Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[CH2:8][C@@H:9]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[OH:10].[CH3:22][C@H:23]1[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH:33]3[CH2:35][O:34]3)[CH:30]=2)[C:25](=[O:36])[O:24]1.CCN(C(C)C)C(C)C>C(O)C>[OH:34][CH:33]([C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:36])[O:24][C@@H:23]([CH3:22])[CH2:32]2)[CH2:35][N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[CH2:8][C@H:9]([OH:10])[C:11]1[C:12]([CH3:21])=[C:13]2[C:14](=[CH:19][CH:20]=1)[C:15](=[O:18])[O:16][CH2:17]2
Reactant: Cc1c([C@@H](O)CN2C[C@@H]3C[C@H]2CN3)ccc2c1COC2=O
Reactant: C[C@H]1Cc2cc(C3CO3)ccc2C(=O)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1c([C@@H](O)CN2C[C@@H]3C[C@H]2CN3CC(O)c2ccc3c(c2)C[C@H](C)OC3=O)ccc2c1COC2=O
Temperature: 80 °C

Procedure:
To a solution of 5-{(1R)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one [INTERMEDIATE 36](100 mg, 0.35 mmol) in ethanol (2 mL) was added (3S)-3-methyl-6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one (INTERMEDIATE 24) (71 mg, 0.35 mmol) and Hunig's base (61 uL, 0.35 mmol). The mixture was heated to 80° C. for 20 hours. The solvent was removed using rotary evaporation and the crude oil was purified via by silica gel chromatography (0-7% MeOH in DCM) to yield the pure respective diastereomers as a faster eluting isomer D1 (LCMS: m/z 493.2 (M+H)+) and slower eluting diastereomer D2 (LCMS: m/z 493.2 (M+H)+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[N:11]1([CH2:17][C:18]2[NH:19][CH:20]=[CH:21][N:22]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(CC)C(C)C)(C)C>C(#N)C>[N:11]1([CH2:17][C:18]2[N:22]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N+:8]([O-:10])=[O:9])[CH:21]=[CH:20][N:19]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: c1c[nH]c(CN2CCOCC2)n1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccccc1-n1ccnc1CN1CCOCC1

Procedure:
Combine 10 g of 2-fluoronitrobenzene, 13 g of 2-((4-morpholinyl)methyl)-imidazole, 18 mL of N,N-diisopropyl ethylamine, and 150 mL of acetonitrile, and heat at reflux for 48 hr. Remove the solvent under vacuum, and dissolve the residue in 500 mL of 2N H2SO4. Wash the aqueous portion with 400 mL of ether, basify with K2CO3, and extract with two 400 mL portions of CH2Cl2. Combine extracts, dry over MgSO4, charcoal treat and remove the solvent under vacuum to provide the title compound.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:27][CH3:28])=[C:10]([NH:12][C:13]2[O:14][C:15]([C:18]3[CH:19]=[C:20]([C:24](=[O:26])[CH3:25])[CH:21]=[CH:22][CH:23]=3)=[CH:16][N:17]=2)[CH:11]=1)(=[O:5])=[O:4])[CH3:2].C(O[CH:34](OC(C)(C)C)[N:35]([CH3:37])[CH3:36])(C)(C)C>CN(C=O)C>[CH3:34][N:35]([CH3:37])/[CH:36]=[CH:25]/[C:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:15]2[O:14][C:13]([NH:12][C:10]3[CH:11]=[C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:7]=[CH:8][C:9]=3[O:27][CH3:28])=[N:17][CH:16]=2)[CH:19]=1)=[O:26]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(-c3cccc(C(C)=O)c3)o2)c1
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(-c3cccc(C(=O)/C=C/N(C)C)c3)o2)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
The title compound (3.0 g, 7.5 mmol) from Example 200 was combined with dimethylformamide ditertbutylacetal (10.0 g, 4.9 mmol) in DMF (ca. 4 mL). After the reaction was stirred at 130° C. for 2 h, the excess solvent was evaporated under reduced pressure. The crude product was coated onto silica gel and chromatographed on silica gel using dichloromethane (98%) and methanol (20%) as eluent affording the title compound (1.6 g, 3.9 mmol) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:21])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH:13]([CH2:17][O:18][CH3:19])[CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:20]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([NH:35][C:36]2[C:41]([Cl:42])=[CH:40][N:39]=[C:38](Cl)[N:37]=2)=[C:27]([S:29]([N:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH:28]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([NH:35][C:36]2[C:41]([Cl:42])=[CH:40][N:39]=[C:38]([NH:21][C:4]3[C:3]([O:2][CH3:1])=[CH:20][C:7]4[CH2:8][CH2:9][N:10]([CH:13]([CH2:14][O:15][CH3:16])[CH2:17][O:18][CH3:19])[CH2:11][CH2:12][C:6]=4[CH:5]=3)[N:37]=2)=[C:27]([S:29]([N:32]([CH3:34])[CH3:33])(=[O:30])=[O:31])[CH:28]=1
