Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[C:23]1[CH:24]=[N:25][N:26](C(OC(C)(C)C)=O)[CH:27]=1.[CH3:35][O:36][C:37]1[CH:38]=[N:39][CH:40]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:42]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CN(C=O)C>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([C:23]4[CH:24]=[N:25][NH:26][CH:27]=4)=[C:2]([C:41]4[CH:40]=[N:39][CH:38]=[C:37]([O:36][CH3:35])[CH:42]=4)[C:10]=23)(=[O:13])=[O:14])[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(-c3cnn(C(=O)OC(C)(C)C)c3)sc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: COc1cncc(-c2c(-c3cn[nH]c3)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 110 °C
Yield: 108.5 %

Procedure:
A mixture of 1,1-dimethylethyl 4-(3-bromo-4-{[(3-chlorophenyl)sulfonyl]amino}-6-methylthieno[2,3-b]pyridin-2-yl)-1H-pyrazole-1-carboxylate (Description 75) (100 mg, 0.171 mmol), 3-methoxy-5-pyridineboronic acid pinacol ester (81 mg, 0.343 mmol), potassium carbonate (71.0 mg, 0.514 mmol), tetrakis(triphenylphosphine)palladium(0) (4.95 mg, 4.28 μmol) and bis(triphenylphosphine)palladium(II) chloride (3.01 mg, 4.28 μmol) were weighed into a microwave vial. 1,4-Dioxane (1.5 mL), DMF (0.75 mL) and water (0.38 mL) were added and the mixture heated in a microwave at 110° C. for 30 min. At this point, both reaction mixtures were combined and concentrated. The residue was passed through an SCX cartridge, eluting with MeOH (100 mL) and then 2M NH3 in MeOH (150 mL). The basic methanolic solution was concentrated and purified by MDAP (acidic conditions), to give the title compound (95 mg). LCMS (A) m/z: 512 [M+1]+, Rt 0.88 min (acidic).
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[NH:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[O:14].C(CN)O.Cl>O>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[OH:9])[CH:2]=[C:18]1[NH:12][C:13](=[O:14])[NH:15][C:16]1=[O:17]
Reactant: O=C1CNC(=O)N1
Reactant: COc1cc(C=O)ccc1O
Agent: Cl
Solvent: O
Solvent: NCCO
Product: COc1cc(C=C2NC(=O)NC2=O)ccc1O
Reaction time: 0.5 h

Procedure:
Vanillin (3.04 g.) and hydantoin (2.0 g.) in water (20 ml were heated on the steam-bath for a few minutes until dissolution occurred. Ethanolamine (0174 g.) was then added and the solution heated at 85°-90° (bath temperature) for 4.5 hours. The solution deposited crystals and solidified within 0.5 hours. Concentrated HCl (5 ml) was added, the mixture was refrigerated overnight (18 hours), filtered, water washed and dried. The title compound was obtained as a yellow solid (4.18 g; 93%), m.p. 266°-271° decomp.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([C:14]([O:16]CC3C=CC=CC=3)=[O:15])=[C:10]([CH3:24])[N:9]2[CH3:25])=[CH:4][CH:3]=1>CO.[H][H].[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[C:11]([C:14]([OH:16])=[O:15])=[C:10]([CH3:24])[N:9]2[CH3:25])=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)OCc2ccccc2)c(=O)n(-c2ccc(F)cc2)n1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1c(C(=O)O)c(=O)n(-c2ccc(F)cc2)n1C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of benzyl 2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (2.6 g, 7.64 mmol) in methanol (25 mL), Pd/C (0.5 g) was added. While blowing in hydrogen gas, the mixture was stirred for 8 hours. The resulting reaction mixture was filtered by passing through a celite pad. The filtrate was concentrated under reduced pressure. The target compound was yielded (1.8 g, 94% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([C:51]([F:54])([F:53])[F:52])=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH:12]3[CH2:15][CH:14]([CH2:16][N:17]([CH2:21][C@@H:22]4[C@H:26]5[O:27]C(C)(C)[O:29][C@H:25]5[C@H:24]([N:32]5[C:36]6[N:37]=[CH:38][N:39]=[C:40]([NH2:41])[C:35]=6[CH:34]=[CH:33]5)[CH2:23]4)[CH:18]([CH3:20])[CH3:19])[CH2:13]3)[N:8](COCC[Si](C)(C)C)[C:7]=2[CH:50]=1>CO>[NH2:41][C:40]1[C:35]2[CH:34]=[CH:33][N:32]([C@@H:24]3[CH2:23][C@H:22]([CH2:21][N:17]([CH2:16][CH:14]4[CH2:15][CH:12]([CH2:11][C:9]5[NH:8][C:7]6[CH:50]=[C:3]([Cl:2])[C:4]([C:51]([F:53])([F:52])[F:54])=[CH:5][C:6]=6[N:10]=5)[CH2:13]4)[CH:18]([CH3:20])[CH3:19])[C@@H:26]([OH:27])[C@H:25]3[OH:29])[C:36]=2[N:37]=[CH:38][N:39]=1
Reactant: CC(C)N(CC1CC(Cc2nc3cc(C(F)(F)F)c(Cl)cc3n2COCC[Si](C)(C)C)C1)C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Agent: Cl
Solvent: CO
Product: CC(C)N(CC1CC(Cc2nc3cc(C(F)(F)F)c(Cl)cc3[nH]2)C1)C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O
Temperature: 40 °C
Reaction time: 6 h
Yield: 27 %

