Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].Br.[Br:14][CH2:15][CH2:16][CH2:17][NH2:18].C(N(CC)CC)C>ClCCl>[Br:14][CH2:15][CH2:16][CH2:17][NH:18][S:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: NCCCBr
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)NCCCBr)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Cyanobenzenesulfonyl chloride (5 g, 0.0248 mol) was added dropwise to a solution of 3-bromopropylamine hydrobromide (6.61 g, 0.0302 mol) and triethylamine (6.26 g, 0.062 mol) in dry dichloromethane (50 ml) at 0° C. and stirred at room temperature overnight under nitrogen atmosphere. The reaction was quenched with water and extracted with dichloromethane. The organic layer was washed with water, brine and dried over sodium sulfate.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][CH2:25][C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])[CH:6]=1)(=O)[CH3:2].[H-].[Na+].Br[CH2:36]C#C.O>CN(C)C=O.C(OCC)(=O)C>[F:23][C:11]1[CH:12]=[C:13]([CH3:22])[C:14]([S:16][CH2:17][C:18]([F:19])([F:20])[F:21])=[CH:15][C:10]=1[N:9]1[C:5]([NH:4][CH2:1][C:2]#[CH:36])=[CH:6][C:7]([O:24][CH2:25][C:26]([F:32])([F:31])[C:27]([F:29])([F:30])[F:28])=[N:8]1
Reactant: C#CCBr
Reactant: CC(=O)Nc1cc(OCC(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C#CCNc1cc(OCC(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
2.0 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole was dissolved in 15 mL of dimethylformamide, and under cooling with ice, the solution was dropwise added to a suspension having 0.23 g of sodium hydride suspended in 10 mL of dimethylformamide, and after completion of the dropwise addition, stirring was carried out at room temperature for 30minutes. The reaction solution was cooled with ice again, and 0.72 g of 1-bromo-2-propyne was added, followed by stirring at room temperature for 1 hour. Then, the reaction mixture was poured into water, extraction with ethyl acetate was carried out, and after washing with water, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was dissolved in 20 mL of ethanol, and 20 mL of a 35 mass % hydrochloric acid aqueous solution was added, followed by stirring under reflux with heating for 2 hours. The reaction mixture was poured into water, extraction with ethyl acetate was carried out, and after washing with water, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 1.4 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)-5-(2-propynylamino)pyrazole.
Reaction SMILES: CCC([O-])(C)C.[Na+].Cl[C:9]1[C:10]([Cl:16])=[N:11][C:12]([Cl:15])=[N:13][CH:14]=1.[CH3:17][CH:18]([CH3:22])[CH2:19][CH2:20][OH:21]>>[Cl:15][C:12]1[N:11]=[C:10]([Cl:16])[CH:9]=[C:14]([O:21][CH2:20][CH2:19][CH:18]([CH3:22])[CH3:17])[N:13]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)CCO
Agent: CCC(C)(C)[O-]
Agent: [Na+]
Product: CC(C)CCOc1cc(Cl)nc(Cl)n1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A solution of 28.6 g (0.26 mol) of sodium tert-amylate in 150 ml of 3-methylbutanol is stirred at 45°-50° C. for 30 minutes, cooled to 20° C. and added dropwise at -30° C. to a solution of 30 ml (0.26 mol) of trichloropyrimidine in 150 ml of 3-methylbutanol. When the solution has been added, the temperature is 0° C. The reaction mixture is left to stand overnight. The solvent is removed and the residue is taken up in 150 ml of water. Extraction three times with toluene, drying of the combined organic phases using MgSO4 and evaporation give 60.36 g (98.7% of theory) of the title compound.
