Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:15]=[C:16](OS(C(F)(F)F)(=O)=O)[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:7].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1B(O)O.C(N(CC)CC)C>CN(C)C=O.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>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:16]1[CH:17]=[C:8]([C:6](=[O:7])[NH:5][CH2:4][CH2:3][N:2]([CH3:26])[CH3:1])[CH:9]=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)cc(C(=O)NCCN(C)C)c1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)NCCN(C)C)cc(-c2cc(Cl)ccc2Cl)c1
Temperature: 100 °C

Procedure:
A mixture of methyl 3-((2-dimethylaminoethyl)carbamoyl]-5-(trifluoromethylsulfonyloxy)benzoate (2 g), 2,5-dichlorophenyl-dihydroxyborane 1.25 g), tetrakis(triphenylphosphine)palladium(0) (0.17 g) and triethylamine (1.52 g) in N,N-dimethylformamide (40 ml) was heated at 100° C. for 3 hours under nitrogen atmosphere. After evaporating the solvent, the residue was dissolved in a mixture of ethyl acetate (100 ml) and water (100 ml). The organic layer was successively washed with 10% potassium carbonate aqueous solution, brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel (100 ml) eluting with a mixture of chloroform and methanol (20:1). The fractions containing the desired products were collected and evaporated in vacuo. The residue was crystallized from diisopropyl ether to afford methyl 5-(2,5-dichlorophenyl)-3-[(2-dimethylaminoethyl)carbamoyl]benzoate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]([CH3:49])=[C:16]([N:33]([CH2:47][CH3:48])[CH:34]2[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]2)[CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:22][CH:21]=2)[CH:19]=1)=[O:13].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[CH:22][CH:21]=2)[CH:17]=[C:16]([N:33]([CH2:47][CH3:48])[CH:34]2[CH2:35][CH2:36][NH:37][CH2:38][CH2:39]2)[C:15]=1[CH3:49])=[O:13]
Reactant: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
tert-Butyl 4-((5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-yl)(ethyl)amino)piperidine-1-carboxylate (1.3 g, 0.1.93 mmol) was taken in DCM (20 mL), to it TFA (10 mL) was added at 0° C. and stirred at rt for 2 h. On completion of reaction, solvent was removed under reduced pressure, reaction was quenched with aqueous sodium bicarbonate and extracted with 10% MeOH/DCM. Combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to obtain crude; which then purified by acetonitrile washing to give the title compound (0.9 g, 81.81%).
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH2:23][C:24]2[S:28][C:27]3[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:26]=3[CH:25]=2)[CH:14]=1.[CH2:34]([O:41][CH:42]1[CH:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:46]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH:45]([CH2:64][O:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[O:44][C:43]1=[O:73])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Cl-].[NH4+]>C1COCC1>[CH2:34]([O:41][C@@H:42]1[C@@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@@H:46]([O:56][CH2:57][C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[C@@H:45]([CH2:64][O:65][CH2:66][C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)[O:44][C:43]1([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH2:23][C:24]2[S:28][C:27]3[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:26]=3[CH:25]=2)[CH:14]=1)[OH:73])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Fc1ccc2sc(Cc3cc(Br)c4ccccc4c3)cc2c1
Reactant: O=C1OC(COCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(c2cc(Cc3cc4cc(F)ccc4s3)cc3ccccc23)O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 0.17 h
Yield: 65.7 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.6 M, 0.97 ml, 1.55 mmol) was added dropwise to a solution of 2-(4-bromonaphthalen-2-yl-methyl)-5-fluorobenzo[b]thiophene (520 mg, 1.41 mmol) in THF (15 ml) at −78° C. and the reaction mixture was stirred at the same temperature for 10 minutes. To this solution, a solution of 3,4,5-trisbenzyloxy-6-benzyloxymethyl-tetrahydropyran-2-one (835 mg, 1.55 mmol) in THF (3 ml) was added dropwise. The mixture was stirred at −78° C. for one hour, and a saturated ammonium chloride aqueous solution was added thereto to stop the reaction. The reaction mixture was extracted with ether, and the organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:20)] to obtain the title compound (770 mg, 66%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)#[N:2].C(O)(=[O:29])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH:6]=[C:7]2[C:8]=1[NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:17][C:18]2=1)(=[O:29])[NH2:2]
Reactant: COc1ccccc1-c1ccc(Nc2ccc(C(=O)O)cc2)c(C#N)c1
Reactant: CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: COc1ccccc1-c1cc(C(N)=O)c2[nH]c3ccc(C(=O)O)cc3c2c1
Temperature: 130 °C