Reactant: COCC(COC)N1CCc2cc(N)c(OC)cc2CC1
Reactant: CN(C)S(=O)(=O)c1cc(Cl)ccc1Nc1nc(Cl)ncc1Cl
Product: COCC(COC)N1CCc2cc(Nc3ncc(Cl)c(Nc4ccc(Cl)cc4S(=O)(=O)N(C)C)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 8-Methoxy-3-(2-methoxy-1-methoxymethyl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 5-Chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide in an analogous manner to Example 61e. Product isolated as a tan foam (0.072 g, 54%). MP: 66-79° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 9.23 (s, 1H), 8.49 (d, 1H, J=8.8 Hz), 8.14 (s, 1H), 7.91 (s, 1H), 7.87-7.85 (m, 1H), 7.52-7.46 (m, 2H), 6.65 (s, 1H), 3.87 (s, 3H), 3.59-3.53 (m, 2H), 3.49-3.43 (m, 2H), 3.33 (s, 6H), 3.08-3.01 (m, 1H), 2.88-2.80 (m, 6H), 2.77 (s, 6H), 2.73-2.68 (m, 2H). MS: 639.19 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)[CH3:2].C([NH:31][CH2:32][CH2:33][N:34]1[C:38](=[O:39])[CH2:37][S:36][C:35]1=[O:40])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1CCCCC1.NCCN1C(=O)/C(=C/C2C=CC=CC=2)/SC1=O>>[NH2:31][CH2:32][CH2:33][N:34]1[C:38](=[O:39])/[C:37](=[CH:7]/[C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)/[S:36][C:35]1=[O:40]
Reactant: O=C1CSC(=O)N1CCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1cccc(C=O)c1
Agent: NCCN1C(=O)S/C(=C\c2ccccc2)C1=O
Solvent: C1CCNCC1
Product: CCOc1cccc(/C=C2\SC(=O)N(CCN)C2=O)c1

Procedure:
The title compound 30b was prepared from 3-ethoxybenzaldehyde (87 μL, 0.62 mmol) and compound 29 (250 mg, 0.62 mmol) and piperidine (7.0 μL, 0.062 mmol) in a manner similar to that described for 30a in 20.4% (50 mg) yield as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:26][C:25]4[CH:28]=[CH:29][CH:30]=[C:23]([O:22][CH3:21])[CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: COc1cccc(CBr)c1
Product: COc1cccc(CN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)c1
Yield: 55 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 6) and 3-methoxy-benzyl bromide. Yield: 55%. 1NMR (CDCl3, 400 MHz): δ2.19 (s, 3H), 2.42 (s, 3H), 3.81 (s, 3H), 3.85 (s, 2H), 4.58 (s, 2H), 5.06 (s, 2H), 6.81-6.88 (m, 3H), 7.26-7.31 (m, 1H), 7.92 (s, 1H), 8.08 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.07 μM.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:35]=[CH:34][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([NH:17][C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]=[C:20]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[N:19]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:2][C:3]2[CH:35]=[CH:34][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([NH:17][C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]=[C:20]([C:28]5[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=5)[N:19]=4)[CH:11]=3)=[O:8])=[CH:5][CH:4]=2)[CH2:39][CH2:38]1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Temperature: 25 °C
Yield: 41 %

Procedure:
To a stirring mixture of 4-chloromethyl-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide (48 mg, 0.096 mmol) and 1-methylpiperazine (16 μl, 0.0.144 mmol) in anhydrous tetrahydrofuran (5 ml) was added N,N-diisopropylethylamine (200 μl). The mixture was refluxed for 20 h. The mixture was cooled to room temperature and then rotary evaporated to dryness. The residue was purified by column chromatography and isolated as a tan solid (22 mg, 41%). 1H NMR (CDCl3): 8.77 (dd, J=1.8, 4.5 Hz, 2H), 8.29 (dd, J=1.5, 4.5 Hz, 2H), 8.01 (s, 1H), 7.85 (s, 1H), 7.83 (d, J=8.1 Hz, 2H), 7.47 (d, J=7.8 Hz, 2H), 7.37 (dd, J=1.5, 8.4 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.04 (s, 1H), 6.74 (s, 1H), 3.57 (s, 2H), 2.47 (s, 8H), 2.29 (s, 6H).
