Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14])[C:6]([NH:8][OH:9])=[O:7].[CH2:17]([C:19]([CH2:26][CH3:27])([C:23](Cl)=[O:24])[C:20](Cl)=[O:21])[CH3:18]>>[CH3:16][O:15][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:12]=1[O:13][CH3:14])[C:6]([N:8]1[C:20](=[O:21])[C:19]([CH2:26][CH3:27])([CH2:17][CH3:18])[C:23](=[O:24])[O:9]1)=[O:7]
Reactant: COc1cc(C(=O)NO)cc(OC)c1OC
Reactant: CCC(CC)(C(=O)Cl)C(=O)Cl
Product: CCC1(CC)C(=O)ON(C(=O)c2cc(OC)c(OC)c(OC)c2)C1=O
Yield: 81.4 %

Procedure:
A mixture consisting of 2.27 g (0.0100 mol) of 3,4,5-trimethoxybenzohydroxamic acid (recrystallized from absolute ethanol prior to the reaction), 5 ml of pyridine, and 100 ml of methylene chloride was prepared in a 250 ml round-bottom flask. The mixture was cooled in an ice bath, and 2.00 g (0.0101 mol) of diethylmalonyl chloride was added dropwise over a 15 minute period. The reaction mixture was stirred for one hour at room temperature after which time all of the hydroxamic acid had dissolved. The solution was extracted three times with 50 ml portions of water, four times 50 ml portions of 5% hydrochloric acid, and two times with 50 ml portions of 5% sodium carbonate. The methylene chloride solution was dried (MgSO4) and evaporated to dryness under reduced pressure to give 2.86g (81.5%) of crude 2-(3,4,5-trimethoxybenzoyl)-4,4-diethylisoxazolidine-3,5-dione; as a solid residue: mp 103-106° C. Recrystallization of 2.72 g of the crude product from 20 ml of absolute ethanol gave 2.14 g of 2-(3,4,5-trimethoxybenzoyl)-4,4-diethylisoxazolidine-3,5mp 107- 109.5° C.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:37]([OH:39])=[O:38])[CH2:30][CH2:31][CH2:32][NH:33][C:34](=[NH:36])[NH2:35])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl>[Pd].CO>[NH2:1][C@@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:37]([OH:39])=[O:38])[CH2:30][CH2:31][CH2:32][NH:33][C:34](=[NH:35])[NH2:36])=[O:27])[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCC[C@@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Reaction time: 8 h

Procedure:
Into 75 ml of MeOH was dissolved 8.9 g (10.4 mmoles) of Z-D-Lys(BOC)-Phe-Arg-CHA.HCl. After adding 1 gram of palladium black, it was catalytically reduced at 30° C. for 8 hours. After the reaction, the catalyst was filtered off and the solvent was distilled off under reduced pressure. Thus, 6.4 g (85.3%; a foamed product) of H-D-Lys(BOC)-Phe-Arg-CHA.2HCl was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([Cl:10])[N:6]=[N:5][C:4]=1[Cl:11].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.C(Cl)Cl>[CH2:12]([NH:19][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([Cl:10])[N:6]=[N:5][C:4]=1[Cl:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1c(Cl)nnc(Cl)c1CBr
Reactant: NCc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(Cl)nnc(Cl)c1CNCc1ccccc1
Temperature: 90 °C
Yield: 97.7 %

Procedure:
To a stirred solution of 3,6-dichloro-4,5-dimethylpyridazine (500 mg, 2.82 mmol) in carbon tetrachloride (10 mL) was added N-bromosuccinimide (503 mg, 2.82 mmol), and AIBN (2.3 mg, 0.014 mmol) in a round bottom flask equipped with condenser. The reaction was continuously irradiated with a 300 W light and refluxed for 5 h. The formed succimide was filtered and the filtrate was concentrated to afford 4-(bromomethyl)-3,6-dichloro-5-methylpyridazine as a brown solid. To a solution of 4-(bromomethyl)-3,6-dichloro-5-methylpyridazine (400 mg, 1.56 mmol) in DMF was added with benzyl amine (188 μL, 1.72 mmol) and TEA (326 μL, 2.34 mmol). The reaction mixture was heated at 90° C. for 2 h, diluted with DCM and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated to afford a brown oil. The crude material was purified by flash chromatography on silica gel, eluting with 30-80% EtOAc:heptane. Fractions containing the desired product were combined and concentrated to afford a the title compound as a greasy solid (430 mg, yield: 54% (two steps)).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C.O>[F:12][C:11]([F:14])([F:13])[C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:5]=1)=[O:15]
Reactant: C1CCNCC1
Reactant: O=C(Nc1ccc(CBr)c(C(F)(F)F)c1)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccc(CN2CCCCC2)c(C(F)(F)F)c1)C(F)(F)F