Procedure:
A 5 ml microwave vial was loaded with 4-(3-cyano-2′-methoxybiphenyl-4-ylamino)benzoic acid (63 mg, 0.161 mmol), Acetic Acid (4 ml) and Palladium(II) acetate (106 mg, 0.472 mmol), sealed and heated to 130° C. for 12 hours. The reaction mixture was filtered through a 0.45 um Nylon filter, the filter rinsed with acetic acid and the collected liquids evaporated. 31.5 mg of 8-carbamoyl-6-(2-methoxyphenyl)-9H-carbazole-3-carboxylic acid were isolated as a brown film and used without further purification. MS (ESI) m/z 359 (M−H).
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][Si:16]([CH2:19]Cl)([CH3:18])[CH3:17]>C(#N)C>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCl
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: C[Si](C)(C)CNC(c1ccccc1)c1ccccc1
Yield: 29.8 %

Procedure:
A mixture of benzhydrylamine (25 g, 136.4 mmol) and trimethylsilylmethyl chloride (8.39 g, 68.4 mmol) in acetonitrile (105 ml) was refluxed overnight. Then the mixture was concentrated under vacuum at 70° C. with a rotary evaporator to remove all volatiles. The white residue was mixed with n-heptane (150 ml) and filtered over a glass filter. The salt residue was washed with n-heptane (2×25 ml). The combined heptane filtrates were concentrated under vacuum to give the crude product as a clear, slightly yellow oil (23 g; >100%). Purification by chromatography on silica gel (700 ml) eluting with n-heptane (2000 ml), followed by n-heptane:ethyl acetate (10:1) gave pure diphenyl-N-((trimethylsilyl)methyl)methanamine (5.5 g, 20.4 mmol; 30%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=[O:8].[C:10]([O:14][C:15](=[O:37])[CH2:16][N:17]1[C:21]2[CH:22]=[CH:23][C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:25][C:20]=2[N:19]=[C:18]1[CH2:34][CH2:35][CH3:36])([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:10]([O:14][C:15](=[O:37])[CH2:16][N:17]1[C:21]2[CH:22]=[CH:23][C:24]([N:26]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[CH3:1])=[O:8])=[CH:25][C:20]=2[N:19]=[C:18]1[CH2:34][CH2:35][CH3:36])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1ccsc1C(=O)Cl
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3sccc3C)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methyl-thiophene-2-carbonyl chloride (41 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C29H33N3O3S+H: 504, observed: 504.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@@H:14]([OH:15])[CH2:13][C@H:12]([O:16][C@H:17]3[C@@H:22]([OH:23])[CH2:21][C@H:20]([O:24][C@@H:25]4[CH2:30][C@H:29]5[CH2:31][CH2:32][C@H:33]6[C@@:38]7([OH:48])[CH2:39][CH2:40][C@H:41]([C:42]8[CH2:47][O:46][C:44](=[O:45])[CH:43]=8)[C@@:37]7([CH3:49])[C@H:36]([OH:50])[CH2:35][C@@H:34]6[C@@:28]5([CH3:51])[CH2:27][CH2:26]4)[O:19][C@@H:18]3[CH3:52])[O:11][C@@H:10]2[CH3:53])[CH2:5][C@H:4]([OH:54])[C@@H:3]1[OH:55].I([O-])(=O)(=O)=O.[Na+].I([O-])(=O)(=O)=O.CO>C(Cl)(Cl)Cl.CO>[CH3:52][C@H:18]1[O:19][C@@H:20]([O:24][C@@H:25]2[CH2:30][C@H:29]3[CH2:31][CH2:32][C@H:33]4[C@@:38]5([OH:48])[CH2:39][CH2:40][C@H:41]([C:42]6[CH2:47][O:46][C:44](=[O:45])[CH:43]=6)[C@@:37]5([CH3:49])[C@H:36]([OH:50])[CH2:35][C@@H:34]4[C@@:28]3([CH3:51])[CH2:27][CH2:26]2)[CH2:21][C@H:22]([OH:23])[C@@H:17]1[O:16][C@@H:12]1[O:11][C@H:10]([CH3:53])[C@@H:9]([O:8][CH:6]([O:7][CH:2]([CH:3]=[O:55])[CH3:1])[CH2:5][CH:4]=[O:54])[C@@H:14]([OH:15])[CH2:13]1
Reactant: C[C@H]1O[C@@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3[C@@H](O)C[C@H](O[C@H]4CC[C@@]5(C)[C@H](CC[C@@H]6[C@@H]5C[C@@H](O)[C@]5(C)[C@@H](C7=CC(=O)OC7)CC[C@]65O)C4)O[C@@H]3C)O[C@@H]2C)C[C@H](O)[C@@H]1O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C=O)OC(CC=O)O[C@H]1[C@@H](O)C[C@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3CC[C@@]4(C)[C@H](CC[C@@H]5[C@@H]4C[C@@H](O)[C@]4(C)[C@@H](C6=CC(=O)OC6)CC[C@]54O)C3)O[C@@H]2C)O[C@@H]1C
Reaction time: 0.25 h

