Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([O:17][CH3:18])[C:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)=[C:10]2[Cl:30].ClC1C2C(=CC=C(C(C3C(C)=NC(C)=CC=3)O)C=2)N=C(OC)C=1CC1C=CC(C(F)(F)F)=CC=1.[CH3:65][N:66]1[C:70]([C:71]([C:73]2[N:77]([CH3:78])[N:76]=[N:75][CH:74]=2)=[O:72])=[CH:69][N:68]=[N:67]1.C(=O)=O.CC(C)=O>C1COCC1>[Cl:30][C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:71]([C:70]3[N:66]([CH3:65])[N:67]=[N:68][CH:69]=3)([C:73]3[N:77]([CH3:78])[N:76]=[N:75][CH:74]=3)[OH:72])[CH:8]=2)[N:13]=[C:12]([O:17][CH3:18])[C:11]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1
Reactant: Cn1nncc1C(=O)c1cnnn1C
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3cnnn3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1

Procedure:
n-BuLi (1.63 M in hexane, 0.139 mL, 0.226 mmol) was added dropwise over 1 minute to a solution of 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (90.1 mg, 0.209 mmol, Intermediate 12: step d in THF (2.1 mL) at ˜−70° C. under argon. After 2 additional minutes, a homogeneous solution of bis(1-methyl-1H-1,2,3-triazol-5-yl)methanone (41.4 mg, 0.215 mmol, Intermediate 13) in THF (2.1 mL) was added dropwise over 1 minute, and the resulting solution was allowed to warm to room temperature overnight as the dry ice/acetone bath expired. The resulting homogeneous yellow reaction was then quenched with 5 M aqueous NH4Cl (0.06 mL), dried (Na2SO4), filtered, and concentrated to dryness. The residue was purified by C18 HPLC (20% to 100% CH3CN, with 0.1% TFA throughout) and the lyophilisate neutralized with 9:1 DCM/MeOH) and 2 M aqueous K2CO3. The organic layer was dried (Na2SO4), filtered, and concentrated to dryness to provide the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J=2.02 Hz, 1H), 7.99 (br. s., 1H), 7.91 (d, J=8.59 Hz, 1H), 7.65 (d, J=8.08 Hz, 2H), 7.41-7.51 (m, 3H), 7.19 (s, 2H), 4.36 (s, 2H), 4.04 (s, 3H), 3.84 (s, 6H); MS m/e 544.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([N+:30]([O-:32])=[O:31])[CH:17]=1.Cl>O1CCCC1>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH:5]([C:4](=[O:3])[CH2:11][CH2:12][CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:17][C:18]=1[N+:30]([O-:32])=[O:31])#[N:29]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1[N+](=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)c([N+](=O)[O-])c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a mixture of 60% sodium hydride in oil (0.85 g) and tetrahydrofuran (20 mL) was added dropwise a mixture of ethyl 3-oxohexanoate (4.50 g) in tetrahydrofuran (10 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. Then, the aforementioned 4′-(bromomethyl)-2′-nitrobiphenyl-2-carbonitrile was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1 M hydrochloric acid (30 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a yellow oil (4.60 g, 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[I:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].C(NCC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[I:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:29]
Reactant: O=C(Cl)c1ccccc1I
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(c2ccc(CNC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3I)cc2)c2ccc3ccccc3c2N1
Yield: 30.8 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 2-iodobenzoyl chloride (0.143 mmol), the title compound (16 mg, yield 31%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [OH:1][C:2]([CH:13]1[S:18][CH2:17][CH2:16][CH2:15][S:14]1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][C:5]#[CH:6].N1C=CN=C1.Cl[Si:25]([CH3:28])([CH3:27])[CH3:26].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:7]1([C:2]([CH:13]2[S:14][CH2:15][CH2:16][CH2:17][S:18]2)([O:1][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:3][CH2:4][C:5]#[CH:6])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[Si](C)(C)Cl
Reactant: C#CCCC(O)(c1ccccc1)C1SCCCS1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C#CCCC(O[Si](C)(C)C)(c1ccccc1)C1SCCCS1
Reaction time: 8 h
Yield: 100.1 %