Procedure:
To a solution of N-(4-bromomethyl-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide (Stage 128.3; 1.465 g, 4.19 mmol) in acetonitril (35 ml) under N2-atmosphere, piperidine (1.25 ml, 12.7 mmol) is added. After 30 min at rt the reaction mixture is diluted with water and partially concentrated in vacuo. The aqueous residue Is acidified to pH 5 by addition of 0.1 N HCl and extracted 3× with AcOEt. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; hexane/AcOEt 3:2) gives the title compound: MS: [M+1]+=355; 1H-NMR (DMSO-d6): 11.48 (s, HN), 8.02 (s, 1H), 7.91 (dd, 1H), 7.77 (d, 1H), 3.52 (s, 2H), 2.32 (sb, 4H), 1.50 (m, 4H), 1.40 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[NH:3]1.[H-].[Na+].Br[CH:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31])[C:20]([O:22][CH3:23])=[O:21].[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[CH3:23][O:22][C:20]([CH:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31])[N:3]1[C:4]2[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=2[N:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]1=[O:1])=[O:21]
Reactant: COC(=O)C(Br)c1ccccc1OC
Reactant: CCOC(=O)n1c(=O)[nH]c2ccccc21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)n1c(=O)n(C(C(=O)OC)c2ccccc2OC)c2ccccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2.61 g (12.7 mmol) of ethyl 2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (IV) were dissolved in dry DMF (40 ml) in a heat-dried flask under a nitrogen atmosphere. 532 mg (13.3 mmol) of sodium hydride (60% suspension in mineral oil) were added while stirring at 0° C., and the reaction solution was then stirred at room temperature for 30 min. After renewed cooling in an ice bath, 3.54 g (13.7 mmol) of methyl bromo-(2-methoxyphenyl)acetate were added and the mixture was stirred while cooling in ice for 1 h and then at room temperature for 2 h. The reaction solution was diluted with ethyl acetate, mixed with 10% aqueous ammonium chloride solution and then extracted with ethyl acetate (3×). The combined organic phases were washed with water and saturated NaCl solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (mobile phase 50% ethyl acetate in heptane). Yield: 3.21 g (66%) of colorless oil
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][CH2:6][NH:7][C:8](=[O:39])[C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[C:23]([N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([CH:35]3[CH2:37][CH2:36]3)[CH2:27][CH2:26]2)=[O:24])=[CH:11][C:10]=1[Cl:38])C.O.O.[OH-].[Li+]>O1CCOCC1>[Cl:38][C:10]1[CH:11]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[C:23]([N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([CH:35]3[CH2:37][CH2:36]3)[CH2:27][CH2:26]2)=[O:24])[C:13]([Cl:15])=[CH:14][C:9]=1[C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:40])=[O:3])=[O:39]
Reactant: CCOC(=O)CCNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 86.3 %

