Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[CH2:15]([NH:19][C:20](=[N:23][C:24]#[N:25])SC)[C:16]#[C:17][CH3:18]>>[C:24]([NH:23][C:20]([NH:19][CH2:15][C:16]#[C:17][CH3:18])=[N:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[O:9][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=1)#[N:25]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CC#CCNC(=NC#N)SC
Product: CC#CCNC(=NCCSCc1ccc(CN(C)C)o1)NC#N

Procedure:
2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamine is reacted in a non-reactive solvent with about an equimolar amount of N-(2-butyn-1-yl)-N'-cyano-S-methylisothiourea [prepared according to the procedure described in U.S. Pat. No. 4,112,234, the complete disclosure of which is incorporated herein by reference] and, after workup and chromatography, the title product is produced.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[S:47](N)([NH2:50])(=[O:49])=[O:48]>O1CCOCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:50][S:47]([N:43]1[CH2:44][CH2:45][CH:40]([C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:39])[CH2:41][CH2:42]1)(=[O:49])=[O:48]
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Reactant: NS(N)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: NS(=O)(=O)N1CCC(C(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Temperature: 130 °C
Yield: 6.9 %

Procedure:
To a solution of N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) (10.0 mg, 0.018 mmol) in 1,4-dioxane (1.0 mL) was added sulfamide (17.1 mg, 0.18 mmol) and the mixture was heated to 130° C. in a microwave for 10 minutes. Purification by preparative LCMS (pH 2) gave the desired compound (0.8 mg, 7% yield). LCMS for C24H27ClN7O3S (M+H)+: m/z=528.2.
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][CH:4]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[OH:23][CH2:22][CH:19]1[CH2:20][CH2:21][N:16]([CH2:2][C:3]2[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][CH:4]=2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reactant: OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1ccc(CN2CCC(CO)CC2)cc1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
tert-Butyl 4-(bromomethyl)benzoate (1 g, 3.13 mmol) and piperidin-4-ylmethanol (0.361 g, 3.13 mmol) were dissolved in acetonitrile (25 mL). K2CO3 (1.300 g, 9.40 mmol) was added and the reaction mixture was heated to reflux for 20 min. The reaction mixture was cooled down to room temperature, filtered and evaporated. The resulting solid was partitioned between ethyl acetate (50 mL) and 1 M HCl (50 mL). The layers were separated and the aqueous layer was washed with ethyl acetate and the organic layers were discarded. The aqueous layer was basified with 8 M NaOH to pH˜10 and extracted 2 times with 50 mL of ethyl acetate. The organic layers were combined, washed with brine and dried over MgSO4, filtered and evaporated. tert-Butyl 4-((4-(hydroxymethyl)piperidin-1-yl)methyl)benzoate (0.95 g, 2.99 mmol, 95% yield) was isolated as yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.95 (d, J=8.34 Hz, 2H), 7.39 (d, J=8.08 Hz, 2H), 3.56 (s, 2H), 3.51 (d, J=6.57 Hz, 2H), 2.90 (d, J=11.37 Hz, 2H), 1.94-2.04 (m, 2H), 1.73 (d, J=14.15 Hz, 2H), 1.61 (s, 9H), 1.40-1.56 (m, 2H), 1.30-1.37 (m, 2H); LC-MS Rt=0.67 min; MS (ESI): 306.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:46])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]4[CH:30]=[C:31]([NH:35][C:36]([NH:38][C:39]5[CH:44]=[CH:43][CH:42]=[C:41](I)[CH:40]=5)=[O:37])[CH:32]=[CH:33][CH:34]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[C:47]1([C:53]#[CH:54])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[Cu]I.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>[CH3:1][C:2]1([CH3:46])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]4[CH:30]=[C:31]([NH:35][C:36]([NH:38][C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([C:54]#[C:53][C:47]6[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=6)[CH:40]=5)=[O:37])[CH:32]=[CH:33][CH:34]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: C#Cc1ccccc1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)Nc5cccc(I)c5)c4)C(=O)O3)ccc2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)Nc5cccc(C#Cc6ccccc6)c5)c4)C(=O)O3)ccc2O1
Reaction time: 0.08 h
Yield: 86.5 %