Procedure:
Digoxin (0.4985 g, 0.64 mmole) was dissolved in 10 ml of chloroform/methanol (3/1.5) and placed into a 100 ml two-necked flask. Sodium periodate (0.3102 g, 1.4 mmoles) was dissolved in 4 ml distilled water and placed into a pressure equalized addition funnel. The periodate solution was slowly added to the flask while stirring and under nitrogen. A white precipitate was immediately formed and the reaction was complete within 15 minutes after addition of the periodate. Reaction progress was monitored by TLC (E. M. Merck, pre-coated TLC sheets, silica gel 60 F254 0.2 mm thickness) in chloroform/methanol 10/1 by volume [Rf 0.16=dialdehyde, one homogeneous spot; Rf 0.07=Digoxin. Both spots became dark brownish when sprayed the TLC plate with methanol/concentrated sulfuric acid (9/1 by volume) and placed in 100° C. oven). The reaction mixture was evaporated on a rotatory evaporator and brought up in 30 ml of chloroform and 3 ml of water. The cloudy solution was extracted and the aqueous layer washed three times with 10 ml chloroform. The organic phases were combined (60 ml) and dried over magnesium sulfate. The organic solvents were evaporated to dryness. A light yellow brownish oily material was left. This material was used immediately in the next reaction.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8]([CH3:10])=O.[CH2:17](S)C.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:7]([S:8][CH2:10][CH3:17])=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: CCS
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CCSc1nc(N)nc(-c2ccco2)c1Br

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, ethanethiol and DBU in dioxane. EI-MS m/e (%): 301 (M{81Br}+, 28), 299 (M{79Br}+, 27), 220 ([M—Br]+, 100), 160 (30), 118 (24).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:19](=[O:20])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.[CH:21]([N:24]([CH:27]([CH3:29])C)CC)([CH3:23])C.N1CCCC1.[I-].[Na+]>CN(C)C=O>[C:13]1([C:10]2[C:9]3[C:19](=[O:20])[CH:5]([CH2:4][CH2:3][CH2:2][N:24]4[CH2:21][CH2:23][CH2:29][CH2:27]4)[CH2:6][CH2:7][C:8]=3[O:12][N:11]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C1c2c(-c3ccccc3)noc2CCC1CCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: O=C1c2c(-c3ccccc3)noc2CCC1CCCN1CCCC1
Temperature: 25 °C

