Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[Li:2].O.[C:4]([CH2:11][CH2:12][CH:13]([NH2:24])[C:14]([OH:23])([C:19]([O:21]C)=[O:20])[C:15]([O:17]C)=[O:16])([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]>O.CO>[Li+:2].[C:4]([CH2:11][CH2:12][CH:13]([NH2:24])[C:14]([OH:23])([C:15]([OH:17])=[O:16])[C:19]([O-:21])=[O:20])([O:6][C:7]([CH3:9])([CH3:10])[CH3:8])=[O:5]
Reactant: [Li]O
Reactant: COC(=O)C(O)(C(=O)OC)C(N)CCC(=O)OC(C)(C)C
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CCC(N)C(O)(C(=O)[O-])C(=O)O
Product: [Li+]
Temperature: 0 °C
Reaction time: 24 h
Yield: 92.7 %

Procedure:
0.3 g of LiOH.H2O are dissolved in 1.5 ml of water and the solution is diluted with MeOH to a total volume of 10 ml. This solution, pre-cooled to 0°-5° C., is added to a solution of 1 g of methyl 5-BOC-amino-2-hydroxy-2-methoxycarbonyl-pentanoate in 10 ml of MeOH, cooled at 0° C. The mixture is kept for 24 h at 0°-5° C., under mild stirring. A white crystalline precipitate separates, which is filtered, washed with MeOH and dried to obtain 0.86 g of 5-BOC-amino-2-hydroxy-2-carboxy-pentanoic acid lithium salt (m.p.>300° C.)
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][NH:6][C:7](=[O:28])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:20][C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][CH:9]=1.[F:30][C:31]([F:43])([F:42])[O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[F:30][C:31]([F:43])([F:42])[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:29])=[O:2])=[O:28])=[CH:9][CH:10]=3)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:26][CH:25]=2)=[CH:35][CH:34]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCCCCC(Oc1ccc(Br)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Product: CCCCCC(Oc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
This compound is made in a substantially similar manner to Example 117 using isomer 1 of 3-{4-[1-(4-bromo-phenoxy)-hexyl]-benzoylamino}-propionic acid methyl ester and 4-trifluoromethoxy-phenylboronic acid as starting materials in step D. MS (ES): 530.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][C:6]1OC(=O)[S:8][N:7]=1.[S:15]([C:25]#[N:26])([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][C:6]1[N:26]=[C:25]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[S:8][N:7]=1
Reactant: O=c1oc(Cc2cccc(Cl)c2)ns1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(S(=O)(=O)c2nc(Cc3cccc(Cl)c3)ns2)cc1
Yield: 58.4 %

Procedure:
13.00 g (52.6 mmol) of 5-(3-chlorobenzyl)-1,3,4-oxathiazol-2-one and 10.50 g (55.2 mmol) of tosyl cyanide are stirred in 15 ml of 1,2-dichlorobenzene at 160° C. for 1 h. Subsequently, the reaction mixture is cooled and purified by column chromatography. 11.2 g of product are obtained (93.3% purity, 54.5% yield).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].CS(O[CH:14]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1)(=O)=O>CN(C=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH:14]2[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17]2)[CH:6]=1
Reactant: Ic1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(n2cc(I)cn2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
At 0° C., a solution of 4-iodopyrazole (3.0 g, 15.46 mmol) in DMF (40 mL) was treated with NaH (60% mineral oil dispersion, 1.11 g, 46.39 mmol) in portions. The mixture stirred for 30 minutes, followed by the slow addition of 1-(tert-butoxycarbonyl)azetidin-3-yl methanesulfonate (5.0 g, 20.1 mmol). The reaction mixture was warmed to RT and then heated at 100° C. for 5 hours. The reaction mixture was poured into ice cold water, stirred for 30 minutes, and resulting precipitate collected by filtration and dried. The resulting residue was washed with pentane and dried to obtain tert-butyl 3-(4-iodo-1H-pyrazol-1-yl)azetidine-1-carboxylate (3.3 g, 62% yield); 1H-NMR (400 MHz, CDCl3): 7.58 (s, 1H), 7.57 (s, 1 H), 5.07-5.0 (m, 1 H), 4.39-4.34 (m, 2H), 4.29-4.25 (dd, 2 H), 1.45 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.O.[NH2:16][NH2:17].[CH2:18]=O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([C:10]([O:12][CH3:13])=[O:11])[CH2:18][NH:17][N:16]=2)=[CH:4][CH:3]=1
Reactant: C=O
Reactant: COC(=O)CC(=O)c1ccc(Cl)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: COC(=O)C1CNN=C1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.2 %