Procedure:
A solution of N-[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenyl]-N′-(3-iodophenyl)urea (393 mg) and phenylacetylene (77 mg) in DMF (6 ml) was treated with diisopropylethylamine (5 ml) and nitrogen was passed through the solution for 5 min. Copper (I) iodide (10 mg) and dichlorobis(triphenylphosphine)palladium(II) (47 mg) were added and the mixture was stirred under nitrogen at 200 for 21.5 h. The solvent was evaporated in vacuo and EtOAc (15 ml) was added. The supernatent solution was collected and the solvent evaporated in vacuo to give a residue which was purified by Biotage. Elution with dichloromethane-ethanol-ammonia (325:8:1) gave the title compound (328 mg). LCMS RT=3.93 min, ES+ve 718 (MH)+.
Reaction SMILES: CC([O-])=O.[Na+].N(C(OCC1C=CC=CC=1)=O)[C@H](C(N[C@H](C([NH:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][C:19](=O)[OH:20])=O)C)=O)C.[NH2:35]C1C=C2C(C(C)=CC(=O)O2)=CC=1>>[NH2:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][C:19](=[O:20])[NH2:35]
Reactant: Cc1cc(=O)oc2cc(N)ccc12
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: NC(=O)C[C@H](N)C(=O)O
Reaction time: 0.33 h

Procedure:
To a AEP (100 ng/well) in assay buffer (50 mM NaOAc, 300 mM NaCL, pH 4.5, 50 μL) was added 10 μL of the inhibitors (in PBS). The plate was then incubated at room temperature for 20 minutes. ZAla-Ala-Asp-MEC was then added (100 μM, Bachem, 60 μL) and 7-amino-4-methylcoumarin release was measured by fluorescence spectroscopy over time. Initial rates were plotted against inhibitor concentration.10
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][N:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:24])[NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][CH:10]=1>C(N(CC)CC)C.CN(C=O)C>[CH3:5][O:4][C:2]([NH:6][N:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:24])[NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][CH:10]=1)=[O:3]
Reactant: CCOC(=O)CNC(=O)Nc1ccc(C=NN)cc1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)Nc1ccc(C=NNC(=O)OC)cc1
Reaction time: 168 h

Procedure:
1.74 g (22.7 mmol) of methyl chloroformate are added dropwise to a solution of 5 g (18.92 mmol) of ethyl (3-(4-(aminoiminomethyl)phenyl)ureido)acetate in 53 ml of triethylamine and 100 ml of DMF. After 7 d at room temperature, solid is filtered off and the filtrate is concentrated in vacuo. The residue is chromatographed on silica gel (ethyl acetate/methanol 95:5).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:26][CH:27]([CH3:33])[CH2:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[Br:1][C:2]1[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([S:29]([CH2:28][CH:27]([CH3:33])[CH3:26])(=[O:31])=[O:30])[CH2:12]2)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: CSc1ncc(Br)c(N[C@H]2CCCNC2)n1
Reactant: CC(C)CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(Br)c(N[C@H]2CCCN(S(=O)(=O)CC(C)C)C2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
A solution of (5-bromo-2-methylsulfanyl-pyrimidin-4-yl)-(S)-piperidin-3-yl-amine (1.0 g, 3.3 mmol) from Scheme 1, step 1, Example 76 and diisopropylethylamine (1.6 ml, 6.6 mmol) in dichloromethane (15 ml) was cooled to 5° C. and treated with a solution of 2-methylpropane-1-sulfonyl chloride (0.52 g, 3.3 mmol) in dichloromethane (2 ml) similar to step 2. This was stirred at room temperature for 16 hours, washed with water, dried (MgSO4) and evaporated to give an oil. This was purified by silica gel chromatography (50-80% ethyl acetate/hexane) to give 1.0 g (65%) (5-bromo-2-methylsulfanyl-pyrimidin-4-yl)-[(S)-1-(2-methyl-propane-1-sulfonyl)-piperidin-3-yl]-amine. MS (ES+): 424
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4](=[O:15])[N:5]([CH2:13][CH3:14])[C:6](=[S:12])[N:7]([CH2:10][CH3:11])[C:8]=1[NH2:9].C(=O)([O-])[O-].[Na+].[Na+].[CH:22]1([C:25](Cl)=O)[CH2:24][CH2:23]1>N1C=CC=CC=1.CCOCC>[CH2:13]([N:5]1[C:4](=[O:15])[C:3]2[NH:2][C:25]([CH:22]3[CH2:24][CH2:23]3)=[N:9][C:8]=2[N:7]([CH2:10][CH3:11])[C:6]1=[S:12])[CH3:14]
Reactant: O=C(Cl)C1CC1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCn1c(=O)c2[nH]c(C3CC3)nc2n(CC)c1=S