Procedure:
12N HCl (1.5 ml) was added slowly to a solution of 7-[(3aS,4R,6R,6aR)-6-({[(3-{[6-chloro-5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]methyl}cyclobutyl)methyl](propan-2-yl)amino}methyl)-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (174 mg, 0.22 mmol) in MeOH (1.5 ml) and stirred at 40° C. for 6 h. The reaction was monitored by LCMS, no starting material seen after 2.5 h. The reaction mixture was concentrated in vacuo, then basified with 7N NH3 in MeOH (5 ml). This was then evaporated to dryness. Purification by silica gel column chromatography, eluting with 7N NH3 in MeOH:DCM (1:9) gave the desired product (36 mg, 27%) as a white solid; MS (ESI+) for C29H35ClF3N7O2 m/z 606.30 [M+H]+; HPLC purity 100% (ret. time, 2.59 min); 1H NMR (500 MHz, MOD) δH ppm 0.93-1.09 (6 H, m), 1.41-1.64 (2 H, m), 1.76-2.06 (1 H, m), 2.15-2.65 (9 H, m), 2.65-2.88 (1 H, m), 2.91-3.13 (3 H, m), 3.80-4.09 (1 H, m), 4.19-4.46 (1 H, m), 4.88-4.94 (1 H, m), 6.46-6.77 (1 H, m), 7.19 (1 H, d, J=3.63 Hz), 7.69 (1 H, s), 7.89 (1 H, s), 8.06 (1 H, s)
Reaction SMILES: [CH2:1]([CH:3]([NH:6][OH:7])[CH2:4][CH3:5])[CH3:2].[O:8]([C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[OH:7][N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:16][CH:17]=1)=[O:23]
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: CCC(CC)NO
Solvent: C1CCOC1
Product: CCC(CC)N(O)C(=O)Nc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
A solution of N-(1-ethylpropyl)hydroxylamine (1.13 g, 11 mmole, Compound 39, Part B) in tetrahydrofuran (30 mL) was charged with 4-phenoxyphenylisocyanate (2.1 g, 10 mmole) and maintained at ambient temperature overnight. The solvent was removed in vacuo to yield 3.2 g of the crude product as a white solid. Recrystallization from hexanesethyl acetate provided 1.6 g of the desired product as a white crystalline solid, m.p. 124°-125° C. Analysis: Calculated for: C18H22N2O3 : %C, 68.77; %H, 7.05; %N, 8.91; Found: %C, 68.44; %H, 7.09; %N, 8.82.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH3:16][CH:17]([CH3:21])[CH2:18][CH:19]=[O:20]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:19]([OH:20])[CH2:18][CH:17]([CH3:21])[CH3:16])=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: CC(C)CC=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CC(O)c1ccc(Br)cc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
4-bromo-iodobenzene (1.42 g, 5.00 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to −40° C. A solution of isopropylmagnesium chloride lithium chloride (5 mL, 1.3 M in THF) was added dropwise over 5 minutes. The mixture was stirred at −40° C. for 30 minutes, then 3-methylbutanal (0.81 mL, 7.5 mmol) was added. The reaction was allowed to warm to room temperature and stir for 1 hour. The reaction was then quenched by addition of saturated ammonium chloride (10 mL) and water (40 mL). The mixture was diluted with ethyl acetate (50 mL), and the layers were separated. The organics were washed with water (50 mL) and brine (25 mL), dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-50% ethyl acetate in heptane) gave (+/−)-1-(4-bromophenyl)-3-methylbutan-1-ol (958 mg, 79%) as a clear oil. 1H NMR (400 MHz, CDCl3, δ): 7.47-7.41 (m, 2H), 7.22-7.17 (m, 2H), 4.68 (dd, J=8.1, 5.4 Hz, 1H), 1.97 (br.s, 1H), 1.71-1.61 (m, 2H), 1.49-1.39 (m, 1H), 0.94-0.90 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=3)[C:10]([CH2:23][CH3:24])=[C:9]([CH3:25])[N:8]=2)=[CH:4][CH:3]=1.[NH2:26][OH:27].Cl.C([O-])([O-])=O.[K+].[K+].CCO>O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH:26][OH:27])=[NH:22])=[CH:16][CH:15]=3)[C:10]([CH2:23][CH3:24])=[C:9]([CH3:25])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(CC#N)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(CC(=N)NO)cc1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
A 50-mL round bottomed flask was charged with 2-[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]acetonitrile (120 mg, 0.325 mmol, 1 eq.), NH2OH/HCl (160 mg, 2.3 mmol, 7 eq), K2CO3 (320 mg, 2.3 mol, 7 eq.), EtOH (10 ml) and water (1 ml). The mixture was stirred under reflux overnight. After cooling to room temperature, the volatile material was removed under reduced pressure. The residue was purified by chromatography on silica gel using 1.5˜4% of methanol in dichloromethane as eluent to give the title compound (61 mg, 47% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.CN(CCN(C)C)C.[CH2:20]([O:22]CC)C.[Li]CCCC.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([CH:20]=[O:22])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)cc(OC)c1
Reactant: CCOCC
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: COc1cc(Cl)cc(OC)c1C=O
Temperature: -78 °C
Reaction time: 4 h
Yield: 33.9 %

