Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:6]2[N:5]=1)=O.[NH2:23][C:24]1[CH:33]=[CH:32][C:27]2[NH:28][C:29](=[O:31])[NH:30][C:26]=2[CH:25]=1>>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:23][C:24]4[CH:33]=[CH:32][C:27]5[NH:28][C:29](=[O:31])[NH:30][C:26]=5[CH:25]=4)=[N:5]3)=[CH:10][CH:11]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: CS(=O)c1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Product: CS(=O)(=O)c1ccc(-c2ccc3cnc(Nc4ccc5[nH]c(=O)[nH]c5c4)nn23)cc1

Procedure:
Following the synthetic and purification procedures described in Example 1293d, 2-methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (75 mg, 0.22 mmol) was coupled with 5-amino-1,3-dihydro-benzimidazol-2-one (57 mg, 0.38 mmol) at 105° C. for 86 h to afford the title compound. Yield of TFA salt: 79 mg (67%) of brown powder. LC/MS: 421 (M+H); HPLC: 97% pure, RT=2.32 min; 1H NMR: (DMSO, δ) 10.65 (s, 1H), 10.48 (s, 1H), 9.38 (s, 1H), 9.02 (s, 1H), 8.49 (d, J=8.6, 2H), 8.04 (d, J=8.6, 2H), 7.35 (m, 2H), 7.29 (s, 1H), 6.98 (d, J=4.8, 1H), 6.91 (d, J=8.6, 1H), 3.27 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([OH:39])[CH2:9][N:10]([CH2:18][C@H:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:29]4[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=4)[CH:25]=3)[O:20]2)C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.Cl.O1CCOCC1>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([OH:39])[CH2:9][NH:10][CH2:18][C@H:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:29]4[CH:30]=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][CH:38]=4)[CH:25]=3)[O:20]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@H](CN(C[C@H](O)c2ccc(N)nc2)C(=O)OC(C)(C)C)O3)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@H](CNC[C@H](O)c2ccc(N)nc2)O3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.5 %

Procedure:
Methyl 4-((2R)-2-{[[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl](tert-butoxycarbonyl)-amino]methyl}-3,4-dihydro-2H-chromen-6-yl)benzoate (Example 377, 80 mg, 0.15 mmol) was added to 4 M hydrochloric acid in dioxane (3 mL, 12 mmol). The solution was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was purified by prep. HPLC, afforded 40 mg (62%) of the desired product. The product had: 1H NMR (CD3ODδ): 8.04 (d, J=8.1 Hz, 2 H), 7.89-8.03 (m, 2 H), 7.68 (d, J=7.8 Hz, 2 H), 7.42-7.49 (m, 2 H), 6.95-7.07 (m, 2 H), 5.02-5.10 (m, 1 H), 4.24-4.52 (m, 1 H), 3.91 (s, 3 H), 3.20-3.52 (m, 4 H), 2.81-3.04 (m, 2 H), 2.11-2.24 (m, 1 H), 1.74-1.92 (m, 1 H); mass spectroscopy gave m/z=434.2 [M+H]+ (calc'd exact mass for C25H27N3O4=433.2).
Reaction SMILES: CO[C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH:30]=1.[CH3:32][O:33][CH2:34][CH2:35][CH2:36][NH2:37]>>[CH3:32][O:33][CH2:34][CH2:35][CH2:36][NH:37][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[N:15]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:14]=2[CH:30]=1
Reactant: COCCCN
Reactant: COC(=O)CCCCCOc1ccc2nc(N3CCOCC3)n(-c3ccccc3)c2c1
Product: COCCCNC(=O)CCCCCOc1ccc2nc(N3CCOCC3)n(-c3ccccc3)c2c1