Reaction SMILES: [Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]2)[C:10]([F:23])=[CH:9][C:8]=1[Cl:24])[C:3]([OH:5])=[O:4].[CH2:25](O)[CH3:26].S(=O)(=O)(O)O>CC1C=CC=CC=1>[CH3:25][CH2:26][O:4][C:3]([CH:2]([Cl:1])[CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[N:14]=[C:15]([CH3:22])[N:16]([CH:19]([F:20])[F:21])[C:17]2=[O:18])[C:10]([F:23])=[CH:9][C:8]=1[Cl:24])=[O:5]
Reactant: Cc1nn(-c2cc(CC(Cl)C(=O)O)c(Cl)cc2F)c(=O)n1C(F)F
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cl)Cc1cc(-n2nc(C)n(C(F)F)c2=O)c(F)cc1Cl
Yield: 92 %

Procedure:
To a flask was added 140 g of the 2-chloro-3-{2-chloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]-4-fluorophenyl}propionic acid, obtained according to the Example 2, 160 g of ethanol, 7 g of sulfuric acid and 700 g of methyl benzene. The mixture was refluxed for 15 hours to remove water. The excess ethanol was recovered by distillation. At room temperature the mixture was washed with 200 g of water, with 200 g of a 4% (wt/wt) aqueous solution of potassium hydroxide and finally with water. The solvent was completely removed under reduced pressure to give carfentrazone-ethyl as a faint yellow transparent and viscous liquid in a yield of 92% with a purity of 98.8%.
Reaction SMILES: Br[CH:2]([CH:20]([CH3:22])[CH3:21])[C:3]([O:5]CC1C=CC=C(OC2C=CC=CC=2)C=1)=[O:4].[CH3:23][C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:25]=1[NH2:26].[I-].[K+]>S(=O)(=O)(O)O>[CH3:23][C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:25]=1[NH:26][C@H:2]([C:3]([OH:5])=[O:4])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)C(Br)C(=O)OCc1cccc(Oc2ccccc2)c1
Reactant: Cc1cccc(C)c1N
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [K+]
Product: Cc1cccc(C)c1N[C@H](C(=O)O)C(C)C
Temperature: 0 °C

Procedure:
To m-phenoxybenzyl α-bromoisovalerate (2 g, 0.0055 mole), 24°, is added 2,6-dimethylaniline (3.33 g, 0.0275 mole) followed by a catalytic amount of potassium iodide (20 mg). The reaction mixture is heated at about 120° for 48 hours, and then poured into ice-water (20 ml) and 2 N sulfuric acid (10 ml) and extracted with ether (3×30 ml). The combined ether extracts are washed with water (2×20 ml) until neutral and with brine (10 ml) followed by drying over calcium sulfate. The reaction product is concentrated under vacuum and isolated by preparative TLC to give m-phenoxybenzyl ester of N-(2,6-dimethylphenyl)valine. MS m/e 403.2 (M+, 7.5).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:17]1C=CC=CC=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>O1CCOCC1>[NH2:17][C:14]([CH:9]1[CH2:10][O:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCOCC1C(=O)O
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCOCC1C(N)=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of the compound prepared in Step 1 (1 eq.), pyridine (0.6 eq.) and di-t-butyl dicarbonate (1.3 eq.) in dioxane (0.6 M), NH4HCO3 (1.26 eq.) was added and the mixture was stirred at room temperature for 20 hours. Mixture was concentrated, taken up in EtOAc and washed with water and brine. Organics were dried over Na2SO4 and evaporated giving the title product as an oil which crystallized at room temperature.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:39]=[CH:38][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:37]=[CH:36][C:28]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:27][CH:26]=3)[N:13]=2)=[CH:8][C:7]=1[Cl:40].FC(F)(F)C(O)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:39]=[CH:38][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:22])([F:21])[F:23])[N:15]=[C:14]([NH:24][C:25]3[CH:37]=[CH:36][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=3)[N:13]=2)=[CH:8][C:7]=1[Cl:40]
