Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]=1[C:18]([O:20]C(C)(C)C)=[O:19])=[O:11].[CH3:33][C:34]1[CH:35]=[CH:36][C:37](B(O)O)=[C:38]2[C:43]=1[N:42]=[CH:41][CH:40]=[CH:39]2.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:37]2[CH:36]=[CH:35][C:34]([CH3:33])=[C:43]3[C:38]=2[CH:39]=[CH:40][CH:41]=[N:42]3)[C:17]=1[C:18]([OH:20])=[O:19])=[O:11]
Reactant: Cc1ccc(B(O)O)c2cccnc12
Reactant: CC(C)(C)OC(=O)c1c(OS(=O)(=O)C(F)(F)F)csc1NC(=O)c1cc2ccccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2csc(NC(=O)c3cc4ccccc4o3)c2C(=O)O)c2cccnc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
Tert-butyl 2-(benzofuran-2-carbonylamino)-4-(trifluoromethylsulfonyloxy)thiophene-3-carboxylate (7), (8-methyl-5-quinolyl)boronic acid (48), Tetrakis(triphenylphosphine)palladium(0), and sodium carbonate, were combined in 2:1:1 ethanol, toluene and water the biphasic mixture was stirred vigorously in sealed vial at 70° C. After 2 hours, the mixture was filtered through Celite and the Celite rinsed with methylene chloride. The organic fraction of the filtrate was washed with water, dried with sodium sulfate, filtered, concentrated, triturated in methanol, centrifuged, decanted and the resulting solid was dried under vacuum and treated with a 1:1 mixture of methylene chloride and trifluoroacetic acid. After 4 hours the mixture was concentrated in vacuo, and the residue triturated in methylene chloride, centrifuged, decanted and dried under high vacuum to give 49A as a white powder (18.1 mg, 31%). 1H NMR (500 MHz, DMSO d6) δ=12.93 (br, 1 H), 12.60 (s, 1 H), 8.94 (m, 1 H), 8.01 (d, 1 H), 7.89 (s, 1 H), 7.87 (d, 1 H), 7.75 (d, 1 H), 7.66 (d, 1 H), 7.57 (t, 1 H), 7.54 (dd, 1 H), 7.44-7.41 (m, 3 H), 7.11 (s, 1 H), 2.76 (s, 3 H) ppm. ESI MS [M+H] 429.22.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]1[O:20][C:19]2[CH:18]=[CH:17][C:11]([C:12](OCC)=[O:13])=[CH:10][C:9]=2[O:8]1.[OH-].[Na+]>CCOCC.O.C1COCC1>[CH2:7]1[O:8][C:9]2[CH:10]=[C:11]([CH2:12][OH:13])[CH:17]=[CH:18][C:19]=2[O:20]1
Reactant: CCOC(=O)c1ccc2c(c1)OCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To a mixture of 0.99 g (26.16 mmol) of LiAlH4 and 80 mL of Et2O, 2.54 g (13.08 mmol) of ethyl 3,4-(methylenedioxy)benzoate (obtained in the preceding section) dissolved in 160 mL of Et2O was added under argon, and the mixture was stirred overnight at room temperature. A mixture of 1.62 mL of H2O and 3.41 mL of THF, followed by 1.62 mL of 15% NaOH and then 4.43 mL of H2O were added dropwise. The resulting mixture was filtered, washed with Et2O and EtOAc, and the solvent was evaporated. The residue was partitioned between H2O and EtOAc, the layers were separated, the aqueous phase was extracted with EtOAc and the combined organic phases were dried over MgSO4 and concentrated, yielding 1.88 g of the desired product (94% yield).
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[CH3:5][C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>ClCCl>[C:2]([O:16][C:14](=[O:15])[C:13]1[CH:12]=[CH:11][C:10]([O:9][C:8]2[CH:19]=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:6]([CH3:5])[CH:7]=2)=[CH:18][CH:17]=1)([CH3:3])([CH3:1])[CH3:4]
Reactant: C=C(C)C
Reactant: Cc1cc(Oc2ccc(C(=O)O)cc2)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Oc2ccc(C(=O)OC(C)(C)C)cc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of isobutylene (34 g) in dichloromethane (100 mL) was added compound 1 (5 g), at 5° C., followed by concentrated sulphuric acid (0.5 mL). The mixture was stirred at ambient temperature for 2 days and poured into saturated sodium bicarbonate solution (200 mL). The aqueous layer was extracted with dichloromethane and the combined organic extracts were dried and evaporated to give an an oil. The oil was chromatographed with 5% ethyl acetate in hexane to give 4-(3-methyl-4-nitro-phenoxy)-benzoic acid tert-butyl ester (compound 2), 2.5 g (42% yield; melting point=81-83° C.).
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:11]([CH2:27][C:28]2[CH:29]=[N:30][C:31]3[C:36]([CH:37]=2)=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>>[OH:8][CH2:9][C:10]1[N:11]([CH2:27][C:28]2[CH:29]=[N:30][C:31]3[C:36]([CH:37]=2)=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1
Reactant: CC(C)c1nc(COCc2ccccc2)n(Cc2cnc3ccccc3c2)c1Sc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)c1nc(CO)n(Cc2cnc3ccccc3c2)c1Sc1cc(Cl)cc(Cl)c1
Yield: 80.2 %

