Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=O)=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.[NH2:21][O:22][CH2:23][CH2:24][OH:25].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CO.C1COCC1>[F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:21][O:22][CH2:23][CH2:24][OH:25])=[O:15])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Reactant: NOCCO
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of 4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid (130 mg, 0.34 mmol) and 2-(aminooxy)ethanol [prepared by the literature procedure: Dhanak, D.; Reese, C. B., J. Chem. Soc., Perkin Trans. 1, 1987; 2829] (52 mg, 0.67 mmol) in MeOH/THF (1:1, 20 mL) was added DMT-MM (187 mg, 0.67 mmol) and the mixture stirred at R.T. for 15 h. The reaction solvent was removed under reduced pressure and the oily residue partitioned between water (100 mL) and EtOAc (100 mL). The EtOAc fraction was then washed with water (2×100 mL) and brine (100 mL), dried (Na2SO4) and the solvent removed under reduced pressure. This afforded a cream solid which was purified by recrystallisation from EtOAc/MeOH to give 4-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a white, crystalline solid (83 mg, 55%), m.p. (EtOAc/MeOH) 148-151° C. 1H NMR [(CD3)2SO, 400 MHz] δ 11.65 (v br s, 1H), 9.48 (br s, 1H), 8.13 (s, 1H), 7.74 (dd, J=10.2, 1.8 Hz, 1H), 7.58 (br d, J=8.6 Hz, 1H), 7.28 (t, J=8.5 Hz, 1H), 5.55 (s, 1H), 4.76 (v br s, 1H), 3.90 (t, J=4.9 Hz, 2H), 3.61 (t, J=4.9 Hz, 2H), 3.36 (s, 3H). Anal. Calcd for C15H15FIN3O4: C, 40.3; H, 3.4; N, 9.4. Found: C, 40.6; H, 3.6; N, 9.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21]Br)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:25]([CH2:26][CH3:27])[CH2:23][CH3:24])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(OCCCCBr)ccc21
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)CCCCOc1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Yield: 84.3 %

Procedure:
4.8 g (13 mmol) 5-(4-Bromo-butoxy)-indole-1-carboxylic acid tert-butyl ester in 5 ml DMF were treated with 5 ml (48.1 mmol) diethylamine at 50° C. for 5 h. The solution was concentrated and extracted with ether and water. The combined organic phases were dried over Na2SO4 to yield 3.95 g (85%) 5-(4-Diethylamino-butoxy)-indole-1-carboxylic acid tert-butyl ester as yellow oil, MS: 361 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[C:5]([O:13][CH3:14])[CH:4]=1.[OH-:15].[K+]>O>[OH:15][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[C:5]([O:13][CH3:14])[CH:4]=1
Reactant: [OH-]
Reactant: COC(=O)c1ccc(CBr)cc1OC
Agent: [K+]
Solvent: O
Product: COc1cc(CO)ccc1C(=O)O
Reaction time: 2 h
Yield: 92.7 %

Procedure:
A mixture of methyl 4-bromomethyl-2-methoxybenzoate (25.0 g, 96.5 mmol), potassium hydroxide (10.83 g, 193 mmol) and water (400 mL) was refluxed with stirring for 2 hr. The reaction mixture was cooled, further basified to pH 14, and extracted three times with ethyl ether. The reaction solution was then acidified to pH 1 and extracted several times with ethyl acetate. The ethyl acetate layers were combined, dried (Na2SO4) and evaporated to yield 16.3 g (93%) of the title compound as an off white solid, m. pt 106-111°, whose purity was suitable for use without further purification. Additional purification is effected by recrystallization from ethyl acetate and hexane, m. pt, 112-115°.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([S:8][CH2:9][C:10]([NH:12][CH2:13][C@@H:14]2[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[CH2:15]2)=[O:11])[S:6][CH:7]=1)#[N:2].[N-:29]=[N+:30]=[N-:31].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[Cl:27])[CH2:20][N:16]1[CH2:17][CH2:18][O:19][C@@H:14]([CH2:13][NH:12][C:10](=[O:11])[CH2:9][S:8][C:5]2[S:6][CH:7]=[C:3]([C:1]3[NH:31][N:30]=[N:29][N:2]=3)[N:4]=2)[CH2:15]1
Reactant: N#Cc1csc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CSc1nc(-c2nnn[nH]2)cs1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1

