Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][C:6](=[O:18])[CH2:5]1)=[N+:2]=[N-:3].[BH4-].[Na+]>C1COCC1.O.O>[N:1]([CH:4]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:7][CH:6]([OH:18])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])CC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])CC(O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To as solution of (Z)-tert-butyl 3-oxo-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (2.0 g, 9.5 mmol) in acetonitrile (3 mL), was added trimethylsilyl azide (3.76 mL, 28.4 mmol) followed by AMBERLITE® IRA 900F resin (loading: 2-3 mmolg-1, 2.4 g) and the resulting mixture was heated at 60° C. behind a blast shield for 16 hr. After cooling to room temperature, the solution was filtered washing the resin with acetonitrile and the filtrate was concentrated under reduced pressure (temperature of bath<40° C.) to give tert-butyl 5-azido-3-oxoazepane-1-carboxylate as a yellow liquid (2.21 g). To a solution of the azide (2.2 g, 8.70 mmol) in THF/water (1/1, 40 mL), was added portionwise NaBH4 (0.82 mg, 21.8 mmol) and the mixture was stirred at room temperature for 2 hr. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-60% EtOAc/isohexane) gave tert-butyl 5-azido-3-hydroxyazepane-1-carboxylate as an oil (2.01 g). To a solution of this oil (2.0 g, 7.8 mmol) in MeOH (20 mL), was added HCl (4 M in 1,4-dioxane, 43 mL, 173 mmol) and the solution was stirred at room temperature for 16 hr. The solvents were removed under reduced pressure and the crude residue was dissolved in MeOH and passed through an SCX column, washing with MeOH and eluting with 7 N ammonia in MeOH to give 5-azidoazepan-3-ol as a yellow oil. To this oil in dry DMSO (20 mL) was added potassium fluoride (1.68 g, 28.9 mmol) and 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (1.17 g, 7.2 mmol) and the mixture heated at 65° C. for 16 hr. The mixture was diluted with water (300 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (3×20 mL), separated, dried over MgSO4 and the solvents removed under reduced pressure. Purification via silica gel column chromatography (0-30% EtOAc/isohexane) gave 5-azido-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-3-ol as a viscous yellow oil (1.9 g, 72% over four steps). 1H NMR (400 MHz, CDCl3) δ 8.06 and 8.02 (2s, 1H), 4.15-3.97 (m, 2H), 3.95-3.83 (m, 4H), 3.58-3.46 (m, 1H), 3.39-3.16 (m, 3H), 2.29-1.91 (m, 4H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][CH2:12]C)[N:3]=1.[B:14]1([OH:24])[C:18]2[CH:19]=[CH:20][C:21]([OH:23])=[CH:22][C:17]=2[CH2:16][O:15]1.[C:25](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:24][B:14]1[C:18]2[CH:19]=[CH:20][C:21]([O:23][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]([CH3:12])[CH3:25])[N:3]=3)=[CH:22][C:17]=2[CH2:16][O:15]1
Reactant: O=C([O-])[O-]
Reactant: CCCOc1nc(Cl)ccc1C#N
Reactant: OB1OCc2cc(O)ccc21
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1nc(Oc2ccc3c(c2)COB3O)ccc1C#N
Temperature: 95 °C
Yield: 40.3 %

