Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=1.C=O.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH3:40])[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:35])([F:36])[F:37])=[CH:18][N:17]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COc1cc(C2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Reaction time: 2 h
Yield: 95 %

Procedure:
2-(2-(2-(2-((2-Methoxy-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (2) (2.249 g, 4.38 mmol) was dissolved in methanol (220 mL) and 37% formaldehyde solution (0.483 mL, 17.5 mmol) was added. After five minutes sodium tris(acetoxy)borohydride (4.641 g, 21.9 mmol) was added and stirring continued at room temperature for two hours. The volatiles were evaporated and the residue suspended in 5% aqueous sodium hydroxide (200 mL). The resulting mixture was extracted with ethyl acetate (5×200 mL) then the combined organic phases were washed with brine (500 mL), dried over sodium sulfate and evaporated. The residue was evaporated from ether and the solvent traces removed under high vacuum to give the title compound (3) (2.196 g, 95% yield) as a white solid; 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.85 (s, 1H), 7.28-7.22 (m, overlaps with CHCl3), 6.88 (dd, J=8.3, 1.9 Hz, 1H), 6.81 (d, J=1.8 Hz, 1H), 5.41 (s, 2H), 3.90 (s, 3H), 3.70 (s, 2H), 3.16-3.06 (m, 4H), 2.99 (d, J=12.1 Hz, 2H), 2.48 (tt, J=10.5, 5.9 Hz, 1H), 2.34 (s, 3H), 2.07 (td, J=11.1, 4.1 Hz, 2H), 1.89-1.77 (m, overlaps with water). LCMS Method C: rt 4.94 min; m/z 528.1 [M+H]+, 550.1 [M+Na]+; m/z 526.2 [M−H]−.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[Br:11][C:12]1[C:17]([F:18])=[CH:16][C:15]([NH2:19])=[C:14]([NH2:20])[CH:13]=1>>[Br:11][C:12]1[CH:13]=[C:14]2[C:15](=[CH:16][C:17]=1[F:18])[NH:19][C:1](=[O:8])[C:2](=[O:4])[NH:20]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cc(F)c(Br)cc1N
Product: O=c1[nH]c2cc(F)c(Br)cc2[nH]c1=O
Temperature: 25 °C

Procedure:
The title compound was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (1.97 mL, 13.5 mmol) and 4-bromo-5-fluoro-1,2-diaminobenzene (277 mg, 1.35 mmol) was heated to reflux under N2 for 12 h. The reaction was allowed to cool to room temperature and the dark-brown solid collected by vacuum filtration and rinsed with ethanol (20 mL) and air dried to give 233 mg (67%) of a powdery brown solid. A portion of this solid (100 mg) was taken and dissolved in 5 mL 1N NaOH. The solution was treated with activated charcoal and filtered through a pad of Celite. The Celite was rinsed with 10 mL additional NaOH solution. The resulting solution was carefully acidified with 1N HCl (pH=5). Bright yellow needles slowly formed in the solution and were collected by vacuum filtration, rinsed with 15 mL of H2O and dried under vacuum (0.1 torr, 78° C.) to yield 40.0 mg of yellow crystals. 1H NMR (d6 -DMSO) δ6.99 (d,1H, J=9.3, H-8), 7.29 (d, 1H, J=6.3, H-6), 11.95 (br s, 2H, 2(NH)). EIMS m/z 260 (M+2, 96), 258 (M+(bp)), 232 (51), 230 (52), 123 (83). EIHRMS calc. for C8H4BrFN2O2 256.9941, found 257.9441.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[C:6]([F:18])[CH:5]=1)[CH3:3].Cl[C:20]1[N:25]=[C:24]([N:26]2[C@@H:30]([CH:31]([CH3:33])[CH3:32])[CH2:29][O:28][C:27]2=[O:34])[CH:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:18][C:6]1[CH:5]=[C:4]([C@@H:2]([NH:1][C:20]2[N:25]=[C:24]([N:26]3[C@@H:30]([CH:31]([CH3:32])[CH3:33])[CH2:29][O:28][C:27]3=[O:34])[CH:23]=[CH:22][N:21]=2)[CH3:3])[CH:9]=[CH:8][C:7]=1[C:10]([N:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)=[O:11]
Reactant: C[C@H](N)c1ccc(C(=O)N2CCCCC2)c(F)c1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(C(=O)N3CCCCC3)c(F)c2)n1
Temperature: 107.5 °C
Yield: 11.6 %