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(NCc3ccc(OCCCBr)c(Cl)c3)nc(OCC(F)(F)F)n2)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(Nc2nc(NCc3ccc(OCCCBr)c(Cl)c3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 100 mL round-bottom flask equipped with a stir bar and charged with tert-butyl 4-((4-((4-(3-bromopropoxy)-3-chlorobenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoate (8.42 g, 13.0 mmol) in CH2Cl2 (15 mL) was added trifluoroacetic acid (15.0 mL, 195 mmol). The solution was stirred at room temperature for 2 h. The solution was diluted with toluene (20 mL) and then concentrated in vacuo to afford crude 4-((4-((4-(3-bromopropoxy)-3-chlorobenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoic acid as a solid foam.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])[C:5]([O:14][CH3:15])=[CH:4][C:3]=1[CH3:16].CCCCCC.CN([CH:26]=[O:27])C>C1COCC1>[CH3:15][O:14][C:5]1[C:6]([O:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:7][C:2]([CH:26]=[O:27])=[C:3]([CH3:16])[CH:4]=1
Reactant: CN(C)C=O
Reactant: COCCCOc1cc(Br)c(C)cc1OC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCCCOc1cc(C=O)c(C)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-bromo-4-methoxy-5-(3-methoxy-propoxy)-2-methyl-benzene (2.50 g, 8.65 mmol) in THF (25 mL), cooled to −70° C., is added a 1.6M solution of n-buthyllithium in hexane (5.94 mL, 9.51 mmol). After 30 min, DMF (1.05 mL, 13.0 mmol) is added and stirring is continued overnight while the reaction mixture is gradually warmed to room temperature. Quenching with ice-cold 1N aqueous HCl is followed by extraction with diethyl ether. The combined organic layers are washed with brine, dried (Na2SO4) and concentrated. Purification by flash chromatography on silica gel (hexane/AcOEt 7:2) gives the title compound as oil. TLC, Rf (hexane/AcOEt 1:1)=0.29. MS: 239.2 [M+H]+. 1H-NMR (CDCl3): δ 2.16 (m, 2H), 2.66 (s, 3H), 3.39 (s, 3H), 3.60 (m, 2H), 3.97 (s, 3H), 4.18 (m, 2H), 6.73 (s, 1H), 7.40 (s, 1H), 10.2 (s, 1H) ppm.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:10]([I:11])=[C:6]2[N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:26]([NH:28][C:29]1([C:35]([NH2:37])=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:27]>C(O)C.C(Cl)Cl>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[C:10]([I:11])=[C:6]2[N:5]=[CH:4][CH:3]=[C:2]([N:32]3[CH2:31][CH2:30][C:29]([NH:28][CH2:26][CH3:27])([C:35]([NH2:37])=[O:36])[CH2:34][CH2:33]3)[N:7]2[N:8]=1
Reactant: Clc1ccccc1-c1nn2c(Cl)ccnc2c1I
Reactant: CCNC1(C(N)=O)CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: CCNC1(C(N)=O)CCN(c2ccnc3c(I)c(-c4ccccc4Cl)nn23)CC1
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of 7-chloro-2-(2-chlorophenyl)-3-iodopyrazolo[1,5-a]pyrimidine (I-1A-1d; 80 mg, 0.21 mmol) and triethylamine (44 μl, 0.32 mmol) in 1:1 ethanol/methylene chloride (2 ml) was added 4-ethylaminopiperidine-4-carboxylic acid amide (I-1A-1g; 40 mg, 0.23 mmol). A colorless precipitate formed after several minutes and the mixture was stirred overnight. The solid precipitate was isolated by vacuum filtration, washed with ethanol and ether, and then dried, in vacuo, to afford product I-1A-1h as an off-white solid (95 mg, 86%): +APcI MS (M+1) 525.4; 1H NMR (400 MHz, CD3OD) δ 8.27 (d, J=5.4 Hz, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.48–7.39 (m, 3H), 6.45 (d, J=5.6 Hz, 1H), 4.14–3.96 (m, 2H), 3.92–3.84 (m, 2H), 2.50 (q, J=7.1 Hz, 2H), 2.23–2.15 (m, 2H), 1.85–1.77 (m, 2H), 1.16 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([O:16][C:17]([F:20])([F:19])[F:18])[CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[F:18][C:17]([F:20])([F:19])[O:16][C:4]1[CH:3]=[C:2]([C:26]2[CH:27]=[CH:28][C:23]([C:22]([F:33])([F:32])[F:21])=[CH:24][CH:25]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: O=C1NCCn2c1cc1cc(OC(F)(F)F)cc(Br)c12