Procedure:
The resultant product (457 mg) of (22-1), sodium azide (78 mg) and ammonium chloride (525 mg) were suspended in dimethylformamide (3 mL), and the mixture was heated under reflux for 4 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (193 mg) as an orange powder.
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][NH:11][C:7]=2[CH:6]=[CH:5][N:4]=1.[I-].[Na+].Cl[Si](C)(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[O:2]=[C:3]1[C:8]2[C:9]([C:12]3[CH:13]=[CH:14][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:16][CH:17]=3)=[N:10][NH:11][C:7]=2[CH:6]=[CH:5][NH:4]1
Reactant: COc1nccc2[nH]nc(-c3ccc(S(N)(=O)=O)cc3)c12
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(-c2n[nH]c3cc[nH]c(=O)c23)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a solution of 4-(4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (60.0 mg) in acetonitrile (3 mL) were added sodium iodide (73.8 mg) and chloro(trimethyl)silane (0.250 mL), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate to ethyl acetate/methanol) to give the title compound (46.7 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][S:15]([CH2:18][CH2:19][OH:20])(=[O:17])=[O:16])=[CH:10][CH:9]=1)(=[O:6])=[O:5].S(=O)(=O)(O)O.[N+:26]([O-])([OH:28])=[O:27]>O>[OH:1][CH2:2][CH2:3][S:4]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][S:15]([CH2:18][CH2:19][OH:20])(=[O:17])=[O:16])=[CH:12][C:13]=1[N+:26]([O-:28])=[O:27])(=[O:6])=[O:5]
Reactant: O=S(=O)(CCO)Cc1ccc(CS(=O)(=O)CCO)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cc(CS(=O)(=O)CCO)ccc1CS(=O)(=O)CCO
Temperature: 110 °C
Reaction time: 2 h

Procedure:
80.5 parts of 1,4-bis(hydroxyethylsulfonylmethyl)benzene are stirred into 612.5 parts of 100% strength sulfuric acid, and the mixture is heated at 35° to 40° C. until a sample shows quantitative esterification in the HPLC chromatogram (about 4 to 5 hours). 57 parts of a mixture of 30 parts by weight of 100% strength nitric acid and 70 parts by weight of 100% strength sulfuric acid (so-called "M3 acid") are then added dropwise over a period of 4 hours at 30° to 40° C., stirring is continued for 2 hours at 45° C. until the nitration is completed (checked by HPLC chromatogram), and the reaction mixture is then decomposed by pouring it into 2,500 parts of cold water. The resulting aqueous acidic solution is then refluxed (about 110° C.) for 5 hours to hydrolyze the sulfuric ester groups, 5 parts of activated carbon are then added, the mixture is clarified and the clarified filtrate is cooled to 0° to 5° C. with stirring. The resulting precipitate is filtered off with suction, washed neutral and dried in vacuo at 80° C. This gives 89.0 parts of 2,5-bis(hydroxyethylsulfonylmethyl)nitrobenzene of the formula ##STR20## in the form of colorless crystals of melting point 125° to 126.5° C., the purity of which (HPLC) is 98.8%.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1.[CH2:36]([O:38]C(=O)C(SC1SC(N)=NC=1)(C)C)C.COC1C=CC(S)=CC=1>>[CH3:36][O:38][C:7]1[CH:6]=[CH:5][C:4]([S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]2[CH2:30][CH2:31][C@H:32]([CH3:35])[CH2:33][CH2:34]2)[C:14](=[O:28])[NH:15][C:16]2[S:17][C:18]([S:21][C:22]([CH3:26])([CH3:27])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=2)=[CH:3][CH:8]=1
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Agent: COc1ccc(S)cc1
Product: COc1ccc(SCCCN(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester and 4-methoxy-thiophenol.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][C:17]([C:23](O)([CH3:25])[CH3:24])=[CH:18][C:19]2=4)[NH:14][C:13]=3[CH3:27])[N:9]([CH3:28])[CH2:8]1)=[O:5])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.N>O1CCCC1.C(OCC)(=O)C>[CH2:29]([N:3]([CH2:1][CH3:2])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][C:17]([C:23]([CH3:25])=[CH2:24])=[CH:18][C:19]2=4)[NH:14][C:13]=3[CH3:27])[N:9]([CH3:28])[CH2:8]1)=[O:5])[CH3:30]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(C(C)(C)O)cc4[nH]c(C)c(c34)C[C@H]2N(C)C1
Agent: CS(=O)(=O)Cl
Agent: N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(C)c1cc2c3c(c(C)[nH]c3c1)C[C@@H]1[C@@H]2C[C@H](NC(=O)N(CC)CC)CN1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
208 mg of 1,1-diethyl-3-[13-(1-hydroxy-1-methyl-ethyl)-2,6- -dimethyl-8alpha-ergolinyl]-urea (0.5 mmol) is dissolved in 20 ml of anhydrous tetrahydrofuran, mixed with 0.7 ml of triethylamine (5 mmol) and 0.4 ml of methanesulfonic acid chloride (5 mmol) and stirred for 30 minutes at room temperature. Ice is added to the mixture, it is made alkaline with conc. ammonia and shaken out with ethyl acetate. The residue is chromatographed on silica gel with dichloromethane/methanol, yield 99 mg (50% of theory).
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:12]=2[CH:11](O)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[O-].[K+].O.N>ClCCl>[CH2:1]([NH:8][CH:9]1[CH:10]=[CH:11][C:12]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:13]=2[CH2:14][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(O)CC(NCc1ccccc1)CC2
Agent: N
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)C=CC(NCc1ccccc1)CC2
Temperature: 210 °C
Yield: 50.7 %