Procedure:
135 mg of 6-[[2-(morpholin-4-yl)-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was reacted with 3-methoxypropylamine according to general operating instructions 4. 94 mg was obtained.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[S:16][C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH3:15])[CH2:11][CH2:12][C:6]=2[CH:5]=1.[S-:17][C:18]#[N:19].[K+].BrBr>>[ClH:1].[ClH:1].[NH2:19][C:18]1[S:17][C:5]2[C:6]3[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH3:15])[CH2:9][CH2:8][C:7]=3[S:16][C:4]=2[N:3]=1
Reactant: N#C[S-]
Reactant: CCCN1CCc2cc(N)sc2CC1
Agent: BrBr
Agent: Cl
Agent: [K+]
Product: CCCN1CCc2sc3nc(N)sc3c2CC1

Procedure:
This compound was prepared from 2-amino-6-propyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine dihydrochloride, potassium thiocyanate and bromine analogous to Example 1.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:4]([CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:5]
Reactant: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C=O)C1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
To a solution tert-butyl 3-{[methoxy(methyl)amino]carbonyl}azetidine-1-carboxylate (93.8 g, 0.3 mol) in tetrahydrofuran at −70° C. was added dropwise lithium aluminum hydride (12.3 g in 320 ml THF). After the addition was complete, the reaction mixture was stirred for 1 h at −70° C. The reaction was quenched by the addition of 13 ml of water, followed by 39 ml of 1N aqueous NaOH solution and 13 ml of water. The mixture was stirred for 1 h, filtered and concentrated. The residue was partitioned between 300 ml of ethyl acetate and 100 ml of water. The layers were separated and the organic layers were washed with 100 ml of brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to afford tert-butyl 3-formylazetidine-1-carboxylate, which was used without additional purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[S:4][C:5]([CH2:8]Cl)=[CH:6][N:7]=1.O.C(=O)([O-])[O-:12].[Na+].[Na+].Cl>C(OCC)(=O)C>[ClH:2].[Cl:2][C:3]1[S:4][C:5]([CH2:8][OH:12])=[CH:6][N:7]=1
Reactant: O=C([O-])[O-]
Reactant: ClCc1cnc(Cl)s1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: OCc1cnc(Cl)s1
Temperature: 80 °C

Procedure:
2-Chloro-5-chloromethylthiazole hydrochloride (100 g, 0.49 mole), and water (100 mL) were charged to a flask. The mixture was stirred and heated to 80° C. for 2.5 hours. The reaction mixture was cooled to about 15° C. and sodium carbonate (51.5 g) was added (to raise the pH to about 8-9). The product was extracted with ethyl acetate (1×500 mL and 1×250 mL). The combined organic extracts were stirred for 20 minutes with 3 g of decolorizing carbon (Norit® SA3 about 100 mesh) and filtered through celite. The celite and flask were washed with an additional 100 mL of ethyl acetate and combined with the filtrate. The filtrate was concentrated under reduced pressure to provide a yellow-orange oil. The oil was dissolved in 500 mL of ethyl acetate and cooled to -10° C., under a nitrogen atmosphere. A solution of HCl (17.82 grams, 1 eq.) in ethyl acetate was slowly added. The temperature was maintained below -5° C. After the addition was complete the slurry formed was stirred for 30 minutes. The product was filtered under vacuum and the flask and product washed with ethyl acetate(100 mL). The title compound, an off white powder, was purged with nitrogen gas until dry. Yield 63.3 g; 69.6%..
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.[S:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:22][CH:21]=2)=[CH:16]1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C.CCN(CC)CC>[S:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[C:27](=[O:29])[O:28][CH2:2][C:3]=3[C:5]3[CH:6]=[CH:7][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][CH:10]=3)=[CH:24][CH:25]=2)=[CH:16]1
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Reactant: O=C(O)Cc1ccc(-c2ccsc2)cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(C2=C(c3ccc(-c4ccsc4)cc3)C(=O)OC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42 %