Procedure:
To a solution of 0.85 g (1.46 mmol) 3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-propionic acid ethyl ester (Example 33) in 7.5 mL dioxane were added 7.5 mL water and 0.076 g (1.81 mmol) lithium hydroxide monohydrate. The resulting suspension was stirred for 2.25 hours at room temperature and dioxane was removed by evaporation. The pH of the solution was adjusted to 2.5 by adding 1.9 mL 1M aqueous hydrochloric acid and the suspension was stirred for 2 hours at room temperature. The suspension was filtered, the filter cake washed with water and dried under high vacuum to give 0.70 g (86%) of the desired compound as an off-white solid. MS (ESI): m/z=555.12 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.CCN(CC)CC.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([S:36]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)(=[O:38])=[O:37])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2ncc3c4c(cnc32)CN(S(=O)(=O)c2ccccc2)CC4)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 3-(4-methoxy-benzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.129 g, 0.43 mmol) in dichloromethane (8 mL) and Et3N (0.13 mL, 0.86 mmol) was added benzenesulfonyl chloride (62 μL, 0.47 mmol). The reaction mixture was shaken at room temperature for 1 hour. The solvent was then removed under reduced pressure and the residue obtained was partitioned between EtOAc and aqueous NaOH. The organic layer was then separated, washed with brine (2×10 mL), concentrated under reduced pressure. The crude product was purified using either flash column chromatography (SiO2, 33% EtOAc in hexane) to give 3-(4-methoxybenzyl)-7-(phenylsulfonyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine as a white solid (0.147 g, 77%) or used in the next step without any further purification. M.p.=136-138° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.39 (s, 1H), 8.12 (s, 1H), 7.88-7.83 (m, 2H), 7.72-7.59 (m, 3H), 7.18-7.13 (m, 2H), 6.86-6.8 (m, 2H), 5.55 (s, 2H), 4.36 (s, 2H), 3.68 (s, 3H), 3.43, t, J=6.4 Hz, 2H), 3.13 (t, J=6.4 Hz, 2H), 2.54-2.48 (m, 2H); LCMS [M+H]: 435.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=O)[CH2:10][CH:11]([C:19]2[CH:34]=[CH:33][C:22]([C:23]([NH:25][CH2:26][CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29])=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[NH2:37][OH:38].C(=O)([O-])O.[Na+]>>[OH:38]/[N:37]=[C:9](/[C:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)\[CH2:10][CH:11]([C:19]1[CH:34]=[CH:33][C:22]([C:23]([NH:25][CH2:26][CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29])=[O:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCC(O)C(F)(F)F)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCC(O)C(F)(F)F)cc1

Procedure:
In analogy to example 151, step 3, 4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)-N-(3,3,3-trifluoro-2-hydroxypropyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as an off-white solid containing <10% of the corresponding Z isomer, MS (ESI+): m/z=502.2 [M+H]+.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:20]2[CH2:19][CH2:18][C@@:17]2([CH3:25])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C:14](=[O:16])[CH3:15])[CH2:5]1)=[N+:2]=[N-:3].C1C=C[NH+]=CC=1.[Br:32][Br-]Br>C(O)C.C(Cl)(Cl)Cl.ClCCl>[N:1]([C@@H:4]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:20]2[CH2:19][CH2:18][C@@:17]2([CH3:25])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C:14](=[O:16])[CH2:15][Br:32])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](N=[N+]=[N-])CC[C@]4(C)[C@H]3CC[C@]12C
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C[C@]12CC[C@@H](N=[N+]=[N-])C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]12
Temperature: 50 °C

Procedure:
To a solution of 3α-azido-5α-pregnan-20-one (51.5 mg, 0.15 mmol) in absolute ethanol (3 mL) and chloroform (3 mL) was added pyridinium bromide perbromide (143 mg, 0.44 mmol) and the resulting mixture was heated at 50° C. for 45 min. Subsequently the mixture was diluted with dichloromethane and the organic layer was washed with water, brine and dried (Na2SO4). Evaporation of the solvent in vacuo and purification of the residue using flash column chromatography and petroleum ether/ethyl acetate 90/10 as elution solvent afforded the compound named above.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[Br:17][C:18]1[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=1>>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:1][CH2:2][CH2:3][CH:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(Br)cc2)CC1
Yield: 127 %