Procedure:
To (S)-(4-(1-aminoethyl)-2-fluorophenyl)(piperidin-1-yl)methanone (0.019 g, 0.076 mmol) was added (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (0.028 g, 0.114 mmol), NMP (0.5 ml) and Hunig's Base (0.033 ml, 0.190 mmol). The reaction was heated at 105-110° C. for 16 hours or until done by LCMS. The reaction was let cool, 0.5 ml of NMP was added, filtered, purified by prep LC and lyophilized to give 4.0 mg of (S)-3-(2-((S)-1-(3-fluoro-4-(piperidine-1-carbonyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one as TFA Salt. LCMS m/z 456.1 (M+H)+, rt 0.74 min.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:44])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:28][CH:29]=5)[N:24]([CH3:35])[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:44])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:28][CH:29]=5)[N:24]([CH3:35])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(C(C)(C)C)ccc34)nc12)C(=O)N1CC(C#N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(C(C)(C)C)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.7 %

Procedure:
To a solution of 2-(6-tert-butyl-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (129 mg, 0.21 mmol) in CH2Cl2 (2 mL) was added TFA (0.75 mL). The reaction mixture was stirred at room temperature for 4 h then concentrated. The residue was redissolved in 10:90:0.5 MeOH/CH2Cl2/NH4OH (3 mL) and stirred at room temperature for 3 h. The reaction mixture was concentrated and the residue was purified by silica gel chromatography with 0% to 5% MeOH/EtOAc to afford 74 mg (73%) of 2-(6-tert-butyl-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a light yellow powder. MS: (M+H)+=485; mp=180-195° C.; 1H NMR (CDCl3, 400 MHz): δ (ppm) 10.08-10.28 (m, 1H), 9.02-9.14 (m, 1H), 8.65 (d, J=7.1 Hz, 1H), 8.46 (d, J=8.6 Hz, 1H), 7.99-8.13 (m, 1H), 7.40-7.49 (m, 1H), 7.36 (s, 1H), 4.86-5.08 (m, 1H), 4.23-4.76 (m, 4H), 4.11 (s, 3H), 3.52-3.59 (m, 1H), 1.55-1.71 (m, 3H), 1.48 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:15][CH:16]=2)[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:10]=1[C:29]([O:31]C(C)C)=[O:30])=[O:8].[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:15][CH:16]=2)[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:10]=1[C:29]([OH:31])=[O:30])=[O:8]
Reactant: CC(C)OC(=O)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC(C)C)cc2n1Cc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(=O)O)n(Cc3ccccn3)c2c1

Procedure:
A solution of isopropyl 3-(3,4-difluorobenzylcarbamoyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (Compound 101, 551 mg, 1.06 mmol) in MeOH (15 ml) and NaOH (1 M, 5.3 ml, 5.3 mmol) was stirred at room temperature for 4 h. The reaction was quenched cautiously with 6 M HCl at 0° C., extracted with EtOAc (×3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (EtOAc, then 8:2 EtOAc-MeOH, then 7:2:1 EtOAc-MeOH-Et3N) to yield the title compound as its Et3N salt.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([CH2:8][CH2:9][OH:10])[CH2:5][CH2:6][OH:7].[CH3:11][S:12](Cl)(=[O:14])=[O:13].N1C=CC=CC=1.Cl>ClCCl>[CH3:11][S:12]([O:1][CH2:2][CH2:3][CH:4]([CH2:8][CH2:9][O:10][S:12]([CH3:11])(=[O:14])=[O:13])[CH2:5][CH2:6][O:7][S:12]([CH3:11])(=[O:14])=[O:13])(=[O:14])=[O:13]
Reactant: OCCC(CCO)CCO
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCC(CCOS(C)(=O)=O)CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To an stirred ice-cooled solution of tris(2-hydroxyethyl)methane (10 g, 0.0676 mol) in dichloromethane (50 ml) was slowly dripped a solution of methanesulphonyl chloride (40 g, 0.349 mol) in dichloromethane (50 ml) under nitrogen at such a rate that the temperature did not rise above 15° C. Pyridine (21.4 g, 0.27 mol, 4 eq) dissolved in dichloromethane (50 ml) was then added drop-wise at such a rate that the temperature did not rise above 15° C., exothermic reaction. The reaction was left to stir at room temperature for 24 h and then treated with 5N hydrochloric acid solution (80 ml) and the layers separated. The aqueous layer was extracted with further dichloromethane (50 ml) and the organic extracts combined, dried over sodium sulphate, filtered and concentrated in vacuo to give tris[2-(methylsulphonyloxy)ethyl]methane contaminated with excess methanesulphonyl chloride. The theoretical yield was 25.8 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18](=[O:19])[C:17]3[C:12](=[C:13]([CH3:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]2[CH:21]([NH:23][CH3:24])[CH3:22])=[CH:5][CH:4]=1.[C:25]([C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([N:23]([CH:21]([C:10]2[N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:18](=[O:19])[C:17]3[C:12](=[C:13]([CH3:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH3:22])[CH3:24])(=[O:37])=[O:36])=[CH:31][CH:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CNC(C)c1nc2c(C)cccc2c(=O)n1-c1ccc(OC)cc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(-n2c(C(C)N(C)S(=O)(=O)c3ccc(C(C)(C)C)cc3)nc3c(C)cccc3c2=O)cc1

