Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:4][C:3]=1[NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14]
Reactant: BrC1CCCC1
Reactant: CCOC(=O)Nc1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Reaction time: 7 h
Yield: 98.3 %

Procedure:
Then, a solution of the resulting ethyl N-(2-fluoro-4-chloro-5-hydroxyphenyl)carbamate (10.0 g, 42.8 mmol) and potassium carbonate (8.87 g, 64.2 mmol) in acetonitrile (150 ml) was stirred for 1 hour at 80° C. Then, cyclopentyl bromide (9.57 g, 84.2 mmol) was added dropwise thereto, followed by reacting for further 7 hours. After completion of the reaction, tile solvent was distilled off under reduced pressure, and the residue was made acidic by adding 1N hydrochloric acid (100 ml) and extracted with ethyl acetate (100 ml×3 times). The organic layer was washed with water, dried, and the solvent was distilled off under reduced pressure to obtain ethyl N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)carbamate (12.7 g, 98% yield).
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:19][CH2:18][S:17][C:9]2[N:8]([CH2:7][C:6]([OH:28])=[O:5])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)Cn1c(SCCOc2ccc(Cl)cc2)nc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1c(SCCOc2ccc(Cl)cc2)nc2ccccc21
Yield: 9.4 %

Procedure:
A solution tert-butyl{2-[2-(4-chloro-phenoxy)-ethylsulfanyl]-benzoimidazol-1-yl}-acetate (Precursor D-01b, 33 mg, 0.79 mmol) is stirred in TFA/dichloromethane (1:1, 0.8 ml) at rt for 3 h. The volatiles are removed in vacuo and the residue is purified by flash-chromatography on silica gel (AcOEt/heptane, 1:1; then pure AcOEt), yielding the title compound (27 mg) in 95% as a white solid: tR=5.73 min (LC-1), MS (pos.): m/z 362.8 [M+H]+, MS (neg.): m/z 360.8 [M−H]+; 1H-NMR (CDCl3): δ (ppm) 3.88 (m, 2H, SCH2), 4.22 (t, 2H, OCH2), 4.88 (s, 2H, CH2CO2), 6.54 (d, 2H, Harom), 7.12 (d, 2 Harom), 7.32-7.46 (m, 3Harom), 7.82 (m, 1Harom).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30](O)=[O:31])=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(C(C)C)CC)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[CH2:33]([NH:40][C:30]([C:29]1[C:22]2[C:21]([NH:20][C@H:18]([C:7]3[N:8]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:9](=[O:11])[C:10]4=[C:2]([CH3:1])[CH:3]=[CH:4][N:5]4[N:6]=3)[CH3:19])=[N:26][CH:25]=[N:24][C:23]=2[NH:27][CH:28]=1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(C(=O)O)c34)n(-c3ccccc3)c(=O)c12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(C(=O)NCc5ccccc5)c34)n(-c3ccccc3)c(=O)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
(S)-4-((1-(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (30 mg, 0.07 mmol), benzylamine (20 mg, 0.19 mmol) and diisopropylethylamine (50 μl, 0.29 mmol) were dissolved in DMF (1.5 ml) and stirred for 30 min. The reaction flask was then sealed and T3P® (50% in DMF, 50 μl) was added dropwise and the reaction mixture was stirred overnight at room temperature. The mixture was poured into ice-water and extracted with ethyl acetate. The resulting organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by flash chromatography (0% to 5% DCM/MeOH) to give 17 mg (46% yield) of the title compound as a white solid.