Procedure:
To 20.0 g of methyl 3-(4-chlorophenyl)-3-keto-propanoate in 100 ml of methanol was added a mixture of 4.7 g of hydrazine monohydrate and 7.6 g of 37% formalin in 50 ml of methanol. The reaction was stirred at room temperature for 18 hrs. The methanol was then removed in vacuo and the product was dissolved in 40 ml of methylene chloride and washed 5 times with 100 ml portions of water. The methylene chloride layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to yield 22 g of 3-(4-chlorophenyl)-4-carbomethoxy-4,5-dihydro-1H-pyrazole which was used without further purification in the next reaction.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.[C:9]([C:13]1[CH:18]=[CH:17][C:16](O)=[C:15]([CH3:20])[CH:14]=1)([CH3:12])([CH3:11])[CH3:10].CCCCCC>CN(C)C=O>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([O:4][CH3:1])=[C:15]([CH3:20])[CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: Cc1cc(C(C)(C)C)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(C(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.1 %

Procedure:
Potassium carbonate (8.4 g) and methyl iodide (2.9 mL) were added to a solution of 4-tert-butyl-2-methylphenol (CAS #98-27-1, 5.0 g) in N,N-dimethylformamide (25 mL), and the mixture was stirred at room temperature for three days. Ice water and hexane were added to the reaction solution, and the organic layer was separated. The resulting organic layer was sequentially washed with water and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 5.16 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:23])[CH:16]=[C:17]2[CH2:21][CH2:20][CH2:19][N:18]2[CH3:22])[CH:12]=[CH:13][CH:14]=1.O.C(OCC)C>O1CCCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:23])[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2[CH3:22])[CH:12]=[CH:13][CH:14]=1
Reactant: COc1cccc(C(=O)C=C2CCCN2C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COc1cccc(C(=O)CC2CCCN2C)c1

Procedure:
11.8 g of lithium aluminum hydride are added portionwise at 0° with stirring to 144.8 g of 1-(3-methoxyphenyl)-2-(1-methyl-2-pyrrolidinyliden)ethanone dissolved in 1.4 liters of tetrahydrofuran. 30 minutes after completion of the addition, 300 ml of water are cautiously added dropwise, with cooling; then 800 ml of diethyl ether are added, and the organic phase is collected. The organic phase is dried over sodium sulfate, the solvent is removed by evaporation, and the oily residue is distilled under a vacuum to obtain 127 g (87% of theory) of the title compound:
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:33])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:14][CH:13]=1.C[C:35]1[S:39][CH:38]=[N:37][CH:36]=1.[CH3:40]COCC>C1(C)C=CC=CC=1>[Br-:1].[CH3:40][N+:37]1([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:9][C:10](=[O:33])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:14][CH:13]=2)[CH:36]=[CH:35][S:39][CH2:38]1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2ccccc2CBr)cc1
Reactant: CCOCC
Reactant: Cc1cncs1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2ccccc2C[N+]2(C)C=CSC2)cc1
Product: [Br-]

Procedure:
A mixture of 3.0 g of N-[2-(bromomethyl)phenyl]-4-(tetradecyloxy)benzeneacetamide and 2.88 g of 5-methylthiazole in 25 ml of toluene is heated at reflux under argon for 2.5 hours. The mixture is poured into 200 ml of ether, cooled, the solid collected, washed with ether and dried to give 3.2 g of the desired product as a white powder, m.p. 124°-127° C.
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].I[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.Cl>O1CCCC1>[F:23][C:22]([F:25])([F:24])[C:19]1[CH:20]=[CH:21][C:16]([C:7]2[C:8]([CH:9]=[O:10])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:17][CH:18]=1
Reactant: O=Cc1ccccc1Br
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: O=Cc1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 136.3 %