Procedure:
In a similar manner as described above, 3-(4-methoxyphenyl)-8-methyl-2-(1-methylaminoethyl)-3H-quinazolin-4-one, as prepared above in Example 5, was condensed with 4-tert-butylbenzenesulfonyl chloride to yield 4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide; MS (ESI) 520 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][NH:7][C:6]1=[O:10].[H-].[Na+].Br[CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]1.C(=O)(O)[O-].[Na+]>C1COCC1>[CH:24]1([N:7]2[CH2:8][CH2:9][CH:5]([CH2:4][C:3]3[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:2]=3[Cl:1])[C:6]2=[O:10])[CH2:23][CH2:22][CH2:21][CH:20]=[CH:19]1
Reactant: BrC1C=CCCC1
Reactant: O=C1NCCC1Cc1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C(Cc2ccc(Cl)cc2Cl)CCN1C1C=CCCC1
Temperature: 0 °C
Yield: 51.2 %

Procedure:
Charge a flask with 3-(2,4-dichloro-benzyl)-pyrrolidin-2-one (Preparation 19) (100 mg, 0.41 mmol), dissolve in THF (4 mL) and cool to 0° C. under nitrogen. Add NaH (15 mg, 0.61 mmol) and stir at 0° C. for 20 minutes. Add 3-bromo-cyclohexene (198 mg, 1.23 mmol) and stir at room temperature overnight. Pour into saturated aqueous sodium bicarbonate and extract with methylene chloride. Dry over sodium sulfate, filter and concentrate. Purify residue over silica gel (5:1 hexanes:ethyl acetate) to afford 68 mg (51%) of the title compound as a white solid. Mass spectrum (apci) m/z=324.1 (M+H).
Reaction SMILES: C([NH:9][C:10]([NH:22][CH2:23][CH2:24][CH2:25][C:26]1[N:27]=[CH:28][NH:29][CH:30]=1)=[N:11][CH2:12][CH2:13][CH2:14][S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=O)C1C=CC=CC=1>Cl>[NH:29]1[CH:30]=[C:26]([CH2:25][CH2:24][CH2:23][NH:22][C:10]([NH:11][CH2:12][CH2:13][CH2:14][S:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[NH:9])[N:27]=[CH:28]1
Reactant: O=C(NC(=NCCCSc1ccccc1)NCCCc1c[nH]cn1)c1ccccc1
Agent: Cl
Product: N=C(NCCCSc1ccccc1)NCCCc1c[nH]cn1

Procedure:
0.84 g (2 mmol) of N-benzoyl-N'-[3-(imidazol-4-yl) propyl]-N"-(3-phenylthiopropyl)-guanidine are heated under reflux in 18% hydrochloric acid for 7 hours and then worked up by a method analogous to that of Example 58. 0.71 g (91%) of a dry, hygroscopic foam is obtained.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)O)[CH2:9][CH2:8]1)=[O:6])[CH3:3].S(Cl)([Cl:25])=O>C1C=CC=CC=1>[ClH:25].[CH2:2]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH:14]([Cl:1])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)N1CCN(CC(O)c2ccc(F)cc2)CC1
Agent: Cl
Solvent: c1ccccc1
Product: CCOC(=O)N1CCN(CC(Cl)c2ccc(F)cc2)CC1
Temperature: 50 °C