Procedure:
2-(1-Hydroxy-1-phenylpent-4-ynyl)-1,3 -dithiane (1.7 g 6.1 mmol) and 1.2 g (15 mmol) of imidazole was stirred in 25 mL of methylene chloride and 0.9 mL (15 mmol) of chlorotrimethylsilane was added. The mixture was stirred overnight when it was poured onto 20 mL of 10% aqueous K2CO3. The organics were washed with brine, dried (Na2SO4) and concentrated at reduced pressure. The residue was mixed with Celite and chromatographed on 110 g of silica (99:1, hexane:ethyl acetate, then 2% ethyl acetate) to give 2.14 g (90%) of a product that crystallized upon concentration at reduced pressure. Analytical TLC (silica, 9:2, hexane:ethyl acetate) Rf0.56; 1H NMR (CDCl3) δ1.65-2.05 (m, 5H), 2.05-2.2 (m, 1H), 2.28-2.4 (m, 1H), 2.45-2.6 (m, 1H), 2.7-2.87 (m, 4H), 4.37 (s, 1H), 7.25-7.4 (m, 3H), 7.42-7.5 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[CH:27][C:26]([CH2:29][N:30]2[CH2:35][CH2:34][S:33](=[O:37])(=[O:36])[CH2:32][CH2:31]2)=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([CH2:29][N:30]3[CH2:31][CH2:32][S:33](=[O:37])(=[O:36])[CH2:34][CH2:35]3)=[CH:27][N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: O=S1(=O)CCN(Cc2ccc(Cl)nc2)CC1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(CN4CCS(=O)(=O)CC4)cn3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (41 mg, 0.13 mmol) and 4-[(6-chloropyridin-3-yl)methyl]thiomorpholine 1,1-dioxide (34 mg, 0.13 mmol) as starting materials.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH2:10][C:11](=[O:31])[C@@H:12]([NH:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]2)[N:18]=[C:17]([C:28]([NH2:30])=[O:29])[CH:16]=1)[CH3:13].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:10][C:11](=[O:31])[CH:12]([NH:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:22][CH2:23][CH:24]([O:27][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[CH2:25][CH2:26]2)[N:18]=[C:17]([C:28]([NH2:30])=[O:29])[CH:16]=1)[CH3:13]
Reactant: C[C@H](Nc1cc(C(N)=O)nc(N2CCC(O)CC2)n1)C(N)=O
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(Nc1cc(C(N)=O)nc(N2CCC(Oc3ccc(C#N)cc3)CC2)n1)C(N)=O
Temperature: 160 °C

Procedure:
A mixture of 4-fluorobenzonitrile (121 mg, 1 mmol), compound 37-7 (308 mg, 1 mmol), and Cs2CO3 (326 mg, 1 mmol) in DMF (2 mL) was heated at 160° C. in a microwave (Biotage initiator) for 20 minutes. The mixture was extracted with EtOAc (2×20 mL) and dried over MgSO4. After the removal of ethyl acetate via rotary evaporator the residue was subjected to flash chromatography using DCM/MeOH as the eluent to give S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(4-(4-cyanophenoxy)piperidin-1-yl)pyrimidine-4-carboxamide (Cpd. No. 100) as a white solid (150 mg). 1H NMR (CD3OD) δ 7.55-7.65 (m, 2H), 7.12 (m, 2H), 6.40 (s, 1H), 4.80 (m, 1H), 4.30 (m, 1H), 3.95 (m, 2H), 3.68 (m, 2H), 1.98 (m, 2H), 1.75 (m, 2H), 1.40 (d, 3H). LC/MS: m/z=410 [M+H]+.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:11]=[C:12]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH2:13][N:14]1[C:22]2[C:18]([N:19]=[C:20]([C:23]([O:26]CC3C=CC=CC=3)([CH3:25])[CH3:24])[N:21]=2)=[C:17]([NH:34][CH2:35][CH3:36])[N:16]=[CH:15]1)C1C=CC=CC=1>C1COCC1.CO.[Pd]>[ClH:1].[CH2:35]([NH:34][C:17]1[N:16]=[CH:15][N:14]([CH2:13][C:12]2[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:10]([OH:9])[CH:11]=2)[C:22]2[C:18]=1[N:19]=[C:20]([C:23]([OH:26])([CH3:25])[CH3:24])[N:21]=2)[CH3:36]
Reactant: CCNc1ncn(Cc2ccc(OC)c(OCc3ccccc3)c2)c2nc(C(C)(C)OCc3ccccc3)nc1-2
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCNc1ncn(Cc2ccc(OC)c(O)c2)c2nc(C(C)(C)O)nc1-2
Yield: 80.2 %