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=C1NCCn2c1cc1cc(OC(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)c12

Procedure:
The title compound, white solid (87 mg, 84%), MS (ISP) m/z=415.4 [(M+H)+], mp 243° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-(trifluoromethoxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 19) (87.3 mg, 0.25 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH2:13][CH3:14])[C:6](=[O:15])[CH2:5]2.[CH3:16][O:17][C:18]([C@@H:20]1[O:22][CH2:21]1)=[O:19].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C.C(OCC)(=O)C>[CH3:16][O:17][C:18](=[O:19])[C@H:20]([OH:22])[CH2:21][NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH2:13][CH3:14])[C:6](=[O:15])[CH2:5]2
Reactant: COC(=O)[C@H]1CO1
Reactant: CCCN1C(=O)Cc2cc(N)cc(F)c21
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCN1C(=O)Cc2cc(NC[C@@H](O)C(=O)OC)cc(F)c21

Procedure:
5-Amino-7-fluoro-1-propyl-1,3-dihydro-indol-2-one (0.300 g, 1.44 mmol), methyl (2R)-glycidate (0.147 g, 1.44 mmol) and lithium trifluoromethanesulfonate (0.220 g, 1.44 mmol) in acetonitrile (5 ml) are heated at 90° C. for 8 hours. The reaction is diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated. The residue is purified by PTLC (5% methanol/dichloromethane) to give the title compound as a yellow solid. HPLC r.t. 4.03 min; MS for C15H19FN2O4 m/z 311.2 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]([CH3:32])[C:7]([CH2:20][NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)(=[O:24])=[O:23])=[CH:8][C:9](=[O:19])[C:10]=1[O:11]CC1C=CC=CC=1)=[O:4].C1(S(C(N)C2N(C)C(C(O)=O)=C(O)C(=O)C=2)(=O)=O)C=CC=CC=1>>[CH3:1][NH:2][C:3]([C:5]1[N:6]([CH3:32])[C:7]([CH2:20][NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)(=[O:24])=[O:23])=[CH:8][C:9](=[O:19])[C:10]=1[OH:11])=[O:4]
Reactant: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2cccc(Cl)c2)n1C
Agent: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(O)c1C(=O)O
Product: CNC(=O)c1c(O)c(=O)cc(CNS(=O)(=O)c2cccc(Cl)c2)n1C
Yield: 59.6 %

Procedure:
6-[(3-Chloro-benzenesulfonylamino)-methyl]-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide (16-05) (193.0 mg, 59.40%, purified by Prep-HPLC) was synthesized as an off white solid from 3-benzyloxy-6-[(3-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-05) (400.0 mg, 0.84 mmol) following the procedure described for 6-(benzene sulfonyl amino-methyl)-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (14-01).
Reaction SMILES: C([C:8]1[NH:12][C:11]([C:13]([NH:15][C@H:16]([C:18]([NH:20][C@H:21]([CH:26]=[O:27])[CH2:22][C:23]([OH:25])=[O:24])=[O:19])[CH3:17])=[O:14])=[CH:10][CH:9]=1)C1C=CC=CC=1.C(C1NC(C(N[C@@H](C(N[C@H]2CC(=O)O[C@@H]2OCC2C=CC=CC=2)=O)C)=O)=CC=1)C1C=CC=CC=1.[K+].[Br-]>CO>[NH:12]1[CH:8]=[CH:9][CH:10]=[C:11]1[C:13]([NH:15][C@H:16]([C:18]([NH:20][C@H:21]([CH:26]=[O:27])[CH2:22][C:23]([OH:25])=[O:24])=[O:19])[CH3:17])=[O:14]
Reactant: C[C@H](NC(=O)c1ccc(Cc2ccccc2)[nH]1)C(=O)N[C@H](C=O)CC(=O)O
Agent: C[C@@H](NC(=O)c1ccc(Cc2ccccc2)[nH]1)C(=O)N[C@H]1CC(=O)O[C@@H]1OCc1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: C[C@H](NC(=O)c1ccc[nH]1)C(=O)N[C@H](C=O)CC(=O)O

Procedure:
(3S)3-[N-(5-Benzylpyrrole-2-carbonyl)-L-alaninyl]amino-4-oxobutanoic acid (36b), was prepared (41%) from 35b by the method described for compound 36a, to afford an off white solid: mp. 109-112° C.; [α]D25 +6.3° (c 0.3, methanol); IR (KBr) 3368, 1724, 1630, 1530, 1453, 1414, 1233, 1049; 1H NMR (d4 methanol) δ 7.25-7.11 (5H, m), 6.76 (1H, d, J=3.5), 5.84 (1H, d, J=3.5), 4.51 (1H, m), 4.43 (1H, q, J=7.1), 4.23 (1H, m), 2.5 (2H, m), 1.35 (3H, d, J=7.0). Anal. Calcd for C19H21N3O5. 1.75H2O: C, 56.64; H, 6.13; N, 10.43. Found: C, 56.34; H, 5.72; N, 10.00.