Procedure:
To a suspension of 2-bromo-1-[4-(methylsulfonyl)phenyl]ethanone (0.27 g, 1 mmol) and 4-(3-thienyl)phenylacetic acid (0.19 g, 0.9 mmol) in acetonitrile (5 mL) was added Et3N (0.33 mL) at 0° C. under nitrogen. After stirring for 20 minutes at room temperature, the mixture was chilled in ice bath. DBU (0.29 mL) was added to the mixture, and stirred for 20 minutes at 0° C. To the mixture was added 1N HCl solution (8 mL) and ice-water (10 mL), and the mixture was stirred for 2 minutes. The whole was extracted with CH2Cl2 (50 mL×3), the combined organic layer washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate/hexane (1/1) followed by recrystallization from ethyl acetate/hexane to provide the title compound (0.15 g, 39% yield).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][CH2:11][C:10](=[O:13])[N:9]([CH3:14])[C:8]3[CH:15]=[N:16][C:17]([NH:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=4)=[N:18][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C[CH2:30][N:31]([CH:35]([CH3:37])C)[CH:32]([CH3:34])C.[CH3:38][N:39](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.NCC1CCNCC1>C(Cl)Cl>[CH:1]1([N:6]2[CH2:12][CH2:11][C:10](=[O:13])[N:9]([CH3:14])[C:8]3[CH:15]=[N:16][C:17]([NH:19][C:20]4[CH:21]=[CH:22][C:23]([C:24]([NH:39][CH:38]5[CH2:34][CH2:32][N:31]([CH3:30])[CH2:35][CH2:37]5)=[O:26])=[CH:27][CH:28]=4)=[N:18][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(C(C)C)C(C)C
Agent: F[B-](F)(F)F
Agent: NCC1CCNCC1
Solvent: ClCCl
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CCC(=O)N4C)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.7 %

Procedure:
4-(9-Cyclopentyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (35 mg, 0.085 mmol), DIPEA (28 μl, 0.17 mmol, 2 eq) and TBTU (30 mg, 0.093 mmol, 1.1 eq) were added to 3 ml DCM and the resulting solution stirred at rt for 30 min before the addition of 4-aminomethylpiperidine (13 μl, 0.10 mmol, 1.2 eq). The RM was then stirred at rt for 16h. The RM was concentrated and the product extracted using DCM/H2O. The organic extracts were combined, washed with sat NaCl, dried using MgSO4, filtered and the filtrate evaporated under reduced pressure and further dried in vacuo to give a yellow oily residue (21 mg, 49%); Rt=9.86 min (0—60—20 min, purity 100%); 1H NMR (CD3OD): δ 1.69-1.75 (m, 6H), 1.82 (bs, 2H), 1.96-1.99 (m, 2H), 2.03-2.05 (bs, 2H), 2.18-2.23 (m, 2H), 2.34 (s, 3H, CH3), 2.68 (dd, J=4.5 Hz, 2H, CH2), 2.95-2.97 (m, 2H), 3.28 (s, 3H, CH3), 3.73 (dd, J=4.5 Hz, 2H, CH2), 3.89-3.94 (m, 1H, CH), 4.01 (s, 3H, CH3), 4.91-4.96 (m, 1H, CH), 7.49-7.51 (m, 2H), 8.02 (bs, 1H), 8.50 (d, J=8.5 Hz, 1H, phe-H); MS+ve: 508.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCC1(c2ccc(F)cc2)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCC1(c2ccc(F)cc2)CCCCC1
Temperature: 60 °C
Reaction time: 7 h
Yield: 97.7 %

Procedure:
To a solution of ethyl 3-(1-(4-fluorophenyl)cyclohexyl)propanoate (Intermediate 7, 1.347 g, 4.84 mmol) in methanol (20 mL) was added 1N sodium hydroxide (9.68 mL, 9.68 mmol), and the mixture was stirred at 60° C. for 7 hrs. After cooling, methanol was evaporated off and the residue was acidified with 12 mL of 1N HCl. The product was extracted with ethyl acetate (2×) and the combined extracts were washed with brine, dried over sodium sulfate and evaporated to give the desired 3-(1-(4-fluorophenyl)cyclohexyl)propanoic acid (1.183 g, 4.73 mmol, 98% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.26 (2H, dd, J=8.80, 5.28 Hz), 7.01 (2H, t, J=8.69 Hz), 2.01-2.10 (2H, m), 1.95-2.01 (2H, m), 1.82-1.88 (2H, m), 1.31-1.62 (8H, m).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:13]([Mg]Br)([CH3:15])[CH3:14]>C1COCC1>[CH3:14][CH:13]([CH3:15])[CH:11]([CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[OH:12]
Reactant: O=CC1CCC2(CC1)OCCO2
Reactant: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: CC(C)C(O)C1CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 8 h