Procedure:
To 8.3 g of 1-ethoxycarbonyl-4-[2-(4-fluorophenyl)-2-hydroxyethyl]piperazine hydrochloride were added 20 ml of benzene and 2.5 ml of thionyl chloride, followed by heating at 50° C. for 10 minutes. The reaction solution was concentrated under reduced pressure, 25% aqueous ammonia solution and water were poured, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and, after removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. To the residue was poured 50 ml of 4M hydrogen chloride/ethyl acetate solution, the solution was concentrated under reduced pressure, and the resulting solid was washed with ether to give 8.1 g of 1-ethoxycarbonyl-4-[2-chloro-2-(4-fluorophenyl)ethyl]-piperazine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:7](=[CH:23][N:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:25]=3)[C:8]([CH2:12][CH2:13][NH:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)=[N:9][C:10]=2[CH:11]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][CH:34]=1>C(Cl)Cl>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40](=[O:41])[N:14]([CH2:13][CH2:12][C:8]2[C:7]3=[CH:23][N:24]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:25]=[C:6]3[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:10]=3[N:9]=2)[C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[CH:35][CH:34]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: N#Cc1ccc(NCCc2nc3cc(Cl)ccc3c3nn(-c4ccccc4)cc23)cc1
Solvent: ClCCl
Product: N#Cc1ccc(N(CCc2nc3cc(Cl)ccc3c3nn(-c4ccccc4)cc23)C(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
A mixture of 150 mg (0.35 mmol) of the compound of Example 1, 100 mg (0.65 mmol) of p-chlorophenylisocyanate, and 10 ml of methylene chloride is stirred at ambient temperature overnight. The resulting precipitate is collected to furnish 121 mg (60%) of title compound: IR (KBr) 3360, 2220, 1660, 1590, 1520, 1500, 1490 cm-1 ; NMR (DMSO-d6) δ 9.56 (s, 1H), 8.8 (s, 1H, exchangeable), 8.8-7.26 (complex m, 16H), 4.45 (t, 2H), and 3.5 (t, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C@@H:8]12[C:17](=O)[O:16][C:14](=[O:15])[C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13]2.CS(O)(=O)=O>C1(C)C(C)=CC=CC=1>[N:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:14](=[O:15])[CH:9]3[CH:8]([CH2:13][CH2:12][CH2:11][CH2:10]3)[C:17]2=[O:16])=[CH:3][CH:4]=1
Reactant: Nc1ccncc1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1C
Product: O=C1C2CCCCC2C(=O)N1c1ccncc1
Reaction time: 18 h

Procedure:
The starting material is prepared as follows: The mixture of 23.5 g of 4- aminopyridine, 38.5 g of cis-1,2-cyclohexanedicarboxylic acid anhydride and 400 ml of xylene is refluxed for 42 hours while stirring and separating the water formed. After the first half-hour, and after 18 hours, 1 ml of methane sulfonic acid is added to the mixture. It is filtered hot, the crystals formed after cooling are filtered off and recrystallized from isopropanol, to yield the 2-(4-pyridyl)-hexahydroisoindole-1,3-dione melting at 165°-168°.
Reaction SMILES: C[CH:2]([CH2:17][N:18]1C(=O)C2=CC=CC=C2C1=O)[C:3](C)(C)[C:4](C)([P:10]([OH:13])([OH:12])=[O:11])[O:5]P(O)(O)=O>Cl>[NH2:18][CH2:17][CH2:2][CH2:3][C:4]([P:10](=[O:11])([OH:12])[OH:13])([P:10](=[O:11])([OH:13])[OH:12])[OH:5]
Reactant: CC(CN1C(=O)c2ccccc2C1=O)C(C)(C)C(C)(OP(=O)(O)O)P(=O)(O)O
Agent: Cl
Product: NCCCC(O)(P(=O)(O)O)P(=O)(O)O