Reaction SMILES: ClC(OCC)=O.[C:7]([NH:10][C@H:11]([C:17]([OH:19])=O)[C@:12]([SH:16])([CH2:14][CH3:15])[CH3:13])(=[O:9])[CH3:8].C(N(CC)CC)C>ClCCl>[C:7]([NH:10][CH:11]1[C:12]([CH2:14][CH3:15])([CH3:13])[S:16][C:17]1=[O:19])(=[O:9])[CH3:8]
Reactant: CC[C@@](C)(S)[C@H](NC(C)=O)C(=O)O
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1(C)SC(=O)C1NC(C)=O
Temperature: 25 °C

Procedure:
Ethyl chloroformate (0.12 ml) was added to a stirred solution of DL-N-acetyl-3-mercaptoisoleucine (0.20 g) in dichloromethane (10 ml) and triethylamine (0.28 ml) at -10° C. The solution was allowed to warm to room temperature, washed with dilute hydrochloric acid and then with sodium bicarbonate solution, dried and evaporated to give 3-acetamido-4-ethyl-4-methyl-2-thietanone as a pale oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][C:11](OCC)=[O:12])=[C:5]([N+:16]([O-])=O)[CH:4]=1.COC1C=CC2OCC(=O)NC=2C=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[S:9][CH2:10][C:11](=[O:12])[NH:16][C:5]=2[CH:4]=1
Reactant: CCOC(=O)CSc1ccc(OC)cc1[N+](=O)[O-]
Agent: COc1ccc2c(c1)NC(=O)CO2
Product: COc1ccc2c(c1)NC(=O)CS2

Procedure:
Prepared from ethyl [(4-methoxy-2-nitrophenyl)thio]acetate (Intermediate 53, 3 g, 11 mmol) according to procedure described for preparation of Intermediate 48. Silica gel chromatography with hexanes/ethyl acetate (3:2) afforded desired product, 2 g (93%).