Reaction SMILES: [CH2:1]([PH:5](=[O:7])[OH:6])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH2:15]([O:17]C(Cl)=O)[CH3:16]>ClCCl>[CH2:15]([O:17][P:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:6])[OH:7])[CH3:16]
Reactant: CCOC(=O)Cl
Reactant: CCCC[PH](=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCP(=O)(O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
51 g of n-butylphosphinic acid are dissolved in 200 ml of dichloromethane, the solution is cooled to 10°, and 42.3 g of triethylamine are added dropwise. An exothermic reaction takes place. The mixture is cooled to 10° again and 45.3 g of chloroformic acid ethyl ester are added dropwise within a period of 75 minutes. A precipitate forms in an exothermic reaction with the evolution of gas. A further 200 ml of dichloromethane are then added and the mixture is allowed to warm to room temperature and is then stirred for 2 hours at room temperature, washed with water and dried over sodium sulfate, and the organic solvent is removed. The crude product is distilled under a high vacuum, yielding n-butyl-phosphonic acid ethyl ester having a boiling point of 95° (5×10-5 bar).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.P(CCCC)(CCCC)CCCC.[CH2:28]([CH:30]1[CH:34]([C:35]2[N:39]3[C:40]4[CH:46]=[CH:45][N:44]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[C:41]=4[N:42]=[CH:43][C:38]3=[N:37][N:36]=2)[CH2:33][CH:32](O)[CH2:31]1)[CH3:29].[F:56][C:57]([F:61])([F:60])[CH2:58][SH:59]>C1COCC1>[CH2:28]([CH:30]1[CH2:31][CH:32]([S:59][CH2:58][C:57]([F:61])([F:60])[F:56])[CH2:33][CH:34]1[C:35]1[N:39]2[C:40]3[CH:46]=[CH:45][N:44]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:52])([CH3:54])[CH3:53])[C:41]=3[N:42]=[CH:43][C:38]2=[N:37][N:36]=1)[CH3:29]
Reactant: FC(F)(F)CS
Reactant: CCC1CC(O)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCC1CC(SCC(F)(F)F)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.2 %

Procedure:
An oven-dried flask was charged with DIAD (0.177 mL, 0.896 mmol) and THF (3.74 mL). The reaction flask was cooled to 0° C. before the addition of P(n-Bu)3 (0.221 mL, 0.896 mmol), 3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol (0.300 g, 0.747 mmol, prepared from Preparation #20 using KK and SS), TEA (0.125 mL, 0.896 mmol) and 2,2,2-trifluoroethanthiol (0.080 mL, 0.896 mmol). The reaction was stirred at ambient temperature for about 16 h. The reaction mixture was partitioned between water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concd under reduced pressure to afford a crude oil. The crude material was purified by silica gel chromatography eluting with a gradient of 0-60% EtOAc in DCM to afford 1-(2-ethyl-4-(2,2,2-trifluoroethylthio)cyclopentyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.165 g, 44%) as an orange solid: LC/MS (Table 1, Method a) Rt=3.02 min; MS m/z: 500 (M+H)+.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][C:3](=[O:9])[CH2:2]2.Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].CCN(C(C)C)C(C)C>C(Cl)Cl>[O:9]=[C:3]1[CH2:2][CH:1]2[N:8]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH:5]([CH2:6][CH2:7]2)[CH2:4]1
Reactant: O=C1CC2CCC(C1)N2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CC2CCC(C1)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
8-azabicyclo[3.2.1]octan-3-one (5.10 g; 31.55 mmol) was dissolved in CH2Cl2 (50 mL) and treated with benzyl chloroformate (4.29 mL; 5.11 g; 29.98 mmol) DIPEA (16.48 mL; 12.23 g; 94.66 mmol) was added drop-wise (exothermic reaction). The resulting clear solution was allowed to stir at room temperature for 30 min and was subsequently diluted with 100 mL CH2Cl2. The organic phase was washed with 1 N HCl (2×100 mL), dried on Na2SO4 and concentrated to provide the crude product (7.2 g). 1H-NMR (400 MHz, CDCl3) δ 7.38 (m, 5H), 5.22 (s, 2H), 4.62 (s, 2H), 2.67 (m, 2H), 2.38 (d, J=15.9 Hz, 2H), 2.12 (m, 2H), 1.71 (dd, J=15.0, 7.2 Hz, 2H).