Procedure:
In 10 ml of c-HCl was dissolved 730 mg (1.36 mmol)of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(quinolin-3-ylmethyl)-1H-imidazole (100b); the mixture was refluxed with heating for 1 hour, and worked up. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution was added, extracted with methylene chloride, the extract was washed with water and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate)to give 500 mg of 2-hydroxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(quinolin-3-ylmethyl)-1H-imidazole (109)(yield 83%). mp 174-175° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5](=O)[CH:6]([CH3:10])[C:7](=O)[CH3:8])[CH3:2].C(=O)(O)[O-].[C:19]1([NH:25][C:26]([NH2:28])=[NH2+:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH3:10][C:6]1[C:5]([CH:4]([O:12][CH2:13][CH3:14])[O:3][CH2:1][CH3:2])=[N:27][C:26]([NH:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:28][C:7]=1[CH3:8]
Reactant: CCOC(OCC)C(=O)C(C)C(C)=O
Reactant: NC(=[NH2+])Nc1ccccc1
Agent: O=C([O-])O
Solvent: CCO
Product: CCOC(OCC)c1nc(Nc2ccccc2)nc(C)c1C
Temperature: 75 °C
Yield: 114.6 %

Procedure:
A mixture of 44 g (purity about 50%, about 0.11 mol) of 1,1-diethoxy-3-methylpentane-2,4-dione (crude product, Example 2a) and 35 g (0.175 mol) of phenylguanidinium bicarbonate in 300 ml of ethanol was heated at 70-80° C. for about 3 hours. The reaction mixture was then concentrated and the residue was filtered, with suction, through silica gel using methyl tert-butyl ether. The solvent was evaporated. Less volatile components were distilled off under a pressure of 0.3 mbar, at a bath temperature of 150° C. The residue obtained was 38 g (quantitative yield) of the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].BrC1C=CC(Cl)=CC=1[CH2:21][O:22][CH2:23]OC>>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[CH2:4][O:5][CH2:21][O:22][CH3:23]
Reactant: O=C(O)c1cc(F)c(F)cc1Br
Reactant: COCOCc1cc(Cl)ccc1Br
Product: COCOCc1cc(F)c(F)cc1Br