Reaction SMILES: Cl[CH:2]([O:4][C:5](=[O:32])[N:6]([C:29](=[O:31])[CH3:30])[CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[CH3:3].[I-].[Na+].[C:35]([O-:39])(=[O:38])[CH2:36][CH3:37].[Cs+].O>C(#N)C>[C:29]([N:6]([CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[C:5]([O:4][CH:2]([O:39][C:35](=[O:38])[CH2:36][CH3:37])[CH3:3])=[O:32])(=[O:31])[CH3:30]
Reactant: CCC(=O)[O-]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OC(C)Cl
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCC(=O)OC(C)OC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
Acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5(R)-ylmethyl}-carbamic acid 1-chloro-ethyl ester (11) (0.20 g, 0.41 mmol) and sodium iodide (0.061 g, 0.41 mmol) are placed in acetonitrile (25 mL) and stirred at RT overnight. Cesium propionate (0.17 g, 0.82 mmol) is then added and the reaction is heated at reflux overnight. After cooling to RT, water is added and the reaction mixture is extracted with EtOAc and then with dichloromethane. The organic phases are washed separately with brine and then the organic layers are combined, dried over MgSO4, filtered, and conc in vacuo. The isolated residue is subjected to silica gel flash chromatography, eluting with MeOH/CH2Cl2 gradient (0-5% MeOH over 1 hour and 20 minutes) to afford the title compound. Isolated yield: 67%. 1H NMR (400 MHz, CDCl3): δ 7.48-7.42 (m, 1H), 7.21-7.17 (m, 1H), 7.13-7.10 (m, 1H), 6.90-6.85 (m, 1H), 4.83-4.69 (m, 1H), 4.14-3.98 (m, 3H), 3.73-3.64 (m, 1H), 3.13-3.04 (m, 5H), 2.52 (d, 3H), 2.48-2.31 (m, 3H), 2.29-2.13 (m, 2H), 1.56-1.51 (m, 4H), 1.15-1.07 (m, 3H).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1([S:14](Cl)=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S(=O)(=O)(O)O>CCOCC.N1C=CC=CC=1>[C:1]1([S:7][S:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: O=S(Cl)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=S(Sc1ccccc1)c1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of 2.2 g. (20 mmol) thiophenol in 30 ml. dry ether one adds 1.8 g. pyridine and adds dropwise thereto, with cooling, a solution of 3.2 g. (20 mmol) benzenesulphinic acid chloride in 20 ml. dry ether. One allows to stir further for 10 min., pours into dil. sulphuric acid, separates off the organic phase, dries and evaporates. There remain 3.2 g. of the title compound (68% of theory) of the m.p. 69°-70° C. (from ligroin).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([CH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[CH2:10][CH2:11][CH2:12][CH3:13].[Cl-].[NH4+]>O1CCCC1>[CH2:9]([CH:14]1[CH2:19][CH2:18][C:17]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:16][CH2:15]1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Brc1ccccc1
Reactant: CCCCCC1CCC(=O)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCC1CC=C(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 2,000 mL (inside volume) three-necked flask equipped with a reflux condenser, 700 mL of anhydrous tetrahydrofuran (THF) and 27 g of magnesium shavings were charged, to which 160 g of bromobenzene were added dropwise at a speed to ensure continuous mild reflux. After the dropping was completed, the mixture was further stirred for 1 h. To this mixture, a solution of 170 g of 4-n-pentylcyclohexanone (available from Tokyo Chemical Industry Co., Ltd.) in 100 mL of THF was added at 50° C. The mixture was then refluxed for 2 h. The obtained reaction product liquid was cooled to room temperature, poured into an aqueous ammonium chloride solution and then extracted with benzene. The benzene solution was added with 1 g of p-toluenesulfonic acid and refluxed while removing water generated. When water was no longer distilled, the reaction mixture was cooled to room temperature, washed with an aqueous sodium hydrogen carbonate solution and then with brine, dried and then concentrated. The residue was purified by silica gel column chromatography to obtain (4-n-pentylcyclohexenyl)benzene. The thus obtained product was dissolved in 1,000 mL of ethyl acetate and subjected to hydrogenation at 0.5 MPa using 2 g