Procedure:
To a mixture of 6-chloro-2-propoxy-nicotinonitrile (0.54 g, 3.0 mmol) and 3H-benzo[c][1,2]oxaborole-1,5-diol (0.40 g, 2.0 mmol) in DMF (10 mL) was added potassium carbonate (0.83 g, 6.0 mmol). The resulting suspension was heated at 95° C. for 48 h. DMF was removed under reduced pressure, the residue was diluted with EtOAc (50 mL), washed with water (10 mL) and brine (2×10 mL), dried over Na2SO4, filtered, and concentrated to give brown oil. Purification was accomplished by reverse phase preparative HPLC using MeOH/H2O (0.1% AcOH) as the eluent to yield the title compound (0.25 g, 26%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.25 (s, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.29 (s, 1 H), 7.17-7.22 (m, 1H), 6.69 (d, J=8.6 Hz, 1H), 4.99 (s, 2H), 4.07 (t, J=6.8 Hz, 2H), 1.65-1.55 (m, 2H), 0.81 (t, J=7.4 Hz, 3H); MS (ES) m/z: 311 (M+1)+; HPLC purity 98.36% (Maxplot), 97.66% (220 nm).
Reaction SMILES: [C:1]1([C:7]2C=C(C=CC=2)N)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.NC1C=C2C(CCCC2=O)=CC=1.[OH:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([NH:36][C:37]2[CH:46]=[C:45]3[C:40]([CH2:41][CH2:42][CH2:43][C:44]3=[O:47])=[CH:39][CH:38]=2)=[O:35])=[CH:29][C:28]=1[O:48][CH3:49].C(=O)C1C=CC=CC=1>Cl.C(O)C>[OH:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([NH:36][C:37]2[CH:46]=[C:45]3[C:40]([CH2:41][CH2:42][C:43](=[CH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:44]3=[O:47])=[CH:39][CH:38]=2)=[O:35])=[CH:29][C:28]=1[O:48][CH3:49]
Reactant: COc1cc(CC(=O)Nc2ccc3c(c2)C(=O)CCC3)ccc1O
Reactant: Nc1cccc(C2=CCCCC2)c1
Agent: Cl
Agent: Nc1ccc2c(c1)C(=O)CCC2
Solvent: CCO
Solvent: O=Cc1ccccc1
Product: COc1cc(CC(=O)Nc2ccc3c(c2)C(=O)C(=Cc2ccccc2)CC3)ccc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Instead of 3-(cyclohexen-1-yl)aniline (Intermediate 2) in Example 9, 7-amino-1-tetralone is treated in a similar manner to Example 9. The resulting 4-hydroxy-3-methoxy-N-[1-oxo-1,2,3,4-tetrahydronaphthalen-7-yl]phenylacetamide (1 g) is dissolved in 30% hydrogen chloride-ethanol (5 ml), and thereto is added benzaldehyde (433 mg). The mixture is stirred at 25° C. for 18 hours. The precipitated crystals are collected by filtration, and washed with diethyl ether to give the desired compound (700 mg).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[S:13](=NC1C=CC=CC=1)=[O:14]>CO.C(O)(=O)C>[S:13](=[N:10][NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=1)=[O:14]
Reactant: NNc1cccc(C(F)(F)F)c1
Reactant: O=S=Nc1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: O=S=NNc1cccc(C(F)(F)F)c1
Yield: 63.7 %