Procedure:
A mixture of 7-benzylamino-3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (6.51 g) and potassium bisulfate (13.0 g) was heated at 210° C. for 20 minutes and suspended in a mixture of dichloromethane (150 ml), water (100 ml), and 28% ammonia solution. The suspension was filtered. The dichloromethane layer was separated, dried over magnesium sulfate, evaporated in vacuo, and chromatographed over silica gel using dichloromethane-methanol as an eluent. The first eluate afforded N-benzyl-6,7-dihydro-2-nitro-5H-benzocyclohepten-7-amine (3.11 g) as a dark brown solid.
Reaction SMILES: C[O:2][P:3]([CH2:23][N:24]1[C:28](=[O:29])[CH:27]=[C:26]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:25]1=[O:34])([CH2:5][CH:6]([C:11](=[O:22])[NH:12][C@H:13]([C:18](=[O:21])[NH:19][CH3:20])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4]>FC(F)(F)C(O)=O>[CH2:30]([C:26]1[C:25]([N:24]([CH2:23][P:3]([CH2:5][CH:6]([C:11](=[O:22])[NH:12][C@H:13]([C:18](=[O:21])[NH:19][CH3:20])[CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:7][CH:8]([CH3:10])[CH3:9])(=[O:2])[OH:4])[C:28](=[O:29])[CH:27]=1)=[O:34])[CH:31]([CH3:32])[CH3:33]
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN1C(=O)C=C(CC(C)C)C1=O)OC
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(O)CN1C(=O)C=C(CC(C)C)C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.7 %

Procedure:
0.145 g (0.29 mmol) of [(2-isobutylmaleimido)methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester was dissolved in 3 ml of trifluoroacetic acid and the solution was stirred at room temperature for 5 hours. After evaporation, the crude product was chromatographed on silica gel using chloroform/methanol/acetic acid/water (120:15:3:2) for the elution. There were obtained 70 mg of [(2-isobutylmaleimido)methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid in the form of a foam.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([I:11])[C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([I:11])[C:5]([C:6]([O:8][CH3:12])=[O:7])=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cnc(Br)cc1I
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)c1cnc(Br)cc1I
Temperature: 60 °C
Yield: 82.7 %

Procedure:
A mixture of 6-bromo-4-iodonicotinic acid (75 mg, 0.23 mmol), potassium carbonate (63 mg, 0.46 mmol), and methyl iodide (0.017 mL, 0.27 mmol) in N,N-dimethylformamide (0.5 mL) was heated at 60° C. for 30 minutes. The cooled reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (15 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as a white solid (65 mg, 83%), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[O:4][CH2:5][CH2:6]O.S(Cl)([Cl:16])=O>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[O:4][CH2:5][CH2:6][Cl:16]
Reactant: OCCOc1c(Cl)cc(Cl)cc1Cl
Reactant: O=S(Cl)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: ClCCOc1c(Cl)cc(Cl)cc1Cl