Reaction SMILES: [Cu+2:1].N.[P:3]([O:7][P:8]([OH:11])([OH:10])=[O:9])([OH:6])([OH:5])=[O:4]>>[O-:5][P:3]([O:7][P:8]([O-:11])([O-:10])=[O:9])(=[O:4])[O-:6].[Cu+4:1]
Reactant: O=P(O)(O)OP(=O)(O)O
Reactant: [Cu+2]
Agent: N
Product: O=P([O-])([O-])OP(=O)([O-])[O-]
Product: [Cu+4]
Reaction time: 0.88 h

Procedure:
This bath contained 22.5 g/liter of copper (II) ion, 1.2 g/liter of ammonia, 175 g/liter of pyrophosphoric acid and 1 g/l of a brightener and had a pH of 8.1 to 8.5. The sample was immersed in this bath at 55° C. for 45 to 60 minutes while applying an electric current of 30 A/foot2.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:14])[O:9][C:8]2[CH:10]=[CH:11][S:12][C:7]=2[C:6](=O)[CH2:5]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:3][C:4]1([CH3:14])[O:9][C:8]2[CH:10]=[CH:11][S:12][C:7]=2[CH:6]=[CH:5]1
Reactant: CC1(C)CC(=O)c2sccc2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(C)C=Cc2sccc2O1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Sodium borohydride (3.27 g, 86.3 mmol) was added to a solution of 5,6-dihydro-5,5-dimethyl-7H-thieno [3,2-b]pyran-7-one (12.1 g, 66.4 mmol) in ethanol (100 mL) and the resultant mixture was stirred at rt for 17 h. The mixture was poured into water (400 mL) and extracted with dichloromethane (2×100 mL). The dichloromethane solution was washed with water (5×), dried over sodium sulfate, and filtered. Molecular sieves (12 g) and p-toluenesulfonic acid (1.2 g, 6.3 mmol) was added to the resultant solution and stirred at 0° C. for 1.5 h. The reaction mixture was filtered, washed with saturated aqueous sodium bicarbonate and dried over sodium sulfate. The solvent was evaporated in vacuo to give the product, 11.0 g (99%), as a red oil which was identical in all respects to the product described in Method A.
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([O:8][CH2:9][CH2:10][NH2:11])([O-:7])=[O:6].C(=O)(O)[O-].[Na+].[C:17]([O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25])(=[O:19])[CH3:18]>O.C(Cl)(Cl)Cl>[C:17]([O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([NH:11][CH2:10][CH2:9][O:8][N+:5]([O-:7])=[O:6])=[O:25])(=[O:19])[CH3:18]
Reactant: NCCO[N+](=O)[O-]
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=[N+]([O-])O
Solvent: O
Product: CC(=O)Oc1cccc(C(=O)NCCO[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
18.6 g (0.110 mole) of 2-nitrooxy-ethylamine nitrate at 0° C. were added to a solution of 40.7 g (0.458 mole) of sodium bicarbonate in 140 ml of water and 120 ml of chloroform. After stirring for 10 min, 22.5 g (0.113 mole) of 3-acetoxybenzoic acid chloride were dropped therein and the resulting mixture was stirred for one hour at 0° C. The reaction mixture was warmed to room temperature, the two phases were separated and the organic phase was washed with water and dried over sodium sulfate. The crude title product was obtained, which was recrystallized from ethyl ether. M.p. 89°-91° C. Yield 26.5 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH2:24][C@H:25]1[CH2:29][CH2:28][C@@H:27]([C:30]([OH:32])=[O:31])[CH2:26]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CS(C)=O.CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:24][C@H:25]4[CH2:29][CH2:28][C@@H:27]([C:30]([OH:32])=[O:31])[CH2:26]4)=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: N[C@H]1CC[C@@H](C(=O)O)C1
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(F)cc3)n2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(N[C@H]4CC[C@@H](C(=O)O)C4)cc3)n2)cc1Cl
Temperature: 160 °C
Yield: 44.4 %

Procedure:
3-(3-Chloro-4-isopropoxyphenyl)-5-(4-fluorophenyl)-1,2,4-oxadiazole (360 mg, 1.082 mmol), (1R,3S)-3-aminocyclopentanecarboxylic acid (154 mg, 1.190 mmol), potassium carbonate (329 mg, 2.380 mmol) and DMF (2 ml) was heated with cooling at 160° C. on the Biotage microwave for 30 minutes. The mixture was diluted with DMSO (6 ml) and MeCN (8 ml), filtered and divided into 8 aliquots for purification by molecular ion directed LCMS. The fractions were combined and evaporated to afford a pale brown solid that was dried in vacuo at about 60° C. for about 3 hours. This gave (1R,3S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenylamino)cyclopentanecarboxylic acid (212 mg, 0.480 mmol, 44.3% yield) as a pale brown solid. LCMS (Table 1, Method a) Rt=3.49 min, m/z 440.20 (M−H)−. 1H NMR (400 MHz, DMSδ ppm 4.81 (s, 1H), 3.96-3.76 (m, 1H), 2.78 (s, 1H), 2.42-2.25 (m, 1H), 2.12-1.95 (m, 1H), 1.89 (d, J=7.72 Hz, 2H), 1.73-1.61 (m, 1H), 1.61-1.48 (m, 1H), 1.39-1.30 (m, 7H), 12.22-12.07 (m, 1H), 6.73 (d, J=8.82 Hz, 2H), 6.87-6.79 (m, 1H), 7.36 (d, J=8.63 Hz, 1H), 7.87 (d, J=8.59 Hz, 2H), 7.98 (ddd, J=9.78, 1.97, 1.06 Hz, 2H).
Reaction SMILES: FC(F)(F)C1C=C(C=CC=1)C=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].C1(C(C2CCCCC2)C(N[C@@H]2[C@H:51]3[C@H:47]([CH2:48][NH:49][CH2:50]3)[CH2:46][CH2:45]2)=O)CCCCC1>>[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][N:24]([CH2:48][C:47]3[CH:51]=[CH:50][N:49]=[CH:45][CH:46]=3)[CH2:25]2)[CH2:21][CH2:20]1)=[O:17]
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Agent: O=Cc1cccc(C(F)(F)F)c1
Product: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccncc3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting isonicotinaldehyde for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.70 (d, J=5.9, 2H), 8.62 (s, 1H), 7.64 (dd, J=3.0, 7.5, 2H), 7.36-7.30 (m, 2H), 7.25 (dd, J=7.0, 12.4, 3H), 4.39-4.30 (m, 1H), 3.51 (d, J=14.2, 0.5H), 3.41 (dd, J=11.5, 14.2, 1H), 3.28 (d, J=14.3, 0.5H), 3.23 (dd, J=1.8, 10.5, 1H), 2.94 (dd, J=2.6, 9.2, 0.5H), 2.69-2.60 (m, 1H), 2.57 (dd, J=2.9, 9.2, 1H), 2.52-2.46 (m, 0.5H), 2.42 (dd, J=7.2, 8.8, 1H), 2.38-2.31 (m, 0.5H), 2.28 (dd, J=2.7, 9.0, 0.5H), 2.24-2.18 (m, 1H), 2.17-2.11 (m, 1H), 1.95-1.82 (m, 1H), 1.77 (dt, J=5.8, 12.3, 0.5H), 1.73-1.64 (m, 0.5H), 1.49-1.25 (m, 2H), 1.23-1.17 (m, 3H), 0.70 (d, J=6.5, 3H); MS (ESI+) m/z 378 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.Cl.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[C@H:20]([CH:24]([CH3:26])[CH3:25])[C:21](O)=[O:22])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[NH2:34][OH:35]>C(Cl)Cl.CN(C)C=O.O1CCCC1>[OH:35][NH:34][C:21](=[O:22])[C@H:20]([N:19]([S:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)(=[O:18])=[O:17])[CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)[CH:24]([CH3:26])[CH3:25]
Reactant: NO
Reactant: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)O)C(C)C)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)NO)C(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (106 mL, 1.22 mol) is added over 1 hour to dimethylformamide (92 mL) in methylene chloride (1250 mL) at 0° C. To this is added a solution of 2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanoic acid hydrochloride (248 g, 0.6 mol) in dimethylformamide (450 mL) over 1 hour, maintaining the temperature at 0° C. This solution is stirred an additional 2 hours at room temperature, and then added dropwise to a mixture of hydroxylamine (460 g of a 50% aqueous solution, 6.82 mol) in tetrahydrofuran (2400 mL). The reaction is stirred an additional 3 hours at 5° C., and then at room temperature overnight. The reaction mixture is filtered, the organic layer is collected, and the solvent is evaporated. The crude product is re-dissolved in methylene chloride (2 L), washed with water (2×1 L), saturated sodium bicarbonate (4×1 L), brine (1 L), dried (Na2SO4), and the solvent is evaporated. The product is dissolved in ethyl acetate (700 mL) and diluted with ether (1400 mL) to induce precipitation. The pure product is collected by filtration to provide N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanamide. After conversion to the hydrochloride salt, a white solid is obtained, m.p. 169°-170° C. (dec).