of 5% by mass-Pd/C as a catalyst. When a theoretical amount of hydrogen was consumed, the catalyst was separated by filtration. The resulting filtrate was concentrated to obtain 220 g of (4-n-pentylcyclohexyl)benzene. As a result of gas chromatographic analysis, it was confirmed that the (4-n-pentylcyclohexyl)benzene purity was 97.8% and the cis/trans molar ratio was 0.67. In 100 g of hexane were dissolved 220 g of (4-n-pentylcyclohexyl)benzene. The resulting solution was cooled to −30° C. Precipitated crystals were collected by filtration in an amount of 100 g. As a result of analyzing the obtained crystals by gas chromatography, it was confirmed that the (4-n-pentylcyclohexyl)benzene purity was 98.0% and the cis/trans molar ratio was 0.02.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][O:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][CH2:12][C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[C:20]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:19]2=[N:18][C:17]=3[NH2:28])=[C:9]([CH3:31])[CH:8]=1.[P:35](OCC)([O:40]CC)([O:37]CC)=[O:36].C[Si](Br)(C)C>C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:28][C:17]1[C:16]2[N:15]=[CH:14][C:13]([CH2:12][CH2:11][C:10]3[CH:29]=[CH:30][C:7]([O:6][CH2:5][C:4]4[CH:3]=[C:2]([P:35](=[O:36])([OH:40])[OH:37])[CH:34]=[CH:33][CH:32]=4)=[CH:8][C:9]=3[CH3:31])=[CH:22][C:21]=2[C:20]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:19]=2[N:18]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCc4cccc(I)c4)cc3C)cc12
Reactant: CCOP(=O)(OCC)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCc4cccc(P(=O)(O)O)c4)cc3C)cc12
Temperature: 90 °C

Procedure:
To a stirred solution of 2-(4-(3-iodobenzyloxy)-2-methylphenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine (1.0 equiv.) in triethyl phosphate (1.05 eq.) was added palladium acetate (0.08 eq.). The resulting reaction mixture was heated at 90° C. overnight. After the reaction was cooled down to room temperature, the residue was taken up in DCM (0.27 M) at 0° C., and was treated with TMSBr (11 equiv.). The reaction was warmed to room temperature over 2 hours, and then quenched with small amounts of MeOH. The DCM was removed by evaporation, and then added DMSO/water. The mixture was adjusted to pH 9 and directly purified on RP-HPLC using a C18 column, eluting with 10-40% 95:5 (MeCN/5 mM NH4OAc) in 10 mM NH4OAc (pH 9) gradient. The fractions containing the product were combined and concentrated in vacuo to give 3-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phenylphosphonic acid (13) as a solid. 1H NMR (Dimethylsulfoxide-d6): δ 8.84 (s, 1H), 8.72 (s, 1H), 8.35 (d, 1H, J=8.4 Hz), 7.67 (d, 1H, J=12 Hz), 7.60-7.54 (m, 1H), 7.30-7.20 (m, 2H), 7.15 (d, 1H, J=8.4 Hz), 7.11 (d, 1 H, J=8.4 Hz), 7.04 (s, 1H), 6.84 (s, 1H), 6.77 (m, 1H), 4.99 (s, 2H), 3.12-2.92 (m, 4H), 2.44 (s, 3 H), 2.27 (s, 3H). LRMS [M+H]=514.2
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>CCO.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:15]=2)[N:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1Cc2cc(Br)ccc2N(Cc2ccccc2)C1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1Cc2cc(-c3ccccc3)ccc2N(Cc2ccccc2)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
Compound 89A (150 mg, 0.36 mmol), phenylboronic acid (57 mg, 0.47 mmol) and 2N aqueous Na2CO3 (1.25 mL, 2.5 mmol) in a mixed solvent of toluene (1.5 mL) and EtOH((0.5 mL) were stirred at RT for 30 min while N2 was allowed to bubble through the mixture, and then tetrakis(triphenylphosphine)-palladium (0) (30 mg) was added. The mixture was stirred at 90° C. under N2 for 1 h. After cooling to RT, the mixture was extracted with EtOAc (15 mL×3), and organic extracts were washed with brine, dried (Na2SO4), and concentrated. The resulting residue was chromatographed (silica gel) eluting with EtOAc (10-50%) in hexane to give the title compound (80 mg, 67%) as a white foam.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:33]=[CH:32][C:7]([O:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[N:11]([CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[C:10]=2[CH3:31])=[CH:6][CH:5]=1.O>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[NH:18][S:19]([CH3:22])(=[O:20])=[O:21])[N:11]([CH2:23][C:24]([OH:26])=[O:25])[C:10]=2[CH3:31])=[CH:32][CH:33]=1