Procedure:
reacting the 2-(2,4,6-trichlorophenoxy)-ethanol with thionyl chloride in the presence of benzyl-trimethyl-ammonium chloride in a ratio of 1:60 by weight, at a temperature of from 50° C. to 80° C., in the presence of carbon tetrachloride as solvent to form 2-(2,4,6-trichlorophenoxy)-ethyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[C:12](=[C:16](O)[CH3:17])[C:11](=O)[CH2:10]1.Cl.[NH2:21][C:22]([NH2:24])=[NH:23].CNC>CCO>[NH2:24][C:22]1[N:23]=[C:16]([CH3:17])[C:12]2[C:13](=[O:15])[CH2:14][CH:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Br:1])[CH2:10][C:11]=2[N:21]=1
Reactant: N=C(N)N
Reactant: CC(O)=C1C(=O)CC(c2ccc(F)cc2Br)CC1=O
Agent: CNC
Agent: Cl
Solvent: CCO
Product: Cc1nc(N)nc2c1C(=O)CC(c1ccc(F)cc1Br)C2
Temperature: 100 °C
Yield: 24 %

Procedure:
To a 150 mL pressure vessel was added 5-(2-bromo-4-fluorophenyl)-2-(1-hydroxyethylidene)cyclohexane-1,3-dione (1E, 1.12 g, 3.42 mmol, 1.0 eq.), EtOH (30 mL), guanidine hydrochloride (818 mg, 8.56 mmol, 2.5 eq.), and dimethylamine (2.0 M in THF, 10 mL, 20.5 mmol, 6.0 eq.). The vessel was sealed and heated for 72 hours at 100° C. LC/MS determined the reaction to be complete. The reaction was cooled and concentrated to give a pasty gray solid. EtOH (˜10 mL) was added to the residue and sonicated to give a suspension. The solid was collected by filtration and rinsed with cold EtOH to give a light-yellow solid (288 mg, 24%). ESI-MS: m/z 350.2 (M+H)+.
Reaction SMILES: C([O:5][C:6]([CH:8]=[CH:9][C:10]1[C:11](=[O:25])[C:12]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:13]=2[NH:14][C:15](=[O:19])[C:16]=1[O:17][CH3:18])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.CO>[Cl:24][C:21]1[CH:22]=[CH:23][C:12]2[C:11](=[O:25])[C:10]([CH:9]=[CH:8][C:6]([OH:7])=[O:5])=[C:16]([O:17][CH3:18])[C:15](=[O:19])[NH:14][C:13]=2[CH:20]=1
Reactant: COc1c(C=CC(=O)OC(C)(C)C)c(=O)c2ccc(Cl)cc2[nH]c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COc1c(C=CC(=O)O)c(=O)c2ccc(Cl)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
4-[2-(Tert-butoxycarbonyl)ethenyl]-8-chloro-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.3455 g) was dissolved in dry methylene chloride (7.5 mL) under argon. The solution was treated with trifluoroacetic acid (7 mL). The solution was stirred at room temperature for 30 minutes. The solution was concentrated under water aspirator vacuum and then it was dried under high vacuum to give a white solid. The solid was dissolved in 125 mL of hot methanol. The solution was filtered and concentrated to 80 mL volume as a white solid formed. It was cooled in an ice bath and the solid was filtered off, washed with cold methanol, and air-dried to give a white solid (0.162 g); mp 281.4°-282.0° C. (dec); 1H NMR (d6 -DMSO) 7.54 (d,1, J=16), 6.52 (d,1, J=16) for trans olefin protons; MS: m/z=308. Analysis for C14H10ClNO5 : Calculated: C, 54.65; H, 3.28; N, 4.55; Found: C, 54.36; H, 3.14; N, 4.37.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][CH:8]2[N:13]3[C:14](=[O:30])[CH:15]([NH2:29])[CH2:16][N:17]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])(=[O:20])=[O:19])[CH:12]3[CH2:11][N:10]([CH:31]([CH3:33])[CH3:32])[C:9]2=[O:34])=[CH:5][CH:4]=1.ClCCCl.CO[CH:43]1[CH2:47][CH2:46][CH:45](OC)O1>O>[Cl:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][CH:8]2[N:13]3[C:14](=[O:30])[CH:15]([N:29]4[CH:43]=[CH:47][CH:46]=[CH:45]4)[CH2:16][N:17]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])(=[O:20])=[O:19])[CH:12]3[CH2:11][N:10]([CH:31]([CH3:33])[CH3:32])[C:9]2=[O:34])=[CH:5][CH:4]=1
Reactant: COC1CCC(OC)O1
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Agent: Br
Solvent: ClCCCl
Solvent: O
Product: CC(C)N1CC2N(C(=O)C(n3cccc3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
64 mg of 6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-3-amino-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione hydrobromide (Example 2) were suspended in 1 ml of water, and 1 ml of DCE was added. This mixture was mixed with 2 equivalents of 2,5-dimethoxytetrahydrofuran and stirred at 80° C. for 1 hour. The DCE phase was removed and the aqueous phase was extracted twice with DCE. The combined extracts were evaporated, and the crude substance was dissolved in a mixture of acetonitrile and water and freeze dried. The pure title compound was removed after purification by HPLC. The system and process described under “general processes” was used for this. MW=608.08 (calculated, monoisotopic); measured value (M+H)+: 609.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].N12CCCN=C1CCCC[CH2:13]2.IC>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH3:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-fluoro-4-nitrophenol (75 g, 0.48 mol) in acetone (700 mL) was cooled in an ice-water bath. 1,8-Diazabicyclo[5,4,0]undec-7-ene (145 g, 0.96 mol) was then added over ca. 5 min. Finally, iodomethane (135 g, 0.96 mol) was added over 10 min. The mixture was stirred at room temperature for 16 hr. Additional 1,8-Diazabicyclo[5,4,0]undec-7-ene (73 g, 0.48 mol) and iodomethane (68 g, 0.48 mol) were added, and the mixture was warmed to 50° C. for 1 hr. After a solid was removed by filtration, the concentrated filtrate was mixed with ethyl acetate and 1 M hydrochloric acid. The organic layer was washed with additional hydrochloric acid and aqueous sodium bicarbonate, concentrated, and stirred in 1% ethyl acetate in hexanes. The resulting solid 3-fluoro-4-nitroanisole (72 g, 88%) was collected and air-dried.
Reaction SMILES: [Br:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])(O)[C:5]2[CH:20]=[CH:21][CH:22]=[CH:23][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[Br:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[CH:14][CH2:15][CH2:16][N:17]([CH3:18])[CH3:19])[C:5]2[CH:20]=[CH:21][CH:22]=[CH:23][C:4]=2[CH:3]=1
Reactant: CN(C)CCCC1(O)c2ccccc2C=C(Br)c2ccccc21
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCC=C1c2ccccc2C=C(Br)c2ccccc21
Reaction time: 2 h