Procedure:
The above crude 3-(3-benzyloxy-4-methoxy-benzyl)-8-(1-benzyloxy-1-methyl-ethyl)-6-ethylamino-3H-purine hydrochloride (3.28 g, 5.7 mmole) was hydrogenated at room temperature and pressure in a mixture of THF:methanol 1:1 (60 ml) with 10% Pd-C (0.66 g). The catalyst was filtered off, the solvents evaporated in vacuo and the residue crystallized from acetone to give 6-ethylamino-3-(3-hydroxy-4-methoxy-benzyl)-8-(1-hydroxy-1-methyl-ethyl)-3H-purine hydrochloride (1.80 g, 80.0%), mp 184-185° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-:13].[Na+].[Na+].O.[Mn]([O-])(=O)(=O)=O.[K+]>C(O)(=O)C>[N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[NH:4][C:3]=1[C:2]([OH:13])=[O:1]
Reactant: O=C([O-])[O-]
Reactant: OCc1nc2ccccc2[nH]1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1nc2ccccc2[nH]1

Procedure:
The 2-hydroxymethylbenzimidazole from Part A (4 gms.) was refluxed in a small amount of saturated sodium carbonate solution with addition of sufficient boiling water to dissolve it. A hot, dilute solution of 6.67 gms. of potassium permanganate then was added slowly with stirring. Upon completion of the addition, the resulting suspension was refluxed for 30 minutes. The resulting hot liquid was separated by filtration from manganese dioxide which had formed. The filtrate then was cooled and rendered acidic (pH 5.0) by addition of acetic acid. The resulting yellow precipitate was filtered, dried, and recrystallized from hot water to obtain 1.98 gms. of the title compound as fine yellow needles.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH2:18]O)[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:21].O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH2:18][Cl:21])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2nccc3c(CO)cccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2nccc3c(CCl)cccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.8 %