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decane-8-carbaldehyde (693 mg, 4.07 mmol, prepared as described in Pearson, et al. in J. Org. Chem. 1997, 62(16), 5284-5292) in THF (20 mL) cooled to −78° C. under argon was added a isopropylmagnesium bromide (6 mL, 12 mmol, 1 M in THF) dropwise. After the complete addition, the reaction mixture was allowed to reach room temperature overnight. It was then re-cooled to −78° C. and quenched with saturated NaHCO3 solution and warmed to room temperature. After extraction with ether, the organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 0-100% ether/DCM) to afford the product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([N+:13]([O-])=O)[CH:5]=1.C(N(CC)CC)C.C(O)=O>CC#N.[Pd]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([NH2:13])[CH:5]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O=CO
Product: COC(=O)c1cc(N)cc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 58.9 %

Procedure:
3,5-Dinitro-benzoic acid methyl ester (Example 312, 13.7 g, 60.6 mmol), Pd/C (Aldrich, 1.34 g, 10%, 0.61 mmol), triethylamine (Aldrich, 36.4 mL, 273 mmol) was dissolved in 30 mL of CH3CN. To the above solution was added a solution of HCOOH (Aldrich, 9.7 mL, 261 mmol) in 30 mL of CH3CN dropwise. The mixture was then refluxed for 2 h. After cooled to room temperature, the mixture was filtered through a Celite pad, washed with EtOAc, and the filtrate was concentrated. The residue was purified by chromatography (5%-10% EtOAc/CH2Cl2) to give 7.0 g (59%) of product. 1H NMR (400 MHz, DMSO-d6) δ 7.74 (t, J=2.0 Hz, 1H), 7.59 (t, J=2.2 Hz, 1H), 7.55 (t, J=2.0 Hz, 1H), 6.16 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[N:20][C:21](Cl)=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[Cl:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30].Cl>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[N:20][C:21]([NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[C:27]([Cl:26])[CH:28]=4)=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)[CH3:2]
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC(=O)CC1CCC(c2ccc(-c3ccc(Cl)nn3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)CC1CCC(c2ccc(-c3ccc(Nc4cccc(Cl)c4)nn3)cc2)CC1
Temperature: 100 °C

Procedure:
To a suspension of {4-[4-(6-chloro-pyridazin-3-yl)-phenyl]-cyclohexyl}-acetic acid ethyl ester (2.0 g, 5.6 mmol, 1.0 equiv) in 40 Ml dioxane was added 3-chloroaniline (0.70 Ml, 6.7 mmol, 1.2 equiv) followed by 2 Ml 4 N HCl in dioxane. The mixture was then heated to 100° C. overnight. The reaction was partitioned between EtOAc and saturated bicarbonate solution, and the organic extracts were then washed with brine and dried. Removal of solvent in vacuo afforded the title compound: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.07-1.17 (m, 2 H) 1.21 (t, J=7.20 Hz, 3 H) 1.42-1.53 (m, 2 H) 1.86 (t, J=10.99 Hz, 4 H) 1.78-1.90 (m, 1 H) 2.18 (d, J=6.57 Hz, 2H) 2.47 (td, J=12.00, 3.03 Hz, 1 H) 4.08 (q, J=7.24 Hz, 2 H) 7.03 (d, J=7.58 Hz, 1 H) 7.26 (d, J=8.08 Hz, 3 H) 7.20-7.28 (m, 2 H) 7.45 (s, 1 H) 7.68 (d, J=9.35 Hz, 1 H) 7.84 (d, J=8.34 Hz, 2 H); (M+H)+ 450.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:20]([O-])=O)=[C:6]([NH:8][C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[C:18]#[N:19])[CH:7]=1.O.O.[Sn](Cl)[Cl:26].Cl>CCO>[ClH:26].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:20]=[C:18]([NH2:19])[C:10]3[C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[S:13][C:9]=3[NH:8][C:6]=2[CH:7]=1
Reactant: N#Cc1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2ccccc12
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: NC1=Nc2ccc(F)cc2Nc2sc3ccccc3c21
Temperature: 25 °C
Yield: 78.7 %