Procedure:
This compound was made from 2-bromo-4,5-difluorobenzoic acid in the same manner as compound 18d: 1H NMR (300 MHz, CDCl3) δ (ppm) 3.42 (s, 3H), 4.57 (d, J=1.2 Hz, 2H), 4.76 (s, 2H), 7.3-7.5 (m, 2H).
Reaction SMILES: C(Cl)Cl.[S:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=2)[O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18])=[CH:5]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+]>C(OCC)C>[S:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=2)[O:12][CH2:13][CH2:14][O:15][CH2:16][CH:17]=[O:18])=[CH:5]1
Reactant: OCCOCCOc1cccc(-c2ccsc2)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCOCCOc1cccc(-c2ccsc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 36 %

Procedure:
A methylene chloride solution (2 ml) of 126 mg of 2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethanol is added to a mixed solution of 352 mg of pyridinium chlorochromate, 274 mg of sodium acetate, 130 mg of molecular sieves (4A) and 5 ml of methylene chloride, the mixture is stirred at room temperature for 1.5 hours, the reaction solution is diluted with ethyl ether, silica gel is added, and the insoluble matters are removed by filtration. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography [Wako gel C-200, 10 g; hexane/ethyl acetate=4/1→2/1] to obtain 45 mg of the captioned compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][NH:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH3:8].ClC1C=CC=CC=1C(C)CN([CH2:47][CH2:48][CH2:49][O:50][C:51]1[CH2:52][C:53](=[CH:57][C:58]([O:60][CH3:61])=[O:59])[CH:54]=[CH:55][CH:56]=1)CC1C=CC=C(C(F)(F)F)C=1Cl>>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH:7]([CH3:8])[CH2:6][N:5]([CH2:47][CH2:48][CH2:49][O:50][C:51]2[CH2:52][C:53](=[CH:57][C:58]([O:60][CH3:61])=[O:59])[CH:54]=[CH:55][CH:56]=2)[CH2:4][C:3]2[CH:17]=[CH:18][CH:19]=[C:20]([C:21]([F:22])([F:23])[F:24])[C:2]=2[Cl:1])=[CH:14][CH:13]=1
Reactant: COC(=O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(C)c2ccccc2Cl)C1
Reactant: COc1ccc(C(C)CNCc2cccc(C(F)(F)F)c2Cl)cc1
Product: COC(=O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(C)c2ccc(OC)cc2)C1
Yield: 26 %

