22]([OH:25])[CH2:23][CH2:24]2)=[O:18])=[CH:28][CH:29]=1
Reactant: O=C(O)c1cc2cc(Cl)cnc2[nH]1
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Solvent: CN1CCOCC1
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)cnc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Preparation 57, 50 mg, 0.25 mmol), 2-(S)-amino-3-(4-fluorophenyl)-1-(4-hydroxypiperidin-1-yl)propan-1-one hydrochloride (85 mg, 0.25 mmol) and DMTMM (85 mg, 0.31 mmol) were dissolved in ethanol (5 ml) and 4-methylmorpholine (31 μl, 0.28 mmol). The reaction mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (30 ml) and EtOAc (3×25 ml). The combined organics were dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel eluting with methanol:dichloromethane (1:19) to give the title compound as a beige solid. m/z (ES+)=445 [M+H]+; RT=3.31 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@H:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([N:17](CC)CC)C.CS(Cl)(=O)=O.O>ClCCl>[CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@H:10]([C:15]#[N:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: C[C@H]1CN(Cc2ccccc2)C[C@H]1O
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: C[C@H]1CN(Cc2ccccc2)C[C@H]1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
cis-1-Benzyl-3-hydroxy-4-methylpyrrolidine (6.81 g) was dissolved in dichloromethane (70 mL). While the solution was chilled in a dry ice/acetone bath, triethylamine (5.21 mL) was added, followed by dropwise addition of methanesulfonyl chloride (2.89 mL) and stirring for 1 hour. Subsequently, water (50 mL) was added and the mixture was allowed to warm to room temperature. The dichloromethane layer was separated and the aqueous layer was extracted with dichloromethane (50 mL). The dichloromethane layers were combined, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (180 mL). To this solution, tetrabutylammonium cyanide (23.9 g) was added and the mixture was refluxed for 7 hours. Subsequently, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (300 mL). This solution was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (hexane: ethyl acetate=1:1) to give cis-1-benzyl-4-methyl-3-pyrrolidinecarbonitrile as a brown oil (4.61 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14](Br)[CH:13]=2)[O:9][N:8]=1.B1([C:27]2[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=2)OCCCO1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>CCCCCC.C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:15]=[C:16]([C:18]#[N:19])[CH:17]=2)[O:9][N:8]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: N#Cc1cc(Br)cc(-c2nc(-c3ccccn3)no2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: N#Cc1cc(-c2cccnc2)cc(-c2nc(-c3ccccn3)no2)c1
Yield: 22.4 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(3-bromo-5-cyanophenyl)-1,2,4-oxadiazole (71 mg, 0.22 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (70 mg, 0.43 mmol), and Pd(PPh3)4 (25 mg, 0.022 mmol) in a solution of ethylene glycol dimethyl ether (3 mL) and 2M sodium carbonate (3 mL) was heated in a sealed vial at 100° C. for 1 hour. Standard work up and silica gel chromatography using a gradient of 50% ethyl acetate in hexane to 100% ethyl acetate followed by trituration with 5% ethyl acetate in diethyl ether afforded 16 mg (22%) of 3-(2-pyridyl)-5-(3-cyano-5-(3-pyridyl)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3): δ− 8.94 (d, 1H), 8.88 (d, 1H), 8.74 (m, 2H), 8.61 (s, 1H), 8.25 (d, 1H), 8.00 (s, 1H), 7.98 (m, 1H), 7.93 (m, 1H), 7.50 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:9][CH2:8][CH2:7][NH:6]1)[CH3:3].[Cl:10][C:11]1[C:17](Cl)=[CH:16][C:14]([NH2:15])=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:10][C:11]1[C:17]([N:6]2[CH2:7][CH2:8][CH2:9][CH:5]2[CH2:4][N:2]([CH3:3])[CH3:1])=[CH:16][C:14]([NH2:15])=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: CN(C)CC1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN(C)CC1CCCN1c1cc(N)c([N+](=O)[O-])cc1Cl

Procedure:
The sub-title compound was prepared from 2-dimethylaminomethyl-pyrrolidine (270 mg, 2.1 mmol), 4,5-dichloro-2-nitroaniline (300 mg, 1.5 mmol) and potassium carbonate (300 mg, 2.2 mmol) in DMSO (3 mL) in analogy to the method described in example 3 step (a).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([NH:11][C:12]3[C:13]([O:18][CH:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:25](O)=[O:26].C[N:29](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N>CN(C=O)C.O1CCOCC1>[CH3:1][C:2]1[C:10]2[C:9]([NH:11][C:12]3[C:13]([O:18][CH:19]([CH3:24])[C:20]([F:21])([F:22])[F:23])=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:25]([NH2:29])=[O:26]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC(C)C(F)(F)F)c12
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(C(N)=O)sc2ncnc(Nc3cccnc3OC(C)C(F)(F)F)c12
Temperature: 25 °C