Procedure:
20 g (0.113 mole) of 3-trifluoromethyl-phenylhydrazine were dissolved in 50 ml of methanol with addition of 5 ml of acetic acid; 16 g (0.115 mole) of sulfinylaniline were added dropwise at a temperature of 22°C. The product crystallized out while the temperature rose to about 30°C. After filtration and drying, 16 g of N-sulfinyl-N-' -(3-trifluoromethylphenyl)-hydrazine of melting point 100°C were obtained. The yield was 64% of theory.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].[H-].[Na+].CS(O[CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:32][C@@H:31]([C:33]2[CH:44]=[CH:43][C:36]3[O:37][C:38]([CH3:42])([CH3:41])[O:39][CH2:40][C:35]=3[CH:34]=2)[O:30][C:29]1=[O:45])(=O)=O.P([O-])([O-])([O-])=O>CN(C=O)C>[CH3:1][N:2]([CH3:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][O:7][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:32][C@@H:31]([C:33]2[CH:44]=[CH:43][C:36]3[O:37][C:38]([CH3:41])([CH3:42])[O:39][CH2:40][C:35]=3[CH:34]=2)[O:30][C:29]1=[O:45]
Reactant: CN(C)c1cccc(CO)c1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOS(C)(=O)=O)C(=O)O3)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1cccc(COCCOCCCCCCN2C[C@@H](c3ccc4c(c3)COC(C)(C)O4)OC2=O)c1
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
A solution of 3-dimethylaminobenzyl alcohol (641 mg) in DMF (3 ml) under nitrogen was treated with sodium hydride (220 mg, 60% in oil) and the mixture stirred at 20° for 15 min. A solution of 2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethyl methanesulfonate (2.00 g) in DMF (5 ml) was added and the mixture was stirred at 20° for 21 h. Phosphate buffer solution (15 ml, pH6.5) was added, the mixture stirred for 15 min and then extracted with EtOAc. The combined organic layers were washed with water, dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by Biotage (40 g). Elution with EtOAc-PE (1:2) gave the title compound (2.125 g). LCMS RT=3.47 min.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[S:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21]>>[C:20]([C@@H:19]([NH:18][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([S:10][CH2:11][CH:12]([CH3:13])[CH3:14])[N:8]=1)=[O:17])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:21])[NH2:22]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: CC(C)CSc1nc(C(=O)O)ccc1C1CC1
Product: CC(C)CSc1nc(C(=O)N[C@@H](CC(C)C)C(N)=O)ccc1C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(isobutylthio)picolinic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials. MS (EI): m/e=364.5 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[Na+].[H-].[Na+].[CH2:39](O)[CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][OH:47].[C:49](Cl)([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>N1C=CC=CC=1>[CH2:18]([O:19][CH2:20][CH:21]([CH2:22][O:23][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][C:49]([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[OH:24])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)CO
Reactant: OCCOCCOCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOCC(O)COCCOCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 42.2 %

Procedure:
10.3 g (30 millimole) of batyl alcohol, 6.1 g (32 millimole) of sodium p-toluenesulfonate, 50 ml of pyridine, 1.6 g (40 millimole) of 60% oily sodium hydride, 45 g (300 millimole) of triethylene glycol, and 8.4 g (30 millimole) of trityl chloride were treated by following a procedure similar to that of Working Example 1, to give 9.1 g (42%) of the above-captioned compound.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C@@H:8]([C@@H:17]1[C@@H:21]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)[CH2:20][N:19]([C:30]([C:32]2[CH:37]=C(C)N=[N:34][CH:33]=2)=[O:31])[CH2:18]1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)(C)(C)C.CC[CH2:43][CH2:44][N+:45](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C@H:8]([C@@H:17]2[C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)[CH2:20][N:19]([C:30]([C:32]3[CH:37]=[N:45][C:44]([CH3:43])=[N:34][CH:33]=3)=[O:31])[CH2:18]2)[CH2:7][OH:6])=[N:11][CH:12]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: Cc1cc(C(=O)N2C[C@H]([C@H](CO[Si](C)(C)C(C)(C)C)Oc3ccc(Cl)cn3)[C@@H](c3ccc(F)c(F)c3)C2)cnn1
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ncc(C(=O)N2C[C@H]([C@H](CO)Oc3ccc(Cl)cn3)[C@@H](c3ccc(F)c(F)c3)C2)cn1
Temperature: 25 °C
Yield: 84 %