Procedure:
The titled compound was prepared from N-(2-Chloro-3-trifluoromethylbenzyl)-2-(4-methoxyphenyl)propylamine in 26% yield in the same manner as the preparation of N-(2-[2-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylamine in Example 184f. MS (ESI) 564 (MH+)
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21](=[O:74])[C@@H:22]([NH:56][C:57](=[O:73])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[CH2:23][S:24][CH2:25][C@H:26]([O:42][C:43](=[O:55])[NH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:27][O:28][C:29](=[O:41])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>C(Cl)Cl>[CH2:45]([NH:44][C:43]([O:42][C@H:26]([CH2:27][O:28][C:29](=[O:41])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:25][S:24][CH2:23][C@H:22]([NH:56][C:57](=[O:73])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[C:21](=[O:74])[NH:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[O:55])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC[C@@H](COC(=O)NCCCCCCCCCC)OC(=O)NCCCCCCCCCC)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC[C@@H](COC(=O)NCCCCCCCCCC)OC(=O)NCCCCCCCCCC)C(=O)NCCOCCOCCOCCP(=O)(O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (14R,18R)-18-(decylcarbamoyloxy)-13,21-dioxo-14-palmitamido-3,6,9,20-tetraoxa-16-thia-12,22-diazadotriacontylphosphonic acid diethyl ester (1 eq) in DCM (0.1 M) was stirred at 0° C. Trimethylsilyl bromide (10 eq) was added and allowed to warm to room temperature. The reaction was then heated to 32° C. and stirred overnight. The reaction was then diluted with DCM and concentrated with a stream of nitrogen then purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-10% MeOH/DCM with 0.5% AcOH to afford (14R,18R)-18-(decylcarbamoyloxy)-13,21-dioxo-14-palmitamido-3,6,9,20-tetraoxa-16-thia-12,22-diazadotriacontylphosphonic acid as a colorless oil. 1H NMR (DMSO-d6): δ 7.32 (t, 1H), 6.65 (t, 1H), 5.63 (t, 1H), 5.24 (t, 1H), 5.16 (t, 1H), 4.68 (m, 1H), 4.48 (m, 1H), 3.46-3.78 (m, 15H), 3.17 (m, 4H), 2.75-2.95 (m, 4H), 2.15-2.35 (m, 4H), 1.56 (m, 4H), 1.49 (m, 4H), 1.20-1.45 (m, 52H), 0.87 (t, 9H). LRMS [1\4+H] =1039.7.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C@@H:19]([CH3:41])[C@H:20]([CH2:39]O)[NH:21][C:22]([O:24][CH2:25][CH:26]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.C1(P(=[CH:70][C:71]([O:73][CH2:74][C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)=[O:72])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:11]([O:18][C@@H:19]([CH3:41])[C@@H:20]([NH:21][C:22]([O:24][CH2:25][CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])/[CH:39]=[CH:70]/[C:71]([O:73][CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)=[O:72])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C[C@H](OCc1ccccc1)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: C[C@H](OCc1ccccc1)[C@H](/C=C/C(=O)OCc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
(From Mandal et al, J. Med. Chem. 2009, 52, 6126-41) To a solution of oxalyl chloride (8.0 mmol) in 30 mL of dry CH2Cl2, stirred at −78° C. under argon was added DMSO (16.0 mmol) via syringe dropwise with vigorous stirring. After 20 min, a solution of Fmoc-D-threoninol benzyl ether (5.0 mmol) in 20 mL of dry CH2Cl2, was added while maintaining the bath temperature at −78° C. Stirring was continued further for 30 min. Dry and distilled DIEA (30 mmol) was then added using a syringe and the reaction mixture then allowed to warm to room temperature without removing bath. The reaction mixture then quenched with 20 mL of ice-cold water and extracted with CH2Cl2 (3×80 mL). The combined organic layers were washed with 1N HCl (3×30 mL), brine (1×30 mL) and dried (MgSO4) and concentrated under vacuum. The crude aldehyde was used immediately for the next step without characterization. A mixture of the Fmoc-amino aldehyde (4.0 mmol) and benzyl (triphenylphosphoranylidene)-acetate (4.4 mmol) in dry CH2Cl2 (20 mL) was stirred for 3 h. The progress of the reaction was monitored by thin layer chromatography. After completion the solvent was removed in vacuo and the residue was purified by silica gel chromatography using EtOAc in hexane. Yield: 1.55 g (68%), white powder. 1H NMR (CDCl3, 300 MHz) δ 1.22 (d, J=5.7 Hz, 3H), 3.7 (m, 1H), 4.2 (t, J=6.6 Hz, 1H), 4.3-4.45 (m, 4H), 4.58 (d, J=11.7 Hz, 1H), 5.2 (s, 2H), 5.98 (d, J=15.3 Hz, 1H), 6.98 (m, 1H), 7.28-7.38 (m, 14H), 7.58 (d, J=7.5 Hz, 2H), 7.74 (d, J=7.5 Hz, 2H). 13C NMR (CDCl3, 75 MHz) δ 16.5, 47.3, 66.3, 66.9, 71.1, 75.1, 120.0, 121.7, 125.0, 127.0, 127.7, 127.8, 127.9, 128.3, 128.5, 128.6, 135.9, 137.7, 141.3, 143.8, 143.9, 147.2, 165.8. Anal (C35H33NO5) C, H, N: Calc'd: C, 76.76; H, 6.07; N, 2.56. Found: C, 76.61; H, 6.06; N, 2.55. HRMS (M+H) Calc'd: 548.2437. Found: 548.2451.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH:4]([CH2:6][CH3:7])O.[CH2:9]([SH:22])[CH:10]([SH:21])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:11]([CH:10]1[CH2:9][S:22][C:4]([CH2:6][CH3:7])=[C:3]([CH2:2][CH3:1])[S:21]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCC(S)CS
Reactant: CCC(=O)C(O)CC
Product: CCCCCCCCCCC1CSC(CC)=C(CC)S1
Yield: 58 %