Procedure:
1-(4-Methylphenyl)-5-hydroxymethylisoquinoline (7.5 g) was dissolved in 80 ml of chloroform, and 12.5 g of phosphorus pentachloride was added under ice cooling. The mixture was stirred at room temperature for 1 hour, and 100 ml of water was added. The mixture was stirred for 30 minutes, and neutralized with potassium carbonate. The chloroform layer was washed in water, and dried. The solvent was distilled off, and the residue was recrystallized from methanol to afford 8.6 g of 1-(4-methylphenyl)-5-chloromethylisoquinoline as slightly yellow prisms having a melting point of 119.8° to 120.1° C.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[O-]CC.[Na+].[Br:12][C:13]1[CH:18]=[CH:17][C:16](/[C:19](/Cl)=[N:20]/O)=[CH:15][CH:14]=1.Cl>CCO>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:4]([C:5](=[O:7])[CH3:6])=[C:1]([CH3:2])[O:3][N:20]=2)=[CH:15][CH:14]=1
Reactant: O/N=C(\Cl)c1ccc(Br)cc1
Reactant: CC(=O)CC(C)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)c1c(-c2ccc(Br)cc2)noc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
Acetylacetone (1.25 mL, 12 mmol) was added to a sodium ethoxide solution 3.09 N (3.95 mL, 12 mmol) in EtOH (22 mL) at room temperature. The resulting yellow solution was cooled with a ice-bath and a cloudy solution of (E)- and/or (Z)-4-bromo-N-hydroxy-benzenecarboximidoyl chloride (2.35 g, 10 mmol) in EtOH (8 mL) was added dropwise within 10 min keeping the temperature below 5° C. The light yellow suspension was stirred at room temperature for 3 h and then acidified with 6 N HCl and then evaporated. The resulting mixture was extracted with ethyl acetate and the combined organic layers were then washed with water and brine, dried over Na2SO4 and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate:=100:0 to 7:3) afforded the title compound (2.35 g, 84%) as a light yellow oil. MS m/e: 280.1/282.1 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[C:9]1[N:13]2[CH:14]=[C:15]([O:18][C@H:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:22]([NH2:29])[CH2:21][CH2:20]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.ClC(Cl)(Cl)C[O:33][C:34](=O)[NH:35][C:36]1[CH:41]=[C:40]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[CH:39]=[C:38]([F:48])[CH:37]=1>>[CH3:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[N:3]1[C:9]1[N:13]2[CH:14]=[C:15]([O:18][C@H:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:22]([NH:29][C:34]([NH:35][C:36]4[CH:41]=[C:40]([N:42]5[CH2:47][CH2:46][O:45][CH2:44][CH2:43]5)[CH:39]=[C:38]([F:48])[CH:37]=4)=[O:33])[CH2:21][CH2:20]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1
Reactant: O=C(Nc1cc(F)cc(N2CCOCC2)c1)OCC(Cl)(Cl)Cl
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(F)cc(N5CCOCC5)c4)c4ccccc43)cn12

Procedure:
The title compound was prepared starting from Intermediate 96c and intermediate 115a using analogous procedures to those described in Example 99. LCMS (Method 5): Rt 4.70 min, m/z 614 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.55 (3H, d, J=6.3 Hz), 0.59 (3H, d, J=6.3 Hz), 1.35-1.53 (3H, m), 1.63-1.69 (2H, m), 1.72-1.78 (1H, m), 1.82-1.99 (2H, m), 2.00-2.13 (2H, m), 3.03 (4H, t, J=4.8 Hz), 3.08-3.20 (2H, m), 3.65-3.69 (2H, t, J=4.8 Hz), 4.80-4.88 (1H, td, J=8.7, 5.5 Hz), 5.50 (1H, t, J=4.0 Hz), 6.31 (1H, dt, J=12.4, 2.0 Hz), 6.68 (1H, br s), 6.71 (1H, d, J=8.9 Hz), 6.81 (1H, dt, J=11.3, 1.9 Hz), 7.18-7.25 (2H, m), 7.29-7.37 (3H, m), 7.62 (1H, dd, J=9.8, 0.6 Hz), 7.86 (1H, d, J=2.0 Hz), 8.51 (1H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na].[CH3:17][C:18]([CH3:20])=O.O>ClCCCl>[CH:18]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1)([CH3:20])[CH3:17]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CC(C)=O
Agent: [Na]
Solvent: ClCCCl
Solvent: O
Product: CC(C)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 32 h