Procedure:
Tetramethyl-1,1-bisphosphono-1-hydroxy-4-phthalimidobutane 40 g (0.091 mole) from Step 4 was dissolved in 200 ml of 6N HCl and the solution refluxed for 18 hours.
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[NH2:17][NH2:18]>N1C=CC=CC=1>[F:16][C:13]1[CH:12]=[C:3]2[C:2](=[CH:15][CH:14]=1)[NH:18][N:17]=[C:4]2[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NN
Reactant: O=C(c1ccccc1)c1cc(F)ccc1F
Solvent: c1ccncc1
Product: Fc1ccc2[nH]nc(-c3ccccc3)c2c1
Yield: 40 %

Procedure:
A solution of 2,5-difluorobenzophenone (0.655 g, 3.0 mmol) and hydrazine (1.0 mL) in dried pyridine (10 mL) was heated at 130° C. for 5 hours and then concentrated and purified by chromatography (SiO2, 15-30% ethyl acetate/hexane) to provide the title compound (0.254 g, 40% yield): mp 124-125° C.; 1H NMR (CDCl3) δ 10.89 (br s, 1H), 7.94 (d, 2H), 7.65 (dd, 1H), 7.42-7.54 (m, 3H), 7.33 (dd, 1H), 7.21 (dt, 1H); EL-MS (m/z) 212 [M]+.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[S:24][C:23]3[C:18](=[N:19][CH:20]=[CH:21][C:22]=3[Cl:25])[CH:17]=2)=[O:15])[CH2:10]1>>[Cl:25][C:22]1[CH:21]=[CH:20][N:19]=[C:18]2[CH:17]=[C:16]([C:14]([N:11]3[CH2:12][CH2:13][CH:9]([NH:8][S:3](=[O:5])(=[O:4])[N:2]([CH3:7])[CH3:1])[CH2:10]3)=[O:15])[S:24][C:23]=12
Reactant: NC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: CN(C)S(=O)(=O)Cl
Product: CN(C)S(=O)(=O)NC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1

Procedure:
The title compound was prepared from dimethylsulfamoyl chloride and (3-amino-pyrrolidin-1-yl)-(7-chloro-thieno[3,2-b]pyridin-2yl)-methanone by a procedure analogous to Example 64C. MS: 389/391 (MH+); HPLC Rf: 4.26 min.; HPLC purity 99%.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:7]([F:17])[C:6]([F:18])=[C:5]([F:19])[C:4]=1[F:20].[Cl:21]C1C=C(C=CC=1)C(OO)=[O:26]>C(Cl)Cl>[F:17][C:7]1[C:8]([S:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:26])=[C:3]([F:2])[C:4]([F:20])=[C:5]([F:19])[C:6]=1[F:18].[ClH:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1c(F)c(F)c(SCc2ccccn2)c(F)c1F
Agent: Cl
Solvent: ClCCl
Product: O=S(Cc1ccccn1)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred suspension of 2-(((pentafluorophenyl)thio)methyl)pyridine, hydrochloride (2.0 g) in methylene chloride (50 ml) at 0° C. was treated portionwise with m-chloroperoxybenzoic acid (1.41 g) over 1/2 hour. The mixture was allowed to warm to ambient temperature, sufficient methylene chloride was added to form a solution, and the mixture was stirred a further 1/2 hour. The solution was washed with saturated Na2CO3 solution and water, dried (MgSO4) and evaporated. The residue was converted into the hydrochloride in acetone with ethereal HCl solution to give the title compound, hydrochloride (1.3 g) mp 154°-6° C. (Found: C,41.6; H,2.15; N,3.8 C12H6F5NOS.HCl requires C41.9; H,2.05; N,4.1%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8](S(C)=O)[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][S:16](=[O:19])[CH2:15][CH2:14]2)[C:5]=1[N+:20]([O-:22])=[O:21])[CH3:2].[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.O>C(O)C>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][S:16](=[O:19])[CH2:15][CH2:14]2)[C:5]=1[N+:20]([O-:22])=[O:21])[CH3:2]
Reactant: CCOc1nc(S(C)=O)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]
Reactant: C1CNCCN1
Solvent: CCO
Solvent: O
Product: CCOc1nc(N2CCNCC2)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]