Procedure:
The method of Example 4 was followed using propioin (4-hydroxy-3-hexanone) (8.2 g) and dodecane-1,2-dithiol (15.1 g) to give 2-decyl-5,6-diethyl-2,3-dihydro-1,4-dithiin as an undistillable oil, yield 58%. NMR, (CDCl3) 0.8-1.28 δ (overlapping triplets), 1.38 δ (broadened singlet), 2.05-2.41 δ (quartet), 2.7-3.38 (multiplet).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[NH2:19])=[CH:6][CH:5]=1.[CH:21](O)=O>COC(OC)OC>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]2[C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=3[N:19]=[CH:21]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(CNc2ccc(C)cc2N)cc1
Reactant: O=CO
Solvent: COC(OC)OC
Product: COC(=O)c1ccc(Cn2cnc3cc(C)ccc32)cc1
Temperature: 25 °C
Yield: 61 %

Procedure:
A stirred solution 4-[(4-methyl-2-nitrophenylamino)methyl]benzoic acid methyl ester (7.0 g, 23 mmol,) in CH3OH was treated with 5% Pd/C (50% wet, 30% w/w) and hydrazine hydrate (5.8 g, 116 mmol). The reaction mixture was heated to reflux temperature for 2 h, cooled to room temperature and filtered through celite. The filtrate was evaporated to give a residue. The residue was dissolved in CH2Cl2, washed with water, dried over anhydrous Na2SO4 and evaporated to afford 4-[(2-amino-4-methylphenylamino)methyl]benzoic acid methyl ester, which was used in the next step without further purification. Yield: 93%. 1H NMR (400 MHz, CDCl3) 8.0 (d, J=8 Hz, 2H); 7.70 (d, J=8 Hz, 2H); 6.60 (m, 2H); 6.49 (d, 1H); 4.3 (s, 2H); 3.90 (d, 3H); 2.21 (s, 3H). LCMS (ESI+) 271 (MH+). A stirred solution of crude 4-[(2-amino-4-methylphenylamino)methyl]benzoic acid methyl ester (6 g, 22 mmol) in trimethylorthoformate was treated with formic acid (1.0 g), refluxed for 2 h, cooled to room temperature and evaporated under reduced pressure. The resultant residue was purified by column chromatography using 1% MeOH/CHCl3 to afford 4-[(5-methylbenzimidazol-1-yl)methyl]benzoic acid methyl ester Yield: 61%. 1H NMR (400 MHz, CDCl3): 8.0 (d, J=8 Hz, 1H); 7.93 (s, 1H); 7.62 (s, 1H); 7.26 (s, 1H); 7.21 (d, J=8 Hz, 2H); 7.08 (m, 2H); 5.39 (s, 2H); 3.90 (s, 3H); 2.47 (s, 3H). LCMS (ESI+) 281 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[OH:18]S(O)(=O)=O.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)[C:5]([C:8]([NH2:9])=[O:18])=[N:6][CH:7]=1
Reactant: Cc1ncccc1Oc1cc(Br)cnc1C#N
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ncccc1Oc1cc(Br)cnc1C(N)=O
Reaction time: 8 h
Yield: 69 %