Reactant: Cc1c(Oc2ccc(Cl)cc2)c2c(NS(C)(=O)=O)cccc2n1CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Oc2ccc(Cl)cc2)c2c(NS(C)(=O)=O)cccc2n1CC(=O)O
Temperature: 55 °C
Reaction time: 3 h

Procedure:
A solution of 1M sodium hydroxide (0.5 ml) was added to a stirred mixture of the product from step (v) (40 mg) in THF (1 ml). After 3 h, further 1M sodium hydroxide (1 ml) was added and the reaction heated at 55° C. for 16 h. Water (10 ml) was added and the THF evaporated under reduced pressure. The solution was acidified with 2M hydrochloric acid and the resulting solid filtered off and dried. Yield 24 mg
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.Cl[CH2:16][C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:20]([S:30][CH2:31][CH2:32][CH3:33])=[N:19][CH:18]=1>CN(C)C=O>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][N:21]1[C:17]([CH2:16][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[CH:18][N:19]=[C:20]1[S:30][CH2:31][CH2:32][CH3:33]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCSc1ncc(CCl)n1Cc1ccccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCSc1ncc(CC(C(=O)OCC)C(=O)OCC)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
To dry dimethylformamide (10 mL) under argon was added sodium hydride (0.14 g, 5.83 mmol) followed by diethyl malonate (0.92 g, 5.75 mmol) in dimethylformamide (2 mL) at 0° C. The mixture was stirred at ambient temperature for one hour. A solution of 5-chloromethyl-1-(2-chlorophenyl)methyl-2-propylthio-1H-imidazole hydrochloride (1.0 g, 2.84 mmol) in dimethylformamide (4 mL) was added over 5 minutes. The reaction mixture was stirred at 25° C. for 18 hours, then partitioned between water and methylene chloride. The organic layer was washed with water, dried, and concentrated. The crude product was flash chromatographed over silica gel with 1:1 hexane/ethyl acetate to give 0.62 g (49.7%) of diethyl [1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]methylmalonate as a pale yellow syrup.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:6]=[C:5]([CH3:18])[C:3]=1[NH2:4].CCN(C(C)C)C(C)C.[Cl:28][CH2:29][C:30](Cl)=[O:31]>ClCCl>[Cl:28][CH2:29][C:30]([NH:4][C:3]1[C:2]([CH3:1])=[CH:8][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][C:5]=1[CH3:18])=[O:31]
Reactant: O=C(Cl)CCl
Reactant: CCCCCCCCOc1cc(C)c(N)c(C)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCOc1cc(C)c(NC(=O)CCl)c(C)c1

Procedure:
Under a nitrogen atmosphere, 2,6-dimethyl-4-(octyloxy)-aniline (7.2 mmols) was dissolved in 50 mL dichloromethane. To this was added DIPEA (9.4 mmols). The reaction mixture was cooled in an ice bath, and chloroacetyl chloride (7.95 mmoles) dissolved in 50 mL dichloromethane was added by dropping funnel. After the addition was complete, the reaction was stirred at room until reaction was complete by TLC (approximately 0.5 hours). The reaction mixture was concentrated, and partitioned between ethyl acetate and water. The organic layer was washed with saturated NaHCO3(×2), brine, dried over MgSO4, and filtered (rinsing with ethyl acetate). The filtrate was concentrated to yield 2-chloro-N-(2,6-dimethyl-4-octyloxyphenyl)-acetamide as a white solid (1.21 grams; 51%). The product was characterized by NMR (DMSO).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH2:1][Br:18])=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 65.4 %

Procedure:
Heat a mixture of 4′-methylacetophenone (5 g, 37.26 mmol), NBS (6.964 g, 39.12 mmol), and AIBN (153 mg, 0.93 mmol) in carbon tetrachloride (120 mL) for 14 h at reflux. Cool to ambient temperature and wash sequentially with water (100 mL), 1M aqueous HCl (100 mL), 5% aqueous NaHCO3 (100 mL) and brine (100 mL). Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting sequentially with hexane and hexane/EtOAc (19:1, 9:1) to provide the title compound as oil (5.191 g, 65%). GC-MS m/z: 213 (M+).