Procedure:
A solution of 1-chloro-3,5-dimethoxybenzene (5 g, 29.0 mmol) and TMEDA (4.37 mL, 29.0 mmol) in diethyl ether (100 mL, 962 mmol) at −78° C. under N2 atmosphere was charged with BuLi (19.91 mL, 31.9 mmol) dropwise over a period of 30 minutes using a syringe pump. After stirring for 4 hours at −78° C., DMF was added and the reaction mixture continued to stir for 1.5 hours after which 1N HCl (˜30 mL) was added (all at −78° C.). The reaction mixture was warmed to room temperature and extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The residue was purified by ISCO using hexanes/EtOAc as eluent. Fractions containing the desired product were concentrated to dryness to give the title material (1.97 g, 9.82 mmol, 33.9% yield) as a light yellow solid. LC (Method B): 1.924 min. LCMS (APCI) calcd for C9H10ClO3 [M+H]+ m/z 201.03, found 201.0. 1H NMR (CDCl3, 400 MHz) δ ppm: 10.28 (s, 1H), 6.87 (s, 2H), 3.86 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[C:10]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>CCOCC>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[OH:17])=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccncc1
Reactant: Cc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1ccc(C(O)(c2ccccc2)c2ccncc2)cc1
Reaction time: 1.5 h

Procedure:
A solution of 0.05 mole of 4-methylphenyl magnesium bromide in 500 ml of anhydrous ether was treated with 4-benzoylpyridine in 500 ml anhydrous ether. After stirring the resulting mixture for 1.5 hours at 25° , an aqueous solution of ammonium chloride was added causing a solid to form which was filtered. Recrystallization of this material from 95% ethanol afforded the desired α-(4-methylphenyl)-α-phenyl-4-pyridine methanol, m.p. 192°-195° C. The corresponding 4-chlorophenyl (m.p. 198°-202° C.) and 4-methoxyphenyl (m.p. 204°-206° C.) derivatives were also prepared by the same method, using equivalent amounts of the appropriate starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([SH:21])=[S:20])[CH2:15][CH2:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH-].[Na+].[CH3:24]O>[Cl-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]2[CH2:14][CH2:15][N:16]([C:19]([S:21][CH3:24])=[S:20])[CH2:17][CH2:18]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CO
Reactant: COc1cc(N2CCN(C(=S)S)CC2)cc(OC)c1OC
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(N2CCN(C(=S)SC)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
In a nitrogen atmosphere, 1.5 g (4.6 mmol.) of 4-(3,4,5-trimethoxyphenyl)-1-piperazinecarbodithioic acid was suspended inmethanol. After addition of 0.2 g of granular sodium hydroxide, the suspension was stirred at room temperature for one hour. The reaction mixture was chilled in a mixture of ice and sodium chloride. To the reaction mixture was dropwise added a solution of 0.29 ml of methyl iodidein 3.7 ml of methanol. After the addition was complete, the mixture was stirred at room temperature for 1 hour. Precipitated crystals were collected by filtration to give 0.8 g of the desired compound as a gray-brown powder, m.p. 135°-137° C. (decomp.), yield 50.8%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.C(N(CC)C(C)C)(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:26]([S:37]([CH3:36])(=[O:39])=[O:38])[S:37]([CH3:36])(=[O:39])=[O:38])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(N(S(C)(=O)=O)S(C)(=O)=O)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 117.8 %