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[NH2:14][C:15]([NH2:17])=[S:16]>C(O)C>[ClH:2].[ClH:1].[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][S:16][C:15](=[NH:14])[NH2:17]
Reactant: ClCc1ccc2ccccc2n1
Reactant: NC(N)=S
Agent: Cl
Solvent: CCO
Product: N=C(N)SCc1ccc2ccccc2n1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
A suspension, kept at 70° C., of 2-chloromethylquinoline hydrochloride (107 g) in ethanol (450 cc) is added dropwise and in the course of 15 minutes to a suspension of thiourea (45.5 g) in boiling ethanol (260 cc). The reaction mixture is stirred for 1 hour 30 minutes at the boil and then cooled to 20° C. The resulting crystals are filtered off, washed twice with ethanol (100 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. 2-(Quinol-2-yl-methyl)-isothiourea dihydrochloride (141 g), melting at 250° C., is thus obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][OH:10])[C:5]([CH2:11][CH:12]([C:18]([O:20]CC)=[O:19])[C:13]([O:15]CC)=[O:14])=[CH:4][N:3]=1>[OH-].[Na+].C(O)C>[CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][OH:10])[C:5]([CH2:11][CH:12]([C:18]([OH:20])=[O:19])[C:13]([OH:15])=[O:14])=[CH:4][N:3]=1
Reactant: CCOC(=O)C(Cc1cnc(C)c(O)c1CO)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ncc(CC(C(=O)O)C(=O)O)c(CO)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 25, of structure XXIX (620 mg, 2.0 mmol) was dissolved in aqueous NaOH (2 M, 4 mL) and stirred at room temperature for 1 hour. The reaction was quenched by adding 6 N HCl to give pH 4 to 5. The solution was diluted with 95% ethanol, separated from the precipitated salts and evaporated to give 540 mg.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].C1C=NC2N(O)N=NC=2C=1.[ClH:28].Cl.[CH:30]([N:33]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)([CH3:32])[CH3:31].C(N(CC)C(C)C)(C)C.Cl>CN(C=O)C.C(Cl)Cl.C(Cl)CCl>[ClH:28].[CH:30]([N:33]1[CH2:39][CH2:38][CH2:37][N:36]([C:13]([C:12]2[CH:11]=[CH:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[N:8][CH:7]=3)=[CH:17][CH:16]=2)=[O:15])[CH2:35][CH2:34]1)([CH3:32])[CH3:31]
Reactant: N#Cc1ccc(-c2ccc(C(=O)O)cc2)cn1
Reactant: CC(C)N1CCCNCC1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N1CCCN(C(=O)c2ccc(-c3ccc(C#N)nc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 1.6 %

Procedure:
4-(6-Cyano-3-pyridinyl)benzoic acid (D9) (0.35 g) was dissolved in dry DMF and treated with EDC (0.51 g) and a catalytic quantity of HOAT. The reaction mixture was stirred at rt for 5 min, followed by the addition of 1-(isopropyl)-hexahydro-1H-1,4-diazepine dihydrochloride (D2) (0.28 g) and N,N-diisopropylethylamine (1 ml), and allowed to stir at rt overnight. After evaporation of solvent the residue was partitioned between DCM (15 ml) and water (15 ml). The DCM layer was dried (magnesium sulfate) and concentrated to leave a crude residue which was purified by flash chromatography [silica gel, step gradient 0-15% MeOH (containing 10% 0.88 ammonia solution) in DCM]. Pure fractions were combined and concentrated to give the free base which was converted into the HCl salt in DCM (2 ml) with 1N ethereal HCl (1 ml). Evaporation of the solvents afforded the title compound (E15) (8 mg). 1H NMR δ (methanol-d4): 1.4 (6H, d, J=6.4 Hz), 2.16 (2H, bs), 3.47-4.2 (8H, m), 4.2-4.4 (1H, m), 7.68 (2H, d, J=8 Hz), 7.85 (2H, d, J=8 Hz), 7.98 (1H, d, J=8 Hz), 8.29 (1H, dd, J=8 Hz), 9.04 (1H, d, J=1.6 Hz). LCMS electrospray (+ve) 349 (MH+).