Procedure:
25.1 g (100 mM) of 5,6-diamino 1,3-diethyl-2-thiouracil HCl were dissolved in 400 ml of pyridine, 12.72 g (120 mM) of sodium carbonate added, and under cooling a solution of 10.77 ml (120 mM) of cyclopropane carbonyl chloride in 50 ml of dried ether added within 10 minutes. After 20 min the solvents were evaporated in vacuo. The residue was treated with 200 ml of water and about 50 ml were removed again in vacuo. The suspension was diluted with 100 ml of 2N aqueous sodium hydroxide (NaOH) and heated under reflux for 30 minutes. A further 80 ml was distilled off during this time. After cooling the solution was acidified with 5N aqueous hydrochloric acid (HCl) to pH 5.5; 200 ml of water was added and the resulting suspension filtered. The solid was collected and washed, redissolved in 200 ml of 1N NaOH, treated twice with 0.4 g of charcoal, filtered and acidified again to pH 4.5. The solid was collected again, washed and dried to give 25.5 g of a solid which was suspended in 400 ml of hot methanol. The solid was collected again, washed and dried to give 23.5 g (89.0%) of 2-thioxanthine with mp subl. 265-7° C.
Reaction SMILES: C1(C[O:5][C:6](=[O:32])[CH:7]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:15]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)=[C:14]([Cl:31])[CH:13]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])CC1.[OH-].[K+]>CCO.O>[CH3:10][CH:9]([CH3:11])[CH2:8][CH:7]([C:12]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:15]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)=[C:14]([Cl:31])[CH:13]=1)[C:6]([OH:32])=[O:5]
Reactant: CC(C)CC(C(=O)OCC1CC1)c1cc(Cl)c(-c2ccc(Cl)c(Cl)c2)c(OCC2CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)CC(C(=O)O)c1cc(Cl)c(-c2ccc(Cl)c(Cl)c2)c(OCC2CC2)c1
Yield: 90.5 %

Procedure:
4-Methyl-2-(2,3′,4′-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pentanoic acid cyclopropylmethyl ester (0.37 g, 0.75 mmol) was dissolved in a mixture of EtOH and H2O (9 mL/1 mL) and KOH (0.2 g, 3.6 mmol) was added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5, and the reaction mixture was extracted with EtOAc (3×10 mL). The organic phase was dried over MgSO4 and evaporated under reduced pressure to give 4-methyl-2-(2,3′,4′-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pentanoic acid as a white solid (0.30 g, 90%). M.p.=118-119° C. 1H NMR (300 MHz, CDCl3/TMS): δ 9.70 (br s, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.42 (d, J=1.6 Hz, 1H), 7.53 (dd, J=8.2, 1.4 Hz, 1H), 7.07 (s, 1H), 6.83 (s, 1H), 3.78 (d, J=6.3 Hz, 2H), 3.63 (t, J=7.3 Hz, 1H), 2.02-1.93 (m, 1H), 1.74-1.65 (m, 1H), 1.59-1.51 (m, 1H), 1.11-1.00 (m, 1H), 0.94 (d, J=6.3 Hz, 6H), 0.54-0.47 (m, 2H), 0.24-0.16 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 179.4, 157.0, 140.3, 134.8, 133.9, 132.5, 131.6, 131.3, 129.9, 129.6, 127.0, 121.5, 111.1, 73.3, 49.4, 42.0, 25.9, 22.6, 22.3, 10.0, 3.1.
Reaction SMILES: CON(C)[C:4](=[O:20])[CH:5]([O:18][CH3:19])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:19][O:18][CH:5]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][CH:11]=1)[CH:4]=[O:20]
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(C=O)c1ccc(N2CCOCC2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 105.8 %