Procedure:
To a solution of [(3R,4S)-3-[(R)-2-(tert-butyl-dimethyl-silanyloxy)-1-(5-chloro-pyridin-2-yloxy)-ethyl]-4-(3,4-difluoro-phenyl)-pyrrolidin-1-yl]-(6-methyl-pyridazin-4-yl)-methanone (0.050 g, 0.085 mmol) dissolved in THF (4 mL) was added 0.10 mL of TBAF (1.0M in THF). The reaction mixture was stirred over night at room temperature. The mixture was diluted with ethyl acetate and washed with water and aq. sodium bicarbonate solution subsequently. The separated organic phase was dried over sodium sulfate and concentrated in vaccuo after filtration. The residue was purified by TLC (SiO2, MeOH/DCM, 1:10) yielded 40 mg (84%) of the title compound as a light yellow oil. ES-MS m/e: 475.1 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH-:10].[K+].[C:12](=[S:14])=S>C(O)CO.[Cu]>[CH3:8][C:6]1[CH:7]=[C:2]2[O:10][C:12](=[S:14])[NH:9][C:3]2=[N:4][CH:5]=1
Reactant: Cc1cnc(N)c(Br)c1
Reactant: S=C=S
Reactant: [OH-]
Agent: [Cu]
Agent: [K+]
Solvent: OCCO
Product: Cc1cnc2[nH]c(=S)oc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
3-Bromo-2-amino-5-methylpyridine (1.0 g, 5.3 mmol), potassium hydroxide (1.19 g, 21.2 mmol) and copper powder (17 mg, 0.27 mmol) were heated to 150° C. in ethylene glycol (2.3 mL). After 4 h, the reaction mixture was allowed to cool to rt, carbon disulfide (10 mL) was added, and heating was continued at 70° C. overnight. Upon cooling to rt, the reaction mixture concentrated under reduced pressure. 1 N HCl (20 mL) was added, and the resulting dark solid was collected by filtration. The solid was washed with water (2×) and air dried followed by drying in a 35° C. vacuum oven, yielding 0.817 g (93%) of the title compound. LC-MS: RT=4.14 min, [M+H]+=167.0, ˜80% pure.
Reaction SMILES: ClC([O:4][CH2:5][CH:6](C)C)=O.CN1[CH2:15][CH2:14][O:13]CC1.C(OC(N[C@H](C(N[C@H](C(NCC(N)=O)=O)CC1N=CNC=1)=O)CCCCNC(OCC1C=CC=CC=1)=O)=O)C1C=CC=CC=1.N[C@H](C(N[C@H](C(NCC(N)=O)=O)CC1N=CNC=1)=O)CCCCN.[C:84]([OH:87])(=[O:86])[CH3:85]>O1CCCC1.[Pd].O>[CH3:6][C:5]([CH2:15][C:14]([CH2:85][C:84]([OH:87])=[O:86])=[O:13])=[O:4]
Reactant: CN1CCOCC1
Reactant: CC(=O)O
Reactant: CC(C)COC(=O)Cl
Agent: [Pd]
Agent: NC(=O)CNC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: NCCCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)NCC(N)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)CC(=O)CC(=O)O

Procedure:
The product was dissolved in anhydrous methanolic hydrogen chloride (saturated at 0° C.) for 30 minutes, followed by removal of solvent under reduced pressure, forming Nim -benzyloxycarbonyl-L-histidyl-glycine amide. This was dissolved in tetrahydrofuran, and isobutyl chloroformate, N-methylmorpholine, and Nα,Nε -dibenzyloxycarbonyl-L-lysyl-L-histidyl-glycine amide (3 hours at -20° C., then 1 hour at ambient temperature). This product was then dissolved in glacial acetic acid and hydrogenated overnight in the presence of 10% Pd-C catalyst. The resultant L-lysyl-L-histidyl-glycine amide was lyophilized from water several times, then purified by liquid chromatography on a C-18 reverse-phase column to yield the desired tripeptide amide as a triacetate salt.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:12]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH2:4][CH2:3][CH2:2][CH2:9][CH2:8][CH3:7])[CH:9]=1)[CH:5]=[O:6])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=Cc1cc(O)cc(O)c1
Reactant: CCCCCCBr
Product: CCCCCCOc1cc(C=O)cc(OCCCCCC)c1