Procedure:
The procedure described in Example 4.1. is repeated. Starting from 1.93 g (8.4 mmol) of 1,1-dimethylethyl 4-(2-hydroxyethyl)-1-piperidine-carboxylate and 5.88 g (33.6 mmol) of 1-bromo-4-fluorobenzene gives 4.1 g of crude product in oil form.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:17][CH2:16][C@H:15](O)[CH2:14][C@H:13]1[CH2:12][S:11][C:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:9]2.[F:27]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.C(N(CC)CC)C>C1COCC1>[F:27][C@@H:15]1[CH2:16][CH2:17][C@:8]2([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[N:9]=[C:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[S:11][CH2:12][C@@H:13]2[CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)CC[C@H](O)C[C@H]2CS1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)CC[C@@H](F)C[C@H]2CS1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
tert-Butyl(±)-[(4aR*,6S*,8aS*)-8a-(2-fluorophenyl)-6-hydroxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in Preparation Example 63-(4) (1.5 g) was dissolved in THF. Then, perfluorobutanesulfonyl fluoride (1.36 mL, specific gravity: 1.682 g/cm3), a triethylamine-trihydrofluoric acid complex (1.23 mL, specific gravity: 0.989 g/cm3) and triethylamine (3.15 mL, specific gravity: 0.73 g/cm3) were sequentially added at room temperature. After completion of the addition, the mixture was stirred for 16 hours. The mixture was heated to 50° C. and further stirred for 24 hours. Perfluorobutanesulfonyl fluoride (0.68 mL), a triethylamine-trihydrofluoric acid complex (0.62 mL) and triethylamine (1.58 mL) were further sequentially added to the mixture, followed by further stirring with heating under reflux for eight hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography to obtain the title compound (106 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([N:17]2[CH2:23][CH:22]3[O:24][CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[CH:3]=1>C(N)(C)C>[CH:11]([NH:14][C:2]1[CH:3]=[C:4]([N:17]2[CH2:23][CH:22]3[O:24][CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:7]=1)([CH3:12])[CH3:10]
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)cc(N3CC4CCC(C3)O4)n2)cc1
Solvent: CC(C)N
Product: CC(C)Nc1cc(N2CC3CCC(C2)O3)nc(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 140 °C
Yield: 198.3 %

Procedure:
In a 2-5 mL microwave vial was placed 3-(6-chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (13, 70 mg, 0.202 mmol) in iPrNH2 (4 ml) to give a yellow suspension. The reaction was heated under microwave irradiation at 140° C. for 90 min. The mixture was concentrated, dissolved in dichloromethane and washed with sat NaHCO3. The organic phase was dried over MgSO4, filtered and concentrated to give 74 mg of the title compound as a yellow solid (99%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=1)=[O:5])C.CO.O.[OH-].[Na+]>C1COCC1>[F:17][C:11]1[CH:10]=[C:9]([CH:7]2[CH2:8][CH:6]2[C:4]([OH:5])=[O:3])[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: CCOC(=O)C1CC1c1ccc(OC)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2CC2C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
After 2-(3-fluoro-4-methoxy-phenyl)-cyclopropane carboxylic acid ethyl ester (1.15 g, 4.83 mmol) was dissolved in THF (6 mL), methyl alcohol (1 mL) and water (1 mL), an excess amount of sodium hydroxide was added, and then the mixture was stirred at room temperature for 4 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure, and 1N HCl was added to adjust the pH of the solution to 2. The organic layer obtained by the extraction with ethyl acetate was separated, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (0.985 g, 97%).
Reaction SMILES: [NH2:1][C:2](=[O:47])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[C:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)=[CH:25][C:24]=2[O:42][C:43]([F:46])([F:45])[F:44])[N:13]=1>CN(C=O)C.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[NH2:1][C:2](=[O:47])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]1[C:17]([C:18]([F:19])([F:21])[F:20])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]3)=[CH:25][C:24]=2[O:42][C:43]([F:46])([F:45])[F:44])[N:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(C#Cc4ccccc4CC(N)=O)n3)c(OC(F)(F)F)c2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)c(OC(F)(F)F)c2)CC1
Reaction time: 24 h
Yield: 88 %