Reaction SMILES: O[C:2]1([CH:14]=[CH2:15])[C:11]2([CH3:12])[C:6](=[CH:7][C:8](=[O:13])[CH2:9][CH2:10]2)[CH:5]=[CH:4][CH2:3]1.S(Cl)([Cl:18])=O.C(=O)(O)[O-].[Na+].[Cl-]>C(Cl)Cl.O.N1C=CC=CC=1>[Cl:18][CH2:15][CH:14]=[C:2]1[C:11]2([CH3:12])[C:6](=[CH:7][C:8](=[O:13])[CH2:9][CH2:10]2)[CH:5]=[CH:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: C=CC1(O)CC=CC2=CC(=O)CCC21C
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC12CCC(=O)C=C1C=CCC2=CCCl
Reaction time: 0.08 h

Procedure:
To a solution of 1-hydroxy-8a-methyl-1-vinyl-1,2,6,7,8,8a-hexahydro-6-naphthalenone (0.204 g.) in anhydrous methylene chloride (20 ml.) was added 0.5 ml. of pyridine. The reaction mixture was cooled in an ice-bath and thionyl chloride (150 mg.) was added. After 5 minutes, the reaction mixture was diluted with methylene chloride (20 ml.) and water (10 ml.) and neutralized with saturated sodium bicarbonate solution (5 ml.). The aqueous layer was extracted with methylene chloride (3×25 ml.) and the combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent gave 217 mg. of the oily chloride.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][C@H:18]([CH3:22])[CH2:17]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[CH:25]1([CH2:28][NH:29][C:30](=[O:41])[NH:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:25]1([CH2:28][NH:29][C:30]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([C:36]([N:19]3[CH2:20][CH2:21][N:16]([CH2:15][C:12]4[CH:11]=[CH:10][C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:23])([F:1])[F:24])=[CH:14][CH:13]=4)[CH2:17][C@H:18]3[CH3:22])=[O:37])=[CH:39][CH:40]=2)=[O:41])[CH2:27][CH2:26]1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Reactant: C[C@@H]1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1C(=O)c1ccc(NC(=O)NCC2CC2)cc1
Temperature: 25 °C
Yield: 15.5 %

Procedure:
(R)-1,1,1,3,3,3-Hexafluoro-2-(4-((3-methylpiperazin-1-yl)methyl)phenyl)propan-2-ol (0.427 mmol, 0.152 g), 4-(3-(cyclopropylmethyl)ureido)benzoic acid (0.427 mmol, 0.1 g) and triethylamine (1.281 mmol, 0.178 mL, 0.130 g) were combined in dichloromethane and stirred at room temperature. 1-Propanephosphonic acid cyclic anhydride (0.640 mmol, 0.381 mL, 0.407 g; 50% solution in ethyl acetate) was added and the reaction allowed to stir for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 5% methanol/dichloromethane) to afford the title compound (38 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH2:5][CH:6]=[CH2:7].[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12]Br>C1COCC1>[CH2:3]([O:8][CH2:12][CH:11]=[O:10])[CH2:4][CH2:5][CH:6]=[CH2:7].[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12][O:8][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: COC(CBr)OC
Reactant: C=CCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCCOCC(OC)OC
Product: C=CCCCOCC=O
Temperature: 25 °C
Yield: 92.9 %

Procedure:
2-(Pent-4-enyloxy)acetaldehyde was prepared in a 2-step process following the literature procedures with modifications (Glaser M, et al. Bioconjugate Chem. 2008, 19, 951-957). Thus, to a stirring suspension of sodium hydride (60% in mineral oil, 2.85 g, 71.4 mmol) in THF (40 mL) under nitrogen atmosphere was added through an addition funnel a solution of 4-penten-1ol (6.15 g, 71.4 mmol) in THF (20 mL) at room temperature. After completion of addition, the mixture was refluxed for 1 h and then cooled to room temperature. A solution of bromoacetaldehyde dimethyl acetal (11.5 g, 68 mmol) in THF (40 mL) was added dropwise at room temperature over a period of 20 min. The reaction mixture was then refluxed for 4 h, cooled to room temperature, and quenched with water (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic solutions were washed with brine (50 mL), dried over Na2SO4 and evaporated under vacuum. The crude residue was purified by flash silica gel chromatography eluting with step gradients of 0-10% ethyl acetate in hexane to afford 5-(2,2-dimethoxy-ethoxy)-pent-1-ene (5.5 g, 31.6 mmol, 44% yield).
Reaction SMILES: O1CC1CCl.[SH-:6].[Na+].O1C[CH:9]1[CH2:10][S:11][CH2:12][CH:13]1O[CH2:14]1.N[C:18](N)=[S:19]>>[S:19]1[CH2:18][CH:9]1[CH2:10][S:11][CH2:12][CH:13]1[S:6][CH2:14]1
Reactant: [SH-]
Reactant: C1OC1CSCC1CO1
Reactant: NC(N)=S
Agent: [Na+]
Solvent: ClCC1CO1
Product: C(SCC1CS1)C1CS1

Procedure:
By a known process, β-epoxypropylchloride was converted using sodium hydrosulfide into bis(β-epoxypropyl)sulfide, which was reacted with thiourea to give bis(β-epithiopropyl)sulfide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([O:19][NH:20][C@H:21]([C:28]([OH:30])=[O:29])[CH2:22][C:23]1[N:27]=[CH:26][NH:25][CH:24]=1)=[O:18].O1[CH2:35][CH2:34][CH2:33][CH2:32]1.C(Br)(Br)(Br)[Br:37]>>[Br:37][CH2:32][CH2:33][CH2:34][CH2:35][O:29][C:28](=[O:30])[C@H:21]([CH2:22][C:23]1[N:27]=[CH:26][NH:25][CH:24]=1)[NH:20][O:19][C:17](=[O:18])[CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: BrC(Br)(Br)Br
Reactant: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)ON[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: C1CCOC1
Product: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)ON[C@@H](Cc1c[nH]cn1)C(=O)OCCCCBr
Reaction time: 24 h

Procedure:
To a solution of [2-[(2,6-dichlorophenyl)amino]benzeneacetyloxy] (L)-histidine (5 g, 11.54 mmoles) in tetrahydrofuran (100 ml) triphenylphosphine (9.08 g, 34.62 mmoles) and carbon tetrabromide (11.48 g, 34.62 mmoles) are added under stirring. The reaction mixture is left at room temperature for 24 hours, then the solvent is removed by evaporation at reduced pressure. The obtained crude product is purified by chromatography on silica gel eluting with n-hexane/ethyl acetate 1/1. (S)-[2-[(2,6-dichlorophenyl)amino]benzeneacetyloxy] (L)-histidine 4-bromobutyl ester is obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:38]=[CH:37][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:34]([CH3:36])[CH3:35])[N:28]=[C:29]([CH2:31][O:32][CH3:33])[N:30]=2)[N:19]=4)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>C(Cl)Cl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[CH:34]([N:27]1[C:26]([C:20]2[N:19]=[C:18]3[N:22]([CH2:23][CH2:24][O:25][C:16]4[CH:15]=[C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:38]=[CH:37][C:17]=43)[CH:21]=2)=[N:30][C:29]([CH2:31][O:32][CH3:33])=[N:28]1)([CH3:36])[CH3:35]