Procedure:
To 5-bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile (15 g, 52 mmol) was added concentrated H2SO4 (30 mL) and the slurry was stirred overnight, at which point the material was fully dissolved. The reaction was poured into 0° C. water in small portions. While maintaining the temp below 20° C., the aqueous layer was basified by the addition of NaOH pellets, to a pH of about 5, at which point a solid formed. The solid was filtered, and the remaining aqueous layer was extracted with EtOAc. The organic layers, combined with the solid, were washed with brine, dried over MgSO4 and concentrated in vacuo to yield 5-bromo-3-(2-methylpyridin-3-yloxy)picolinamide (11 g, 69%).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:15]([CH:17]=[CH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([O-])=O>[C].[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:16]=[C:15]([CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7]
Reactant: CC(C)(C)OC(=O)c1ccc(C=CCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(CCCc2ccccc2)cc1N
Reaction time: 0.5 h
Yield: 109 %

Procedure:
62 mg of 5% palladium-carbon was added to 3 mL of ethyl acetate solution containing 0.31g of tert-butyl 2-nitro-4-(3-phenyl-1-propenyl)benzoate at room temperature and stirred under hydrogen atmosphere at the same temperature for 5 hours and 30 minutes. Insoluble were removed by filtration, and the solvent was evaporated under reduced pressure to obtain 0.31 g of tert-butyl 2-amino-4-(3-phenylpropyl)benzoate as yellow oil.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[C:17]([C:21]4[CH:26]=[C:25](NC)[N:24]=[C:23]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)[CH:22]=4)[CH:18]=[N:19][CH:20]=3)[CH:12]=[N:11]2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].BrC1C=C(C2C=[C:46]([C:48]([OH:51])(C)[CH3:49])N=C(C3C=CC=CN=3)C=2)C=NC=1>>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[C:17]([C:21]4[CH:26]=[C:25]([CH2:46][CH:48]([OH:51])[CH3:49])[N:24]=[C:23]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)[CH:22]=4)[CH:18]=[N:19][CH:20]=3)[CH:12]=[N:11]2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)(O)c1cc(-c2cncc(Br)c2)cc(-c2ccccn2)n1
Reactant: CNc1cc(-c2cncc(-c3cnn(C4CCN(C(C)C)CC4)c3)c2)cc(-c2ccccn2)n1
Product: CC(O)Cc1cc(-c2cncc(-c3cnn(C4CCN(C(C)C)CC4)c3)c2)cc(-c2ccccn2)n1

Procedure:
is prepared analogously to (5″-[1-(1-Isopropyl-piperidin-4-yl)-1H-pyrazol-4-yl]-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 2.175) by replacing (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 2.1; step1) with 2-(5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-propan-2-ol (Example 2.80; step2)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].O1CCOCC1.CC1(C)C(C)(C)OB([C:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]=2)O1.C(=O)(O)[O-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]=2)=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=[N+]([O-])c1ccc(Br)c(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
Add 2-bromo-5-nitrobenzotrifluoride (250 mg, 0.926 mmol) to dioxane (3 mL), then add tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (207 mg, 0.926 mmol), tetrakis(triphenylphosphine)palladium [Pd(PPh3)4, 35 mg, 0.03 mmol] and saturated sodium bicarbonate solution (1 mL) under nitrogen atmosphere. Stir the reaction mixture overnight at 120° C. TLC (PE:EtOAc=5:1) shows the reaction is complete. Partition the mixture between EtOAc and water, dry the organic layer over sodium sulfate, filter and concentrate the filtrate under reduced pressure. Purify the residue by flash chromatography (silica gel, PE:EtOAc=5:1) to afford the desired product (289 mg, 84%).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[N:12]=2)[CH:4]=1)[CH3:2].[OH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:23]3[CH2:24][CH2:25][CH:20]([OH:19])[CH2:21][CH2:22]3)[N:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2cccc(C=O)n2)c(C)[nH]c1=O
Reactant: OC1CCNCC1
Product: CCc1cc(-c2cccc(CN3CCC(O)CC3)n2)c(C)[nH]c1=O

Procedure:
5′-Ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-6-carbaldehyde prepared in accordance with PREPARATION 11 is reacted with 4-hydroxypiperidine as described in Method A, Example 123 to give the title compound. MS: m/e=328 (M+H).