Procedure:
To a solution of N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide (1.5 g, 5.1 mmol) in anhydr CH2Cl2 (12 mL) and anhydr toluene (6 mL) at −78° C. was added a solution of DIBALH (1 M in hexanes, 7.8 mL, 7.8 mmol) dropwise over 5 min. After stirring at −78° C. for 1 hr, the reaction was quenched with the dropwise addition of EtOAc. The mixture was stirred 2 min then Et2O and saturated aqueous NH4Cl were added and the mixture was warmed to room temp. After stirring for 30 min the mixture was diluted with EtOAc and H2O and the layers separated. 10% Aqueous potassium sodium tartrate was added to the aqueous layer and it was extracted with EtOAc/Et2O. The combined organics were washed with saturated aqeuous NH4Cl and dried over Na2SO4 to give 2-methoxy-2-(4-morpholinophenyl)acetaldehyde as a yellow oil (1.27 g). The product was used in the next synthetic step without further purification.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[CH2:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:12][CH2:13]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1
Reactant: BrCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(Cc3ccccc3)CC2)cc1

Procedure:
1-(1-Benzyl-piperidin-4-yl)-4-(4-methanesulfonyl-phenoxy)-1H-pyrazolo[3,4-d]pyrimidine was prepared according to General Procedure F by the reaction of 4-[4-(4-methanesulfonyl-phenoxy)pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 59) with trifluoroacetic acid in dichloromethane followed by reaction with benzyl bromide (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.93-1.99 (m, 2H), 2.20-2.22 (m, 4H), 2.93-2.99 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.55 (s, 2H), 4.75-4.81 (m, 1H), 7.26-7.35 (m, 5H), 7.62-7.64 (m, 2H), 8.04-8.06 (m, 2H), 8.37 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=464.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[SH:9].[H-].[Na+].[Cl:12][C:13]1[CH:18]=[C:17]([N+]([O-])=O)[CH:16]=[CH:15][N:14]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([S:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])[CH:16]=[CH:15][N:14]=1
Reactant: Sc1cccc(Cl)c1Cl
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(Sc2cccc(Cl)c2Cl)ccn1
Yield: 56.4 %

Procedure:
Using the method of Example 3, Step A, 2,3-dichlorobenzenethiol (1.69 g, 9.46 mmol), 60% sodium hydride in mineral oil (378 mg, 9.46 mmol), and 2-chloro-4-nitropyridine (1.50 g, 9.46 mmol) were reacted to provide 2-chloro-4-(2,3-dichlorophenylthio)pyridine (1.55 g, 56% yield) as a white powder. 1H NMR (CDCl3) δ 8.19 (d, 1H), 7.61 (d, 1H), 7.54 (d, 1H), 7.29 (t, 1H), 6.95 (s, 1H), 6.87 (d, 1H).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:13]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1)(=[O:20])=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[CH2:1]([NH:5][CH2:33][C:30]1[CH:31]=[CH:32][C:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[S:18](=[O:20])(=[O:19])[NH:17][C:13]([CH3:14])([CH3:16])[CH3:15])=[CH:28][CH:29]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCNCc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of 3.9 mL (2.9 g, 39.5 mmole) of n-butylamine and 1.3 mL (0.95 g, 9.4 mmole) of triethylamine in 40 mL of dry methylene chloride was added 3.39 g (7.9 mmole, based on 89% purity) of [2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl bromide (prepared as in Step D). The mixture was stirred under N2 at room temperature overnight and then concentrated to dryness. The viscous oil was dissolved in some fresh methylene chloride and evaporated onto silica gel (the minimum amount required to give a dry powder). This was layered on top of a silica gel flash column, which was eluted initially with 1:1 hexane-EtOAc and then with a larger volume of EtOAc alone. The fractions containing pure product were combined and concentrated in vacuo to yield 2.1 g (70%) of the title compound as a white solid, mp 98°-99° C., homogeneous by TLC (EtOAc); FAB-MS m/e 375 (M+1)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)C.Cl.O1CCOCC1>[ClH:21].[ClH:21].[Cl:21][C:17]1[N:16]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:20]=[CH:19][N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccnc(Cl)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Clc1nccc(NC2CCNCC2)n1