Reactant: COCc1nc(-c2cn3c(n2)-c2ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc2OCC3)n(C(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCc1nc(-c2cn3c(n2)-c2ccc(C4CCNCC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (158 mg, 0.30 mmol) in DCM (1.5 mL) was added trifluoroacetic acid (1.5 mL, 20.2 mmol) and the reaction mixture stirred at RT for 30 min. The reaction mixture was concentrated in vacuo and the residue azeotroped with ether. The resultant oil was triturated with diethyl ether to give 2-(2-Isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetate salt as a solid which was collected by filtration (103 mg, 64%). LCMS RT=3.03 min, [M+H]+=423. 1H NMR 400 MHz (DMSO-d) δ: 8.56 (1 H, s), 8.33 (1 H, d, J=8.33 Hz), 7.90 (1 H, s), 7.00 (1 H, dd, J=8.38, 1.78 Hz), 6.85 (1 H, d, J=1.73 Hz), 5.81-5.80 (1 H, m), 4.46 (4 H, d, J=2.51 Hz), 4.33 (2 H, s), 3.34 (2 H, d, J=12.58 Hz), 3.27 (3 H, s), 2.98-2.95 (2 H, m), 2.82 (1 H, t, J=11.91 Hz), 1.93 (2 H, d, J=13.66 Hz), 1.75 (2 H, t, J=12.95 Hz), 1.44 (6 H, d, J=6.60 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[C:12]([C:20](O)=[O:21])=[CH:11]2)=[CH:7][C:6]([C:23]([F:26])([F:25])[F:24])=[CH:5][N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:52][C@@H:53]([CH3:56])[CH2:54][NH2:55].C(N(CC)CC)C>CN1C(=O)CCC1.O>[F:52][C@@H:53]([CH3:56])[CH2:54][NH:55][C:20]([C:12]1[C:13]2=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=[C:18]2[N:10]([CH2:9][C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([C:23]([F:24])([F:25])[F:26])[CH:7]=2)[CH:11]=1)=[O:21]
Reactant: COc1ncc(C(F)(F)F)cc1Cn1cc(C(=O)O)c2ncc(C)cc21
Reactant: C[C@H](F)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ncc(C(F)(F)F)cc1Cn1cc(C(=O)NC[C@H](C)F)c2ncc(C)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.6 %

Procedure:
See FIG. 21(b). In a 25 mL thermal vial was charged with 1-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (100 mg, 0.27 mmol) and HATU (125 mg, 0.33 mmol) were taken in NMP (4 mL) and stirred for 10 min at rt. Then (S)-2-fluoropropan-1-amine hydrochloride (37.3 mg. 0.33 mmol) and triethyl amine (0.114 mL, 0.82 mmol) were added and stirred for 1 h at RT. The LCMS showed completion of the reaction. The reaction mixture was poured into water and extracted with chloroform. The organic layer was dried and concentrated and crude was submitted to reverse phase purification. The pure fractions were concentrated to get (S)—N-(2-fluoropropyl)-1-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (82 mg, 70.6%) a solid. ES+MS m/z: 425 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.15-1.44 (m, 3 H ) 2.44 (s, 3 H ) 3.39-3.79 (m, 2 H ) 3.98 (s, 3 H ) 4.75 (td, J=6.50, 3.39 Hz, 1 H ) 4.92 (td, J=6.50, 3.20 Hz, 1 H ) 5.48 (s, 2 H ) 7.81 (d, J=2.26 Hz, 1 H ) 7.91-8.03 (m, 1H) 8.25 (s, 1 H ) 8.34-8.42 (m, 1 H ) 8.53-8.62 (m, 1 H ) 8.90 (t, J=5.93 Hz, 1 H ).