Procedure:
A suspension of 1-(4-nitrophenyl)piperazine (20 g, 190 mmol, 2 eq), sodium triaectoxyborohydride (41 g, 97 mmol, 2 eq), and acetone (18.8 g, 21.3 mL, 290 mmol, 3 eq) in DCE (400 mL) is stirred in a water bath at rt for 32 h. Water (100 mL) is slowly added (gas evolution) and resulting biphasic solution is stirred for 1 h. The phases are separated and the DCE extract is washed with water (2×100 mL). The combined aqueous extracts are extracted with DCE (2×50 mL), and the combined DCE extracts are filtered through a phase separation tube. The filtrate is concentrated on a rotary evaporator and the yellow oil obtained dried under vacuum for a further 2 h. The oily product obtained solidified on standing to provide 1-isopropyl-4-(4-nitrophenyl)piperazine as a yellow solid (16.5 g, 66% recovery). The product is used in the next step without further purification. LCMS Purity: 80% by ELS detection; LCMS-ESI (m/z): calcd for C13H19N3O2 249.1; [M+H]+ found, 250.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[C:3]=1[CH3:10].[NH:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: Cc1c(Br)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1c(Br)cccc1Cn1cnc2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.7 %

Procedure:
A mixture of 1-bromo-3-(bromomethyl)-2-methylbenzene (250 mg, 0.947 mmol), 1H-benzo[d]imidazole (336 mg, 2.84 mmol) and potassium carbonate (131 mg, 0.947 mmol) in acetonitrile (5 mL) was stirred at rt for 5 h, The mixture was diluted with EtOAc and filtered, and the solid was washed with EtOAc. The filtrate was washed with water, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 60:40 hexane-EtOAc to EtOAc), to provide 1-(3-bromo-2-methylbenzyl)-1H-benzo[d]imidazole as a white solid (233 mg, 82%). 1H NMR (400 MHz, chloroform-d) δ 8.14 (1H, s), 7.68-7.78 (1H, m), 7.56 (1H, d, J=7.9 Hz), 7.36-7.44 (1H, m), 7.25-7.34 (2H, m), 7.03 (1H, t, J=7.8 Hz), 6.82 (1H, d, J=7.7 Hz), 5.58 (2H, s), 2.45 (3H, s). Mass spectrum m/z 301, 303 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[CH2:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10].O>N1C=CC=CC=1>[CH2:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:1][C:2]2[S:3][CH:4]=[N:5][N:6]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nncs1
Solvent: O
Solvent: c1ccncc1
Product: CCCCc1ccc(S(=O)(=O)Nc2nncs2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
To a stirred solution of 2-amino-1,3,4-thiadiazole (2.0 g, 19.7 mmol) in pyridine (30 mL) under argon at −20° C. was added p-butylbenzenesulfonyl chloride (4.89 g, 21 mmol) over 10 min. The reaction mixture was stirred at room temperature for 16 hours. Water (300 mL) was added to quench the reaction. The mixture was extracted with CH2Cl2 and the organic extracts washed with 2N HCl (2×150 mL), brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluted with methanol:DCM 1:33 to give the product (3.46 g, 11.6 mmol, 59% yield) as a solid, mp 120-121° C.; 1H NMR (300 MHz, CDCl3) δ 0.91 (t, 3H, J=7 Hz), 1.29-1.37 (m, 2H), 1.56-1.61 (m, 2H), 2.65 (t, 2H, J=7 Hz), 7.27 (d, 2H, J=8 Hz), 7.84 (d, 2H, J=8 Hz), 8.25 (s, 1H); 13C NMR (75 MHz, CDCl3) 13.9, 22.3, 33.2, 33.6, 126.5, 129.1, 138.1, 142.7, 148.6, 167.4; MS (Q-TOF) Calcd for C12H16N3O2S2 298.0684, found 298.0695 (M+H)+; Calcd for C12H15N3N3O2S2 320.0503, found 320.0361 (M+Na)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]([O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[NH2:13])=[O:5])[CH3:2].CCOCC>COC(OC)N(C)C>[CH2:14]([N:3]([CH2:1][CH3:2])[C:4]([O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[N:13]=[CH:1][N:3]([CH3:14])[CH3:4])=[O:5])[CH3:15]
Reactant: CCN(CC)C(=O)Oc1cnccc1N
Agent: COC(OC)N(C)C
Solvent: CCOCC
Product: CCN(CC)C(=O)Oc1cnccc1N=CN(C)C