Procedure:
A solution of 4-(2-chloro-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (3.2 g, 10.23 mmol) in ethanol (40 mL) and 4 M HCl in dioxane (70 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 213.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N:10]3[CH2:15][CH2:14][CH:13]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:28]=1.Br[CH2:30][CH2:31][CH3:32]>>[CH3:19][C@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH2:17][O:16][CH:13]1[CH2:14][CH2:15][N:10]([C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:30][CH2:31][CH3:32])=[CH:28][C:6]=3[N:7]=2)[CH2:11][CH2:12]1
Reactant: C[C@@H](COC1CCN(c2nc3cc(O)ccc3o2)CC1)NC(=O)OC(C)(C)C
Reactant: CCCBr
Product: CCCOc1ccc2oc(N3CCC(OC[C@H](C)NC(=O)OC(C)(C)C)CC3)nc2c1

Procedure:
By a method similar to Example 6, step A, and using tert-butyl [(1S)-2-{[1-(5-hydroxy-1,3-benzoxazol-2-yl)piperidin-4-yl]oxy}-1-methylethyl]carbamate (412 mg) and 1-bromopropane (0.282 mL), the title compound (367 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[N:5]=[N:4][N:3]=1.[CH2:13]([N:15](CC)[CH2:16][CH3:17])[CH3:14].ClC(OCC(C)C)=O.C(NCC)C>CN(C)C=O>[CH2:13]([N:15]([CH2:16][CH3:17])[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][N:6]1[C:2]([CH3:1])=[N:3][N:4]=[N:5]1)[CH3:14]
Reactant: Cc1nnnn1CCCC(=O)O
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCN(CC)C(=O)CCCn1nnnc1C
Yield: 62.2 %

Procedure:
4-(5-Methyl-1,2,3,4-tetrazol-1-yl)butyric acid (1.7 g) is dissolved in dimethylformamide (50 ml) and triethylamine (1.1 g) is added to the solution. Isobutyl chloroformate (1.5 g) is added dropwise to the mixture with stirring and ice-cooling and the mixture is stirred at room temperature for 30 minutes. Diethylamine (0.9 g) is added dropwise to the mixture with stirring at room temperature. The mixture is stirred for 3 hours. Dimethylformamide is distilled off and the residue is purified by silica gel column chromatography (silica gel made of Merck & Co.). The column is eluted with chloroform-methanol (50:1) to obtain N,N-diethyl-4-(5-methyl-1,2,3,4-tetrazol-1-yl)butyric acid amide (1.4 g), b.p. 190°-200° C. (bath temperature)/0.04 mmHg, nD25 =1.4908.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:26]([CH:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)([CH3:28])[CH3:27].C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:30]1[CH2:31][CH2:32][CH2:33][CH:29]1[CH:26]([CH3:28])[CH3:27])=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(C)C1CCCN1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCCC2C(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-isopropylpyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.71 minutes; C24H26Cl2N4O2 (473.40); mass spectrum: (M−H)−=472/474/476 (chlorine isotope).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([NH2:8])[CH:7]=1.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.O.O.Cl[Sn]Cl>C1COCC1>[NH2:9][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[NH:8][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1cc(Br)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2cc(Br)ccc2N)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
In aflame dried, round bottom flask, 5-bromo-2-nitro-aniline (2) (10.66 g, 49.09 mmol), (scheme 1, Example 1), and 4-methoxybenzoyl chloride (8.37 g, 49.09 mmol) were added. The mixture was heated to 90° C. The melted solids were stirred overnight to give a yellow-brown solid. THF (250 mL) was then added and the solution was treated with SnCl2.2H2O (55.38 g, 245.45 mmol, 5.0 eq) and stirred at room temperature for 2 hrs. Approx. half of the THF was evaporated then 200 mL of EtOAc and 100 mL sat. NaHCO3 were added. The precipitated tin salt was taken out by filtration and a work-up was done on the filtrate with EtOAc. The combined organic layers were washed with water and brine and dried over MgSO4. Most of the EtOAc was evaporated then hexane was added and the precipitate was collected by filtration to give the title compound 114 as a beige powder (13.40 g, 85% yield). 1H NMR (DMSO-d6) δ(ppm): 9.52 (s, 1H), 7.93 (d, J=9.0 Hz, 2H), 7.34 (d, J=2.3 Hz, 1H), 7.08 (dd. J=8.6, 2.3 Hz, 1H), 7.02 (d, J=9.0 Hz, 2H), 6.71 (d, J=8.6 Hz, 1H) 5.10 (s, 2H), 3.82 (s, 3H).