Procedure:
To magnesium turnings (1.23 g, 50.7 mmol) in a dry flask under nitrogen was added anhydrous tetrahydrofuran (THF, 10 mL). The mixture was mechanically stirred while a solution of 1,2-dibromoethane (1.22 g, 6.5 mmol) in THF (10 mL) was added dropwise. Upon completion, a solution of the dimethyl acetal of 2-bromobenzaldehyde (3.00 g, 13.0 mmol) and 1,2-dibromoethane (2.44 g, 13.0 mmol) in THF (10 ml) was added at a rate to maintain gentle reflux. Upon completing, a second solution of 1,2-dibromoethane (1.22 g, 6.5 mmol) in THF (10 mL) was added dropwise. The mixture was then refluxed an additional 20 minutes and decanted into an addition funnel attached to a second reaction flask containing a solution of 4-iodobenzotrifluoride (2.72 g, 10.0 mmol) and iodo(4-trifluoromethyl)bis(triphenylphosphine)palladium (II) (0.21 g, 0.9 mmol) in refluxing THF (20 mL). The Grignard reagent was added dropwise and the mixture refluxed for 11/2 hr. After cooling to room temperature, 3N hydrochloric acid was added (30 mL) and the THF evaporated on the rotary evaporator. The residue was extracted with diethyl ether. The ether extract was washed with 3N hydrochloric acid (20 mL) water (4×25 mL), and saturated sodium chloride solution (10 mL). The ether solution was then dried (MgSO4), treated with charcoal, filtered and evaporated to give a dark yellow oil (3.41 g). This was chromatographed on the Waters Prep 500 HPLC using a 1:1 mixture of methylene chloride and hexane. The product was isolated after evaporation of solvent as a light yellow oil (2.41 g, 96.4%). 'H NMR (CDCl3): 7.6 (m, 7, Ar--H), 8.0 (m, 1, 3-H), 9.9 (s, 1, CHO).
Reaction SMILES: [Br-].[C:2]([C:5]([CH3:30])([CH3:29])[CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[H-].[Na+].[C:33]([C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)(=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>CS(C)=O.C1(C)C=CC=CC=1>[CH3:29][C:5]([CH3:30])([CH2:6][CH2:7][CH2:8]/[CH:9]=[C:33](/[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)\[C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)[C:2]([OH:4])=[O:3]
Reactant: CC(C)(CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: O=C(c1ccccc1)c1cccnc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(CCC/C=C(/c1ccccc1)c1cccnc1)C(=O)O
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
5-Carboxy-5,5-dimethylpentyltriphenylphosphonium bromide (3 g, 6 mmole) was dissolved in anhydrous dimethylsulfoxide (30 ml) under a nitrogen atmosphere, and sodium hydride (0.25 g, 64 mmole) was added to the solution at 30° to 35° C., followed by stirring at 25° to 30° C. for 30 minutes. 3-Benzoylpyridine (0.9 g, 5 mmole) was added to the solution, followed by stirring at room temperature for another 1 hour. Water (100 ml) and toluene (100 ml) were added to the reaction solution, the organic layer was separated, and the water layer was adjusted to pH 6.0 with 2N hydrochloric acid. The product was extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dried and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel, and development was effected with ethyl acetate to yield (E+Z)-2,2-dimethyl-7-phenyl-7-(3-pyridyl)-6-heptenoic acid (2-a, 2-b) (1.36 g, 88%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[C:30]1([S:36]C2C=CC=CC=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Na]>CN(C)C=O>[CH3:29][C:26]1[CH:25]=[CH:24][C:23]([C:20]2[CH:21]=[CH:22][C:16]3[O:15][CH2:14][CH2:13][C:12]([C:10]([NH:9][C:6]4[CH:7]=[CH:8][C:3]([CH2:2][S:36][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:4][CH:5]=4)=[O:11])=[CH:18][C:17]=3[CH:19]=2)=[CH:28][CH:27]=1
Reactant: c1ccc(Sc2ccccc2)cc1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSc4ccccc4)cc2)CCO3)cc1
Yield: 113.9 %

Procedure:
A solution of N-(4-chloromethylphenyl)-7-(4-methyl-phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.15 g) and sodium phenyl sulfide (0.05 g) in dimethylformamide (10 ml) was stirred at room temperature over night. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7-(4-methylphenyl)-N-(4-(phenylthiomethyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 82) (0.13 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:4]=1[NH2:5].[C:14](Cl)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:4]=1[NH:5][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: COc1ccc(C(F)(F)F)cc1N
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(C(F)(F)F)cc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 2-methoxy-5-(trifluoromethyl) aniline (1 eq) in DCM at 0° C. was added TEA (1 eq) followed by dropwise addition of pivaloyl chloride (1 eq). The reaction mixture was warmed to room temperature and left stirred overnight. Diluted with DCM and washed with satd. sodium bicarbonate, water, brine and dried over sodium sulfate. Filtered, evaporated and dried under vacuum to provide pure product as an off white solid in 95% yield. ES/MS m/z 276.1 (MH+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([CH2:6][C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][N:16]([S:19]([C:22]5[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=5)(=[O:21])=[O:20])[C:13]=4[N:14]=[CH:15][C:10]3=[N:9][N:8]=2)[CH2:2]1.Cl[C:30]1[CH:35]=[N:34][C:33]([C:36]#[N:37])=[CH:32][N:31]=1.CCN(C(C)C)C(C)C.C(Cl)Cl>C(O)CC>[S:19]([N:16]1[C:13]2[N:14]=[CH:15][C:10]3[N:11]([C:7]([CH2:6][C@@H:3]4[CH2:4][CH2:5][N:1]([C:30]5[N:31]=[CH:32][C:33]([C:36]#[N:37])=[N:34][CH:35]=5)[CH2:2]4)=[N:8][N:9]=3)[C:12]=2[CH:18]=[CH:17]1)([C:22]1[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=1)(=[O:21])=[O:20]
Reactant: N#Cc1cnc(Cl)cn1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C[C@@H]4CCNC4)n23)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C[C@@H]4CCN(c5cnc(C#N)cn5)C4)n23)cc1
Temperature: 150 °C
Yield: 27.7 %