Procedure:
tert-Butyl 4-(4-((4-((2-(2-amino-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-(trifluoromethoxy)phenyl)piperidine-1-carboxylate (I49) (72.0 mg, 0.108 mmol) was dissolved in dry DMF (7 mL) under an atmosphere of nitrogen, and a slurry of 10% Pd(OH)2/C (0.050 g) in EtOAc (2 mL) was added. The mixture then was stirred vigorously under hydrogen for 24 hours. Upon completion, the reaction was filtered through a pad of celite, which was washed with EtOAc (40 mL). The combined filtrates were concentrated in vacuo to give a pale yellow oil. The crude product was purified by silica gel chromatography (12 g Si Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I50) (0.064 g, 88% yield) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 9.80 (s, 1H), 8.60 (s, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.39 (s, 1H), 7.32-7.26 (m, 2H), 7.21 (dt, J=6.7, 3.4 Hz, 1H), 7.18-7.08 (m, 3H), 6.90 (s, 1H), 4.09 (d, J=12.1 Hz, 2H), 3.45 (s, 2H), 3.09-2.94 (m, 4H), 2.88-2.72 (m, 3H) 1.79 (d, J=12.3 Hz, 2H), 1.59-1.38 (m, 11H). LCMS Method C: rt 6.75 min, m/z 668.1 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:19])[CH:7]([C:10]1[C:18]2[CH:17]=[CH:16][S:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)C#N)(C)(C)C.[OH-].[K+].O>C(O)CO>[S:15]1[CH:16]=[CH:17][C:18]2[C:10]([CH2:7][C:6]([OH:19])=[O:5])=[CH:11][CH:12]=[CH:13][C:14]1=2
Reactant: CC(C)(C)OC(=O)C(C#N)c1cccc2sccc12
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: O=C(O)Cc1cccc2sccc12
Temperature: 95 °C

Procedure:
To a solution of benzo[b]thiophen-4-yl-cyano-acetic acid tert-butyl ester (1 eq.) in ethylene glycol were added an aqueous solution of 38 percent (w/w) potassium hydroxide and water. The reaction was heated at 95° C. for 2 h. The reaction mixture was partitioned between water and toluene, and the organic layer was discarded. The aqueous layer was acidified with aqueous HCl (6N) until pH=2 and extracted three times with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. To the resulting residue was added a mixture of Et2O/pentane and the precipitate was collected by filtration to provide benzo[b]thiophen-4-yl-acetic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][CH:8]([CH2:13][S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][C:10]([OH:12])=O)([CH3:4])([CH3:3])[CH3:2].O[N:23]=[C:24]([NH2:36])[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1.C(C1NC=CN=1)(C1NC=CN=1)=O>CN(C=O)C.C(=O)(O)[O-].[Na+]>[C:15]1([S:14][CH2:13][CH:8]([CH2:9][C:10]2[O:12][N:23]=[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[N:36]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC(CCCCNc1ccccn1)=NO
Reactant: CC(C)(C)OC(=O)CC(CSc1ccccc1)CC(=O)O
Agent: O=C([O-])O
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC(CSc1ccccc1)Cc1nc(CCCCNc2ccccn2)no1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.7 %

Procedure:
The product from step 2 (54 mg, 0.175 mmoles), N′-hydroxy-5-(pyridin-2-ylamino)pentanimidamide (40 mg, 0.192 mmoles) and carbonyl diimidazole (45 mg, 0.28 mmoles) were combined in DMF 1.5 mL and stirred at RT for 4 h then heated at 65° C. overnight. N′-hydroxy-5-(pyridin-2-ylamino)pentanimidamide (36 mg 0.175 mmoles) and carbonyl diimidazole (50 mg, 0.31 mmoles) were added in and reaction was stirred at RT for 2 h follwed by heating to 80° C. for 24 h. Reaction was cooled, diluted with a sodium bicarbonate solution (6 ml, 1:1 saturated bicarbonate solution and water) and extracted with ethyl acetate 3×3 mL. The combined organics were washed with water 2×3 mL, brine 3 mL, dried and passed through a pad of silica eluting with a further 10 mL of ethyl acetate. The solvent was removed under reduced pressure to give the product 50.4 mg (60%). MS (ESI+) for C26H34N4O3S m/z 483 (M+H)+.