Procedure:
10-Bromo-5-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene (14.75 g., 0.0396 mole) is dissolved in 100 ml. of trifluoroacetic acid. Trifluoroacetic anhydride, 50 ml., is added and the solution heated to refluxing with stirring for 11/2 hours. The excess trifluoroacetic anhydride and the trifluoroacetic acid are distilled, the residue suspended in water and the mixture rendered alkaline with sodium hydroxide solution. The base is extracted into ether. After washing the extract with water, the ether is distilled, leaving the oily product as the residue in a yield of 13.75 g. (98%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)[N:3]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: Oc1ccc(Cl)cc1
Product: COc1ccc2c(Oc3ccc(Cl)cc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-chloro-phenol to give [1-(4-chloro-phenoxy)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 367(MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:33][C:31]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([F:24])[CH:32]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: N#Cc1ccc(O)cc1F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(C#N)c(F)c4)ncnc32)CC1

Procedure:
4-[4-(4-Cyano-3-fluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure B by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 2-fluoro-4-hydroxybenzonitrile (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA) in dimethylformamide. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.94-2.04 (m, 4H), 2.99-3.07 (m, 2H), 4.08-4.11 (m, 2H), 5.01-5.05 (m, 1H), 7.47-7.50 (m, 1H), 7.75-7.79 (m, 1H), 8.08-8.12 (m, 1H), 8.42 (s, 1H), 8.60 (s, 1H). Mass spectrum MH+=439.