Procedure:
5-Methyl-4-(2-(1,1,1-trifluoropropan-2yloxy)pyridin-3-ylamino)thieno[2,3-d]pyrimidine-6-carboxylic acid (278 mg), HATU (320 mg) and Hünig's Base (144 μl) were dissolved in DMF (6.5 ml) at 0° C. The reaction was stirred for 30 minutes after this time NH3 in dioxane (0.5 M; 5.3 ml) was added. The reaction was allowed to warm to room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was extracted with dichloromethane and water. The organic layer was separated, dried and evaporated. The crude product was purified by chromatography (silica/dichloromethane: methanol: NH3 90:10:1).
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10].[C:18]([C:20]1[CH:37]=[CH:36][C:23]([O:24][CH2:25][CH:26]([NH:28][C:29](=[O:35])[C@H:30]([CH2:32][CH2:33][CH3:34])[NH2:31])[CH3:27])=[CH:22][CH:21]=1)#[N:19].O>C(Cl)Cl>[C:18]([C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][CH:26]([NH:28][C:29](=[O:35])[C@H:30]([CH2:32][CH2:33][CH3:34])[NH:31][C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])[CH3:27])=[CH:36][CH:37]=1)#[N:19]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCC[C@H](N)C(=O)NC(C)COc1ccc(C#N)cc1
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: CCC[C@H](NC(=O)Oc1ccccc1)C(=O)NC(C)COc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 54.7 %

Procedure:
0.5 g of N-methylmorpholine, and subsequently 0.8 g of phenyl chloroformate were added to a suspension containing 1.4 g of N1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-norvalinamide suspended in 40 ml of methylene chloride at -15° C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.1 g of the desired product in the form of a colorless plated crystal (yield: 57%).
Reaction SMILES: Cl.Cl.[I:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[N:10][C:11]=2[NH2:13])[N:6]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:5]=1.[CH3:20][N:21]([CH3:26])[CH2:22][C:23](O)=[O:24].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(NC(C)C)C>ClCCl>[NH2:13][C:11]1[N:10]=[CH:9][N:8]=[C:7]2[N:6]([CH:14]3[CH2:19][CH2:18][N:17]([C:23](=[O:24])[CH2:22][N:21]([CH3:26])[CH3:20])[CH2:16][CH2:15]3)[N:5]=[C:4]([I:3])[C:12]=12
Reactant: Nc1ncnc2c1c(I)nn2C1CCNCC1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CCNC(C)C
Agent: Cl
Solvent: ClCCl
Product: CN(C)CC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)CC1
Yield: 88.9 %

Procedure:
3-iodo-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride salt (3 g, 7.19 mmol) was suspended in dichloromethane (350 mL) then N,N-dimethyl glycine (1.02 g, 9.88 mmol), 1-hydroxy-7-azabenzotriazole (1.08 g, 7.91 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.89 g, 9.89 mmol), and N-ethyl-N-isopropylamine (5.06 g, 39.2 mmol) were added over 4 days. The reaction was diluted with dichloromethane (300 mL) then washed with water (150 mL) and brine (150 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 1-[4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidino]-2-(dimethylamino)-1-ethanone as a tan solid (2.74 g, 6.39 mmol).
Reaction SMILES: C(OC(CCCCC)CCCC(CCCCCCC(OCC)=O)(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)(=O)C.[C:40]([O:43][CH:44]([CH2:74][CH2:75][CH2:76][CH2:77][CH3:78])[CH2:45][CH2:46][CH2:47][C:48]([CH2:63][CH2:64][CH2:65][CH2:66][O:67][CH2:68][C:69]([O:71][CH2:72][CH3:73])=[O:70])(C(OC(C)(C)C)=O)[C:49]([O:51]C(C)(C)C)=[O:50])(=[O:42])[CH3:41]>>[C:49]([CH:48]([CH2:47][CH2:46][CH2:45][CH:44]([O:43][C:40](=[O:42])[CH3:41])[CH2:74][CH2:75][CH2:76][CH2:77][CH3:78])[CH2:63][CH2:64][CH2:65][CH2:66][O:67][CH2:68][C:69]([O:71][CH2:72][CH3:73])=[O:70])([OH:51])=[O:50]
Reactant: CCCCCC(CCCC(CCCCOCC(=O)OCC)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OC(C)=O
Agent: CCCCCC(CCCC(CCCCCCC(=O)OCC)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OC(C)=O
Product: CCCCCC(CCCC(CCCCOCC(=O)OCC)C(=O)O)OC(C)=O

Procedure:
This compound is prepared essentially by the method described in Example 1, Step D except that the di-tert.-butyl 2-(4-acetoxynonyl)-2-(6-ethoxycarbonylhexyl)-malonate of the example is replaced by di-tert.-butyl 2-(4-acetoxynonyl)-2[4-(ethoxycarbonylmethoxy)-butyl]-malonate. The title compound is purified by column chromatography on silica gel.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([CH3:19])[CH3:18])[CH:9]=2)=[CH:4][CH:3]=1.CO/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25].Br.C(O)(=O)C>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([CH3:19])[CH3:18])[C:9]=2/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25])=[CH:4][CH:3]=1
Reactant: CC(C)n1cc(-c2ccc(F)cc2)c2ccccc21
Reactant: CO/C=C/C(=O)OC
Agent: Br
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Reaction time: 5 h
Yield: 8.9 %

Procedure:
1.27 g of 3-(4-fluorophenyl)-1-isopropyl-1H-indole, 1.16 g of methyl trans-3-methoxyacrylate and 12 mL of glacial acetic acid were mixed, then, 797 mg of 30 wt % hydrogen bromide/acetic acid solution was added dropwise into the mixture at an inner temperature of 25° C., the mixture was stirred for 5 hours at the same temperature to cause a reaction. After completion of the reaction, the same post treatment was conducted as in Example 1 to obtain 0.15 g of methyl trans-3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]acrylate (yellow solid). Yield: 8%.