Procedure:
The title compound was prepared according to the method described in Example 9 above from 3,5-dihydroxy-benzaldehyde and 1-bromohexane.
Reaction SMILES: C(OC([N:8]([C:13]1[CH:14]=[C:15]([CH:49]=[CH:50][C:51]=1[O:52][CH3:53])[C:16]([S:18][CH2:19][C:20]([O:22][C@H:23]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)[CH2:24][C:25]1[C:30]([Cl:31])=[CH:29][N+:28]([O-:32])=[CH:27][C:26]=1[Cl:33])=[O:21])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C>C(Cl)Cl.Cl.O1CCOCC1>[Cl:33][C:26]1[CH:27]=[N+:28]([O-:32])[CH:29]=[C:30]([Cl:31])[C:25]=1[CH2:24][C@@H:23]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:42])[F:43])=[C:36]([O:44][CH2:45][CH:46]2[CH2:47][CH2:48]2)[CH:35]=1)[O:22][C:20](=[O:21])[CH2:19][S:18][C:16](=[O:17])[C:15]1[CH:49]=[CH:50][C:51]([O:52][CH3:53])=[C:13]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:14]=1
Reactant: COc1ccc(C(=O)SCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(C(=O)SCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 58 %

Procedure:
To a solution of (S)-4-(2-(2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoylthio)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.082 g, 0.100 mmol) in DCM (4 ml), HCl 4M in dioxane was added, and the reaction was stirred at RT for 3 days. The volatiles were removed under vacuum, and the residue was purified by chromatography on silica gel column (DCM:MeOH=95:5) to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-methoxy-3-(methylsulfonamido)benzoylthio)acetoxy)ethyl)pyridine 1-oxide (0.042 g, 0.058 mmol, 58.3% yield, MS/ESI+ 721.32 [MH]+, [αD]=−31.40, c=0.5, MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:6]=2[CH:22]=1.[CH:23]([O-])([O-])OCC.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:23]=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:6]=2[CH:22]=1
Reactant: COc1ccc(C2=NCC(NN)=Nc3ccc(Cl)cc32)cc1
Reactant: CCOC([O-])[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C2=NCc3nncn3-c3ccc(Cl)cc32)cc1

Procedure:
To a suspension of 1.6 parts of 7-chloro-2-hydrazino-5-(p-methoxyphenyl)-3H-1,4-benzodiazepine prepared in Example 2 in 50 parts by volume of ethanol is added 3.0 parts of ethyl orthoformate, and then 0.5 part by volume of concentrated sulfuric acid is added dropwise with stirring. The whole mixture is stirred for a while and then neutralized with an aqueous slution of sodium bicarbonate, followed by evaporaton of the solvent. Water is added to the residue, whereby 8-chloro-6-(p-methoxyphenyl)-4H-s-triazolo (4,3-a) (1,4) benzodiazepine is yielded as crystals. Recrystallization from acetone and and then from ethyl acetate yields pale yellow flakes melting at 216° C to 217° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([F:11])[C:8]=1[CH2:9]O)[CH3:2].[Br:12]P(Br)Br>ClCCl>[BrH:12].[Br:12][CH2:9][C:8]1[C:7]([F:11])=[CH:6][N:5]=[CH:4][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cncc(F)c1CO
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Br
Product: CCc1cncc(F)c1CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3-ethyl-5-fluoropyridin-4-yl)methanol (1.5 g, 9.7 mmol) in anhydrous dichloromethane (75 mL) was added tribromophosphane (1 mL, 10.5 mmol). The mixture was stirred at room temperature overnight. Dichloromethane was evaporated. The residue was dried in vacuo, affording 4-(bromomethyl)-3-ethyl-5-fluoropyridine hydrobromide. The crude product was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].[C:11]([NH:13][C:14](=[N:17][CH3:18])SC)#[N:12]>>[C:11]([NH:13][C:14]([NH:17][CH3:18])=[N:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10])#[N:12]
Reactant: CN=C(NC#N)SC
Reactant: NCCCCCCCCN
Product: CNC(=NCCCCCCCCN)NC#N
Yield: 58.4 %