Procedure:
A mixture of (S)-1-(pyrrolidin-3-ylmethyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.160 g, 0.404 mmol, prepared using B from Preparation #A.1 and E with HCl), 2-chloro-5-cyanopyrazine (0.084 g, 0.60 mmol, ArkPharm) and DIEA (0.28 mL, 1.6 mmol) in n-PrOH (2.0 mL) was heated in a CEM microwave at about 150° C. for about 30 min (250 psi maximum pressure, 10 min maximum ramp, 200 maximum watts). The reaction mixture was cooled to ambient temperature and DCM (20 mL) was added. The solution was washed with water (20 mL) and brine (20 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The residue was taken up in DCM (10 mL), adsorbed onto silica gel (1 g), and purified by silica gel chromatography eluting with 100% EtOAc to give a pink solid. The material was triturated with a mixture of EtOAc (10 mL) and 10% MeOH in DCM (10 mL). The insoluble material was collected by filtration to give (S)-5-(3-((6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)pyrrolidin-1-yl)pyrazine-2-carbonitrile as an off-white solid (0.056 g, 27%): LC/MS (Table 1, Method c) Rt=1.34 min; MS m/z: 500 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[C:6]([C:11]([O:13][CH3:14])=[O:12])=[N:7][CH:8]=[CH:9][CH:10]=1.N1C=CC=CC=1.[CH2:21]([O:28][C:29](ON1C(=O)CCC1=O)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH2:21]([O:28][C:29]([NH:1][CH2:2][CH2:3][NH:4][C:5]1[C:6]([C:11]([O:13][CH3:14])=[O:12])=[N:7][CH:8]=[CH:9][CH:10]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ncccc1NCCN
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ncccc1NCCNC(=O)OCc1ccccc1

Procedure:
A solution of methyl 3-[(2-aminoethyl)amino]pyridine-2-carboxylate (3.9 g, 18.6 mmol) in CHCl3 (25 mL) was treated with pyridine (3 mL, 37.3 mmol) then 1-{[(benzyloxy)carbonyl]oxy}pyrrolidine-2,5-dione (Aldrich, 5.57 g, 22.3 mmol) for ½ hr. The reaction was quenched with water and extracted three times with CHCl3. The organic layer was dried with Na2SO4, filtered and evaporated to give an oil. The crude was purified on silical gel using an ISCO normal phase system and eluting with a gradient of 50% to 90% EtOAc Hexanes. The clean fractions were combined to give the product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][NH2:9])=[CH:5][CH:4]=1.CCN(CC)CC.Cl[C:20]([O:22][CH3:23])=[O:21].O>C1COCC1>[CH3:23][O:22][C:20]([NH:9][CH2:8][CH2:7][C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:21]
Reactant: COC(=O)Cl
Reactant: COc1ccc(CCN)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)NCCc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a solution of 4-methoxy-phenethylamine (5.81 mL, 39.7 mmol) in anhydrous THF (200 mL) was added Et3N (6.6 mL, 48 mmol). The solution was cooled to 0° C. and methyl chloroformate (15.38 mL, 199 mmol) was added slowly via syringe. The reaction was stirred at 0° C. for 2 hours and then allowed to warm to room temperature and stirred overnight. To the reaction mixture was added H2O (50 mL) and the resulting solution was extracted into Et2O (1×100 mL) and then into EtOAc (2×75 mL). The combined organic fractions were washed with brine (200 mL) and 1 M HCl (200 mL), dried over Na2SO4, filtered and concentrated under vacuum, affording 7.98 g (96%) of the title compound as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([C:12]1[CH:21]=[CH:20][C:15]([CH2:16][N:17]=[C:18]=[S:19])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>C(#N)C>[C:8]([C:12]1[CH:21]=[CH:20][C:15]([CH2:16][NH:17][C:18]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[S:19])=[CH:14][CH:13]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: Nc1ccccn1
Reactant: CC(C)(C)c1ccc(CN=C=S)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)c1ccc(CNC(=S)Nc2ccccn2)cc1
Yield: 32.9 %