Procedure:
To a solution of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) in THF (2 mL) were added N,N-diisopropyl ethyl amine (0.15 mL, 0.86 mmol), 4-dimethylaminopyridine (8 mg, 0.06 mmol) and methanesulfonyl chloride (53 μL, 0.69 mmol). The resulting suspension was then stirred for 18 h at ambient temperature. Further N,N-diisopropyl ethyl amine (0.15 mL, 0.86 mmol) and methanesulfonyl chloride (54 μL, 0.689 mmol) was added and stirred was continued for 24 h at 50° C. The reaction mixture was extracted with aqueous HCl (1 M, 15 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers were washed with brine (half-saturated, 20 mL) and aqueous sodium carbonate (saturated, 20 mL). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=60:20:20 to 0:80:20) afforded the title compound (205 mg, 71%) as a white solid. MS: m/e=505.0 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[N:1]1([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: C1CNCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CN2CCCNCC2)cc1
Yield: 56.2 %

Procedure:
Alternatively, a mixture of hexahydro-1H-1,4-diazepine (17.47 g, 174.4 mmol) and methyl 4-(bromomethyl)benzoate (5.0 g, 21.8 mmol) was heated with triethylamine (24 mL, 174.4 mmol) in tetrahydrofuran (872 mL) to reflux for three hours. After cooling, the mixture was treated with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 3.04 g of methyl 4-[(hexahydro-1H-1,4-diazepin-1-yl)methyl]benzoate, 1H NMR (300 MHz, CDCl3) δ7.98 (d, 2H), 7.42 (d, 2H), 3.90 (s, 3H), 3.70 (s, 2H), 2.97 (m, 2H), 2.91 (m, 2H), 2.67 (m, 2H), 2.66 (m, 2H), 1.77 (m, 2H)
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:36])[C@H:6]([O:14][C:15]1[C:20]([Br:21])=[CH:19][C:18]([C:22]2[C:30]3[C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[S:27][C:26]=3[CH:25]=[CH:24][CH:23]=2)=[CH:17][C:16]=1[Br:35])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C1COCC1.CO.O>[Br:35][C:16]1[CH:17]=[C:18]([C:22]2[C:30]3[C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[S:27][C:26]=3[CH:25]=[CH:24][CH:23]=2)[CH:19]=[C:20]([Br:21])[C:15]=1[O:14][C@H:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:5]([OH:36])=[O:4]
Reactant: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2cccc3sc4ccccc4c23)cc1Br
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2cccc3sc4ccccc4c23)cc1Br
Reaction time: 1.5 h
Yield: 80 %

Procedure:
1.0 N Aqueous potassium hydroxide (0.81 mL, 0.81 mmol) was added to a stirred solution of (R)-2-[2,6-dibromo-4-(dibenzothiophen-1-yl)-phenoxy]-3-phenyl-propionic acid methyl ester (0.242 g, 0.406 mmol) in THF (4 mL) and methanol (2.5 mL). After 1.5 h at ambient temperature, the reaction mixture was diluted with water, acidified with 10% aqueous HCl and filtered. The solid was washed with water and triturated with pet. ether. The solid was dried in vacuo at 70° C. to provide the title compound as a white solid (0.190, 80%): [a]D25=+19.73 (10.14 mg/mL CHCl3); NMR (CDCl3): δ 7.89 (dd, J=8, 1 Hz, 1H), 7.83 (ddd., J=8, 1, 1 Hz, 1H), 7.63 (d, J=2 Hz, 1H), 7.62 (d, J=2 Hz, 1H), 7.45 (dd, J=8, 6 Hz, 2H), 7.41-7.154 (m, 8H), 5.33 (t, J=8 Hz, 1H), 3.54 (dd, J=5, 2 Hz, 1H), 3.52 (dd, J=8, 4 Hz, 1H); MS (EI): [M+], 2 bromine isotope pattern, 580 (20%), 582 (40%) 584 (25%); Anal. Calc. for C27H18Br2O3S: C, 55.69, H, 3.11, N, 0.00. Found: C, 55.23, H, 2.97, N, 0.07; Analytical HPLC :98.8%.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:8](O)=[O:9].P(Cl)(Cl)(Cl)(Cl)[Cl:25]>C1C=CC=CC=1>[F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:8]([Cl:25])=[O:9]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CS(=O)(=O)Nc1ccc(C(=O)O)cc1Oc1ccc(F)cc1F
Solvent: c1ccccc1
Product: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 110.7 %