Procedure:
4-Amino-3-pyridinol N,N-diethylcarbamate (5.80 g) was refluxed for 30 minutes in 50 mL of N,N-dimethylformamide dimethyl acetal. At the end of this time the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (5% Et3N/ethyl acetate) to give, after concentration of the product-containing fractions, 4.63 g of chromatographically pure product. An analytically pure material was obtained by recrystallization from Et2O, m.p. 67°-69° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].C(N(CC)CC)C.[C:33]([CH2:36][O:37][C:38]1[CH:39]=[C:40]([S:49](Cl)(=[O:51])=[O:50])[CH:41]=[CH:42][C:43]=1[O:44][CH2:45][C:46](=[O:48])[NH2:47])(=[O:35])[NH2:34]>C(#N)C>[C:33]([CH2:36][O:37][C:38]1[CH:39]=[C:40]([S:49]([N:21]2[C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=[C:17]2[S:15]([CH2:14][C:3]2[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=2)=[O:16])(=[O:51])=[O:50])[CH:41]=[CH:42][C:43]=1[O:44][CH2:45][C:46]([NH2:47])=[O:48])(=[O:35])[NH2:34]
Reactant: NC(=O)COc1ccc(S(=O)(=O)Cl)cc1OCC(N)=O
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1ccc(OCC(N)=O)c(OCC(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
2-[3-Methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-1H-benzimidazole (369.3 mg) was suspended in acetonitrile (10 ml)-triethylamine (2 ml) and 3,4-bis(carbamoylmethoxy)benzenesulfonyl chloride (340 mg) was added. The reaction mixture was stirred at room temperature overnight. Solids were filtered and washed with acetonitrile (10 ml) followed with acetone (5 ml). The solids were again resuspended in methanol (3 ml), filtered and dried in vacuo to give 2-(2-carbamoylmethoxy-4-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-benzimidazole-1-sulfonyl}-phenoxy)acetamide (527 mg).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[C:6]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:21]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=2)[CH2:1]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: NC(=O)c1ccc(Oc2cccc3c2CCNC3)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: NC(=O)c1ccc(Oc2cccc3c2CCN(Cc2ccccc2)C3)nc1
Yield: 23.7 %

Procedure:
Combine 6-(1,2,3,4-tetrahydro-isoquinolin-5-yloxy)-nicotinamide (100 mg, 0.3 7 mmol), benzaldehyde (39 μL, 0.38 mmol), sodium triacetoxyborohydride (101 mg, 0.48 mmol), acetic acid (22 μL, 0.39 mmol), and 1,2-dichloroethane (5 mL) then stir at room temperature for 18 hours. Dilute the reaction with saturated aqueous sodium bicarbonate solution and extract with dichloromethane (3×25 mL). Dry the combined dichloromethane extracts with sodium chloride/magnesium sulfate, filter, and concentrate on a rotary evaporator to yield 45 mg of the crude product. The crude product is purified by flash column chromatography on silica gel eluting with (0.5% conc. ammonium hydroxide/5% ethanol) to (1% conc. ammonium hydroxide/10% ethanol) in chloroform to yield 6-(2-benzyl-1,2,3,4-tetrahydro isoquinolin-5-yloxy)-nicotinamide (31 mg, 0.09 mmol): m/z=360.1 (M+1); 3H NMR (DMSO-d6, 300.00 MHz): 8.56 (s, 1H); 8.16-8.12 (m, 1H); 7.38-7.15 (m, 6H); 6.94-6.89 (m, 3H); 6.17 (s, 2H); 3.74-3.61 (m, 4H); 2.69-2.66 (m, 4H), HPLC=99% (30/70 to 90/10 ACN/(0.1% TFA in water), Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nm).