Procedure:
Combine 2-(5-fluoro-2-nitro-phenylamino)-benzo[b]thiophene-3-carbonitrile (2.15 g, 6.87 mmol) and Tin(II) chloride, dihydrate (4.65 g, 20.6 mmol) in a mixed solvent of EtOH (25 mL) and 5.0 N HCl (25 mL), heat the suspension to reflux for 3 hours, cool to RT. Suction filtration obtains the title compound 1.73 g (yield 78%) as a yellow solid by. Mass spectrum: ACPI (m/e): 284((M+1-HCl); 1H NMR (300 MHz, DMSO-d6) δ 11.46 (br, 1H), 10.02 (br, 1H), 9.02 (br, 2H), 7.90-7.87 (m, 1H), 7.71-7.68 (m, 1H), 7.46-7.40 (m, 1H), 7.33-7.28 (m, 1H), 7.12-6.94 (m, 2H), 6.85-6.81(m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=1)=[O:5].Cl[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][N:26]=[CH:27][CH:28]=2)[N:23]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=2[NH:1][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][N:26]=[CH:27][CH:28]=3)[N:23]=2)=[CH:8][CH:9]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccccc2N)cc1
Reactant: Clc1ccc2ccncc2n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Product: CC(C)(C)c1ccc(NC(=O)c2ccccc2Nc2ccc3ccncc3n2)cc1
Temperature: 80 °C