Procedure:
A mixture of 3-(2,4-difluorophenoxy)-4-methanesulfonamidobenzoic acid (0.6 g) and phosphorus pentachloride (0.4 g) in benzene (6 ml) was warmed, dissolved, and then stirred for 25 minutes at room temperature. The mixture was concentrated under reduced pressure to give a powder of 3-(2,4-difluorophenoxy)-4-methanesulfonamidobenzoyl chloride (0.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([O:14][CH3:15])=[N:10][N:9]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])[C:8]2=[O:24])=[CH:4][CH:3]=1.[NH2:27][OH:28]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([O:14][CH3:15])=[N:10][N:9]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)/[C:19](/[NH2:20])=[N:27]/[OH:28])[C:8]2=[O:24])=[CH:25][CH:26]=1
Reactant: NO
Reactant: COc1nn(-c2cccc(C#N)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Solvent: CCO
Solvent: O
Product: COc1nn(-c2cccc(/C(N)=N/O)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 80 °C
Yield: 99 %

Procedure:
According to Scheme 9 Step 1: To a stirred solution of 3-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)benzonitrile (1 50 mg, 0.41 mmol) in ethanol (5 ml) was added hydroxylamine (0.100 ml of a 50% solution in water, 1.2 mmol) and the mixture was heated at 80° C. overnight. The reaction mixture was quenched with a saturated ammonium chloride solution and extracted with ethyl acetate (×3). The combined organic layers were successively washed with water, with brine,dried over MgSO4, filtered and concentrated to afford (Z)-3-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-N′-hydroxybenzamidine (150 mg, 99%) which was used in the next step without any further purification.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=1.[C:13]([O:17][C:18]([N:20]1[CH2:23][CH:22]([O:24][C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=2O)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([N:20]1[CH2:23][CH:22]([O:24][C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=2[O:10][CH2:9][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:11])([F:1])[F:12])[N:8]=2)[CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: OCc1cccc(C(F)(F)F)n1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2O)C1
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2OCc2cccc(C(F)(F)F)n2)C1

Procedure:
Prepared from the title compound of Step A and 3-(5-Chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester using general procedure 7.
Reaction SMILES: C1CCC([N:7]=C=NC2CCCCC2)CC1.[CH3:16][C:17]1([CH3:58])[C:21](=[O:22])[N:20]([C@@H:23]([CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:24]([NH:26][C@H:27]([CH3:32])[CH2:28][C:29]([OH:31])=O)=[O:25])[C:19](=[O:37])[N:18]1[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:46]([NH:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[CH3:55])=[O:47])=[C:41]([O:56][CH3:57])[CH:40]=1.C1C=CC2N(O)N=NC=2C=1.N>CN(C=O)C>[CH3:58][C:17]1([CH3:16])[C:21](=[O:22])[N:20]([C@@H:23]([CH2:33][CH:34]2[CH2:35][CH2:36]2)[C:24]([NH:26][C@H:27]([CH3:32])[CH2:28][C:29]([NH2:7])=[O:31])=[O:25])[C:19](=[O:37])[N:18]1[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:46]([NH:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[CH3:55])=[O:47])=[C:41]([O:56][CH3:57])[CH:40]=1
Reactant: COc1cc(CN2C(=O)N([C@@H](CC3CC3)C(=O)N[C@H](C)CC(=O)O)C(=O)C2(C)C)ccc1NC(=O)Nc1ccccc1C
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(CN2C(=O)N([C@@H](CC3CC3)C(=O)N[C@H](C)CC(N)=O)C(=O)C2(C)C)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
131 mg (0.636 mmol) of DCC were added to a solution of 330 mg (0.555 mmol) of the compound of Example 1 and 125 mg (0.926 mmol) of HOBT in 4 mL of absolute DMF, the mixture was stirred at room temperature for 1 hour and then 47 μL (0.555 mmol) of a 25% strength aqueous ammonia solution were added. The mixture was allowed to stand overnight at room temperature, a further 16 μL of a 25% strength aqueous ammonia solution were added and the mixture was stirred for 4 hours. After filtration, the filtrate was concentrated in vacuo, the residue was dissolved in ethyl acetate and the ethyl acetate phase was washed twice in each case with an aqueous KHSO4/K2SO4 solution, a saturated NaHCO3 solution and water. After drying the organic phase over sodium sulfate and filtering, the solvent was removed in vacuo and the residue was chromatographed over silica gel using ethyl acetate. After concentrating the product fractions and freeze drying, 272 mg (82%) of the title compound were obtained.