Procedure:
A mixture of 1,8-diaminooctane (14.1 g) with N-cyano-N'-methyl-S-methyl isothiourea (5.2 g) was maintained at 60° for 5 hours to give a solid product which was washed with ether and recrystallised from acetonitrile/ether to give N-cyano-N'-methyl-N"-(8-aminooctyl)guanidine (5.3 g) m.p. 81°-83°
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1.[CH3:25][C:26]([CH3:28])=O.[BH3-]C#N.[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][N:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH:26]([CH3:28])[CH3:25]
Reactant: Fc1cccc(CNCc2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)N(Cc1cccc(F)c1)Cc1nccn1Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 26 %

Procedure:
A mixture of [1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylmethyl]-(3-fluoro-benzyl)-amine, (200 mg, 0.55 mmol), acetone (81 uL, 1.10 mmol) and 3A molecular sieves (300 mg) in MeOH (3 mL) was stirred at ambient temperature under N2. After 5 h, NaBH3CN was added and the mixture stirred for an additional 2 h. Water (2 mL) was added and the reaction mixture concentrated in vacuo. The residue was taken up in 1N NaOH (20 mL) and extracted with CH2Cl2 (3×30 mL). The combined extracts were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by chromatography (silica gel, 100% EtOAc) and the isolated product converted to the di-hydrochloride salt by treatment with excess anhydrous HCl in methanol solution. The volatiles were removed in vacuo to afford the desired product 6a (58 mg, 26%) as an off-white solid: ESI MS m/z 406 [C21H22Cl2FN3+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)=[CH:3][CH:2]=1.[Br:16]Br>C(Cl)(Cl)Cl.ClCCl>[Br:16][C:15]1[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[N:11][C:10]=12
Reactant: c1cnc2cc(-c3ccncc3)nn2c1
Reactant: BrBr
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Brc1c(-c2ccncc2)nn2cccnc12
Reaction time: 1.5 h
Yield: 92 %

Procedure:
To 2-(pyridin-4-yl)pyrazolo[1.5-a]pyrimidine (0.30 g) in 15 mL chloroform was added dropwise a solution of 86 μL bromine in 1 mL chloroform. After 1.5 hours. at ambient temperature, the mixture was diluted with dichloromethane, washed with 10% aqueous potassium carbonate, dried over sodium sulfate, filtered, and evaporated to afford 386 mg (92% yield) product as a tan solid. MS showed a M+1 molecular ion of m/z 277.4 by positive APCI.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:35]([F:38])([F:37])[F:36])[O:14][N:13]=[C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]([NH:27][CH2:28][C:29](=O)[C:30]([F:33])([F:32])[F:31])=[O:26])=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[NH2:39][OH:40].Cl.CC([O-])=O.[K+]>CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:35]([F:36])([F:37])[F:38])[O:14][N:13]=[C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]([NH:27][CH2:28]/[C:29](=[N:39]\[OH:40])/[C:30]([F:33])([F:31])[F:32])=[O:26])=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: NO
Reactant: O=C(NCC(=O)C(F)(F)F)c1ccc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(NC/C(=N\O)C(F)(F)F)c1ccc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 130 °C
Yield: 51 %

Procedure:
To a solution of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(3,3,3-trifluoro-2-oxopropyl)-1-naphthamide (Preparation 11, 100 mg, 0.2 mmol) in EtOH (5 mL) was added hydroxylamine.HCl (30 mg, 0.4 mmol), water (1 mL), and KOAc (40 mg, 0.4 mmol). Reaction was heated to 130° C. for 40 minutes in a microwave. Water was added to the crude reaction and extracted with EtOAc (2×75 mL). The combined organics were dried (Na2SO4) and concentrated under vacuum. The crude material was chromatographed (24 g Redi-Sep column) eluting from 100% EtOAc to 50:50 EtOAc:heptane to afford (E)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(3,3,3-trifluoro-2-(hydroxyimino)-propyl)-1-naphthamide (52 mg, 51%) as a solid. 1HNMR (CDCl3) δ ppm: 9.06 (1H), 8.81 (1H), 8.26 (1H), 7.71-7.57 (4H), 7.51 (1H), 6.48 (1H), 4.64 (2H) 4.28 (1H), 3.89 (1H); m/z (Cl) 596 [M+H]+.