Procedure:
1 gm (2.9 mols) of 6-ethoxy-2-methylsulfinyl-5-nitro-4-(1-oxido-thiomorpholino)-pyrimidine [m.p. 164°-165°C, prepared from 6 ethoxy-2-methylthio-5-nitro-4-(1-oxido-thiomorpholino)-pyrimidine and 30% hydrogen peroxide in dilute acetic acid] was refluxed together with 5 gm (58 millimols) of piperazine in 50 ml of ethanol for 10 minutes. The reaction mixture was then poured into water, and the aqueous mixture was extracted with chloroform. The chloroform phase was dried, evaporated to dryness, and the residue was recrystallized from ethanol. Yield: 0.9 gm (84.7% of theory); m.p. 220°-222°C.
Reaction SMILES: C(Cl)Cl.[N+:4]([O-:7])([OH:6])=[O:5].OS(O)(=O)=O.O[CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18].[K+]>O>[N+:4]([O:7][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])([O-:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: O=C([O-])CCCO
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(O)CCCO[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
CH2Cl2 (10 ml) was added to the HNO3/H2SO4 mixture, and the resulting solution was stirred for 15 minutes. Potassium 4-(hydroxy)butanoate (500 mg, 3.52 mmol) was then added in small portions to the methylenechloride solution kept at 0-5° C. The mixture was kept under stirring for 6 hours while the temperature was allowed to reach 25° C. gradually. Water (50 ml) was added to the reaction mixture and the resulting mixture was extracted with CH2Cl2 (3×25 ml). The combined organic phases were washed with water, dried over MgSO4 and concentrated to dryness under reduced pressure. 4-(Nitrooxy)butanoic acid was obtained as a yellow oil (300 mg, 57%) and used in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=3)[C:12]3[C:17]([CH:18]=2)=[C:16]([O:19][CH3:20])[CH:15]=[CH:14][CH:13]=3)=[O:9])=[CH:4][CH:3]=1.[ClH:32].[NH3:33]>>[ClH:32].[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28](=[NH:33])[NH2:29])[CH:23]=3)[C:12]3[C:17]([CH:18]=2)=[C:16]([O:19][CH3:20])[CH:15]=[CH:14][CH:13]=3)=[O:9])=[CH:30][CH:31]=1
Reactant: N
Reactant: COc1cccc2c1cc(C(=O)NCc1ccc(O)cc1)n2Cc1cccc(C#N)c1
Agent: Cl
Product: COc1cccc2c1cc(C(=O)NCc1ccc(O)cc1)n2Cc1cccc(C(=N)N)c1
Yield: 79 %

Procedure:
This compound was prepared from 1-(3-cyano-benzyl)-4-methoxy-1H-indole-2-carboxylic acid 4-hydroxy-benzyl amide (200 mg, 0.49 mmol), hydrogen chloride, and liquid ammonia analogously to example 19/3. Purification by reversed phase chromatography on RP18 material with water/ethanol/acetic acid 7:3:0.1 and lyophilization gave 179 mg of the desired product (79%). M.p. 202° C. (dec.). MS: 429.2 (100%; M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][C:7]=1[C:8]#[N:9].Cl[C:21]1[CH:22]=[C:23]2[N:30]([CH:31]3[CH2:33][CH2:32]3)[CH2:29][CH2:28][N:24]2[C:25](=[O:27])[N:26]=1>>[CH:31]1([N:30]2[C:23]3[N:24]([C:25](=[O:27])[N:26]=[C:21]([O:15][CH2:14][C:11]4[CH:12]=[CH:13][C:6]([O:5][C:4]5[CH:16]=[CH:17][C:18]([F:19])=[C:2]([F:1])[CH:3]=5)=[C:7]([CH:10]=4)[C:8]#[N:9])[CH:22]=3)[CH2:28][CH2:29]2)[CH2:33][CH2:32]1
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(F)c(F)c1
Reactant: O=c1nc(Cl)cc2n1CCN2C1CC1
Product: N#Cc1cc(COc2cc3n(c(=O)n2)CCN3C2CC2)ccc1Oc1ccc(F)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 2-(3,4-difluorophenoxy)-5-(hydroxymethyl)benzonitrile and 7-chloro-1-cyclopropyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.