Procedure:
2-aminopyridine (86 mg) was dissolved in acetonitrile (10 ml) and to the solution were added 4-t-butylbenzylisothiocyanate (190 mg) and triethylamine (140 μl), followed by refluxing for 27 hours. The resulting mixture was extracted with water and dichloromethane, dried, concentrated under reduced pressure, and then crystallized (dichloromethane/petroleum ether) to yield the compound (90 mg, 33%) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH2:27][NH:26][CH2:25][CH2:24]4)=[O:20])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8].CCN(C(C)C)C(C)C.Cl[C:41]([O:43][CH3:44])=[O:42].[Li+].[OH-]>CN(C=O)C.O>[CH3:44][O:43][C:41]([N:26]1[CH2:25][CH2:24][C:23]2[C:28](=[CH:29][CH:30]=[C:21]([C:19](=[O:20])[NH:18][C:15]3[NH:14][C:13]4[CH:12]=[CH:11][CH:10]=[C:9]([C:7](=[O:8])[NH:6][C:2]5[NH:1][CH:5]=[CH:4][N:3]=5)[C:17]=4[N:16]=3)[CH:22]=2)[CH2:27]1)=[O:42]
Reactant: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1ccc2c(c1)CCNC2
Reactant: COC(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N1CCc2cc(C(=O)Nc3nc4c(C(=O)Nc5ncc[nH]5)cccc4[nH]3)ccc2C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 31 %

Procedure:
41 mg (0.08 mmol) of 1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide in 0.6 mL of DMF and 0.176 mL (1 mmol) of DIEA was treated with 0.024 mL (0.3 mmol) of methyl chloroformate and stirred at room temperature for 14 h. The reaction mixture was then treated with 0.15 mL of 2 N aq. LiOH. Water was added to the reaction mixture. The precipitated solid was collected by filtration and washed with water to yield 11.4 mg (0.0248 mmol, 31%) of 6-[4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-ylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid methyl ester. LCMS: 460 (M+1)+.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C:13]1([CH3:23])[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH3:29][NH:30][CH3:31].C(N(CC)CC)C>C(#N)C>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C:13]1([CH3:23])[CH2:17][CH2:16][CH:15]([C:18]([N:30]([CH3:31])[CH3:29])=[O:20])[C:14]1([CH3:21])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(C)CCC(C(=O)O)C1(C)C
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(C)CCC(C(=O)N(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
To a 20-mL scintillation vial were added the product from Example 96 (118 mg, 0.300 mmol), dimethylamine hydrochloride (Aldrich, 36.7 mg, 0.450 mmol), and 2-(1H-benzo[d][1,2,3]tria-zol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (TBTU, Bachem, 144 mg, 0.450 mmol) Anhydrous acetonitrile (3 mL) was added to form a yellow slurry. Neat triethylamine (Aldrich, 182 mg, 1.80 mmol) was added to form a tan solution. The reaction was stirred at 25° C. in a shaker block for 24 hr. The volatiles removed by rotary evaporator to give a brown oil. The product was purified by flash chromatography (silica gel: 10-45% ethyl acetate in hexanes). The product was recrystallized from hexanes to afford 67.0 mg (53%) of the title compound. 1H NMR (DMSO-d6) δ 0.49 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.25 (s, 3H), 1.26 (s, 3H), 1.28-1.33 (m, 2H), 1.37-1.46 (m, 1H), 1.57 (s, 9H), 1.57-1.70 (m, 3H), 2.01-2.10 (m, 1H), 2.62-2.67 (m, 2H), 2.74-2.83 (m, 1H), 2.83 (s, 3H), 3.05 (s, 3H), 3.33-3.39 (m, 1H), 8.49 (s, 1H). MS (ESI+) m/z 422 (M+H)+. Anal. calcd. for C23H39N3O2S: C, 65.52; H, 9.32; N, 9.97. Found: C, 65.13; H, 9.22; N, 9.55.