Procedure:
A mixture of 2-amino-N-(4-tert-butyl-phenyl)-benzamide (Step A, 163 mg, 0.61 mmol), 2-chloro-[1,7]naphthyridine (100 mg, 0.61 mmol), Pd2(dba)3 (6.0 mg, 0.006 mmol), 2-dicyclohexyl phosphino-2′-(N-N-dimethyamino)biphenyl (6.0 mg, 0.015 mmol), and LiN(TMS)2 (1 M solution in THF, 2.3 mL) was heated at 80° C. for 12 h in a sealed tube. The mixture was concentrated in vacuo and the crude material was purified with flash chromatography (SiO2, 20% EtOAc/hexane) and crystallization from EtOH to give the desired compound. MS (ES+): 397.0 (M+H)+. Calc'd for C25H24N4O-396.48.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH:18]=[N:19][OH:20])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CCO>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][NH:19][OH:20])[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ON=CCn1cc(Cc2ccccc2)c2ccccc21
Agent: Cl
Solvent: CCO
Product: ONCCn1cc(Cc2ccccc2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of the oxime from Step 3 (400 mg, 1.52 mmole) in EtOH (7 mL) at 0° C. there was added pyridine-borane complex (288.5 mg, 3.10 mmole) and 4M ethanolic HCl (1.16 mL, 4.65 mmol). The mixture was stirred at 0° C. for 20 minutes, then allowed to warm up to r.t. Most of the EtOH was evaporated away, H2O (20 mL) and 1N aqueous HCl (10 mL) was added, and the mixture was extracted twice with Et2O. The aqueous fraction was then made basic with 2.5N aqueous NaOH, and extracted twice with Et2O. From these extracts a crude product was obtained which was purified by chromatography on silica gel, eluting with 5% EtOH in CH2Cl2 to afford the title product as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CN(C)CCCN(C)C.CS(Cl)(=O)=O.[NH2:36][C:37]1[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][CH:38]=1.C(N(CC)C(C)C)(C)C>O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([NH:36][C:37]3[CH:38]=[CH:39][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:45][CH:46]=3)[CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: OC(c1ccc(-c2ccc(Cl)cc2)cc1)C1CCCCC1
Agent: CN(C)CCCN(C)C
Agent: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1ccc(NC(c2ccc(-c3ccc(Cl)cc3)cc2)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, to a mixture of (4′-chlorobiphenyl-4-yl)(cyclohexyl)methanol obtained in step B, N,N,N′,N′-tetramethyl-1,3-propanediamine (0.265 mL) and toluene (4.432 mL) was added methanesulfonyl chloride (0.124 mL) at 0° C., and the reaction mixture was stirred at room temperature for 4 hr. To the reaction mixture were added methyl 4-aminobenzoate (301 mg) and N,N-diisopropylethylamine (0.464 mL) at room temperature, and the mixture was stirred at 100° C. overnight. To the reaction mixture was added water at room temperature, the mixture was extracted with ethyl acetate, and the extract was washed with water and 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 (ethyl acetate/hexane) to give the title compound (382.4 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:18])[C:14]=1[S:15][CH2:16][CH3:17])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:19][C:20]1[N:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23].Cl.CN(C)CCCN=C=NCC.O>N1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:18][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][CH:27]=[N:28][C:20]=3[CH3:19])[C:14]=1[S:15][CH2:16][CH3:17])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: Cc1ncccc1C(=O)O
Reactant: CCSc1c(Cl)cc2c([nH]c3cnccc32)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: O
Product: CCSc1c(Cl)cc2c([nH]c3cnccc32)c1NC(=O)c1cccnc1C
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 40.7 %

Procedure:
A 25 ml round-bottom flask with magnetic stirrer was charged with 6-chloro-7-ethylsulfanyl-9H-β-carbolin-8-ylamine (37.2 mg, 0.13 mmol) and 2-methylnicotinic acid (36.2 mg, 0.26 mmol) in 3 ml anhydrous pyridine. To the resulting light-orange mixture at RT was added solid 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (73.2 mg, 0.38 mmol) and the resulting reaction mixture was heated to 80° C. for 5 days. Next, the reaction mixture was cooled to RT and concentrated to afford a brown, viscous syrup. The syrup was dissolved in a minimal amount of MeOH (˜2 ml), slowly added to a 5:1 mixture of H2O/saturated sodium bicarbonate (˜20 ml), and stirred at RT for 2.5 hr. The resulting precipitated solid was collected via suction filtration, washed with 1:1 hexanes/diethyl ether (2×20 ml), and air-dried to afford 21.0 mg of N-(6-chloro-7-ethylsulfanyl-9H-β-carbolin-8-yl)-2-methyl-nicotinamide as a tan solid (˜38%). LCMS (ammonium acetate standard method) retention time=2.33 min. (M+=397; M−=395).
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1>C1C=CC=CC=1.O1CCCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)=[CH:5][CH:4]=1
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [Br-]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: Clc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
Thallous bromide (22.46 gm, 0.079 mole) is added to a solution of p-chlorophenyl magnesium bromide (0.0395 mole) in a mixture of benzene (25 ml.) and tetrahydrofuran (25 ml.) and the mixture stirred and refluxed under nitrogen for 7 hours. The reaction mixture is cooled, poured into 150 ml. of dilute hydrochloric acid, and the 4,4'-dichlorobiphenyl extracted with ether (2 × 30 ml.). The combined extracts are dried over anhydrous sodium sulfate, and the solvent removed to leave 2.9 gm. of crude white product. This is filtered through a short column of alumina using chloroform as eluent, to give, after removal of the solvent, 2.70 gm. (61%) of pure 4,4'-dichlorobiphenyl, m.p. 148°.