Procedure:
To a solution consisting of 5-(3-chloropropyl)-6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one (3.75 g) and dimethylformamide (37.0 ml) was added diisopropylethyl amine (6.81 ml), pyrrolidine (2.17 ml) and sodium iodide (5.85 g) at room temperature with stirring. The reaction was flushed with nitrogen and warmed at 73°-76° C. for 1.25-2 hours. Upon cooling to room temperature, dilute aqueous sodium bicarbonate and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous layer extracted twice with ethyl acetate and once with ether. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, 2% triethylamine/0-10% methanol/ether) afforded 3.10 g of 6,7-dihydro-3-phenyl-5-[3-(1-pyrrolidinyl)-propyl]-1,2-benzisoxazol-4(5H)-one as an oil which solidified on standing. The salicylate was prepared with 1.07 eq. salicylic acid in ether. The resulting solid was redissolved with methanol. Addition of pentane led to precipitation of the target salt. Filtration and washing with pentane gave 6,7-dihydro-3-phenyl-5-[3-(1-pyrrolidinyl)-propyl]-1,2-benzisoxazol-4(5H)-one salicylate, m.p. 106°-107° C.
Reaction SMILES: Cl.C(N=C=N[CH2:7][CH2:8][CH2:9]N(C)C)C.[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)C#C>C(Cl)(Cl)Cl>[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:9][C:8]#[CH:7])=[O:25])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)CCCCCc1ccccc1
Reactant: CCN=C=NCCCN(C)C
Agent: C#CCO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: C#CCOC(=O)CCCCCc1ccccc1
Temperature: 0 °C
Yield: 25.9 %

Procedure:
Five hundred milligrams of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a mixture of 500 mg of 6-phenylhexanoic acid and 20 ml of dry chloroform at room temperature with stirring. After the resultant mixture had been stirred for 30 minutes at room temperature, 146 mg of propargyl alcohol was added thereto at room temperature. Thereafter, the resulting mixture was stirred for 12 hours at room temperature, poured into ice water and extracted with chloroform. The chloroform extract was washed with an aqueous saturated ammonium chloride solution and then with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was subjected to chromatography on silica gel to obtain 155 mg of propargyl 6-phenylhexanoate.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([O:9][C:10]3[CH:15]=[CH:14][C:13]([CH2:16][CH2:17]O)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.CN(C1C=CC=CN=1)C.CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([CH3:1])[CH:20]=[CH:19][C:5]=3[N:6]=2)=[CH:11][CH:12]=1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2nc(Oc3ccc(CCO)cc3)sc2c1
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc2nc(Oc3ccc(CCS(C)(=O)=O)cc3)sc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.3 %

Procedure:
To a solution of 2-[4-(6-methyl-benzothiazol-2-yloxy)-phenyl]-ethanol (6.8 g, 23.8 mmol) and dimethylaminopyridine (290 mg, 2.4 mmol) in CH2Cl2 (80 mL) was added (i-Pr)2NEt (4.9 g, 28.6 mmol) followed by the addition of methanesulfonyl chloride (2.2 mL, 28.6 mmol) at 0° C. The reaction was warmed to rt and stirred for 15 min. The reaction was washed with satd. aq. Na2CO3 (75 mL), 5% aq. H2SO4 (75 mL) and brine. The organic layer was dried (Na2SO4), filtered and concentrated to afford the title compound (7.3 g, 85%). 1H NMR (500 MHz, CDCl3): 7.61 (d, J=8.3 Hz, 1H), 7.47 (s, 1H), 7.36-7.29 (m, 4H), 7.20 (dd, J=8.3, 1.2 Hz, 1H), 4.45 (t, J=6.8 Hz, 2H), 3.10 (t, J=6.8 Hz, 2H), 2.91 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[C:26]2[CH:27]=[CH:28][C:29](=[O:35])[N:30]([CH2:32][CH2:33]O)[CH:31]=2)=[CH:21][CH:20]=1.N(C(N(C)C)=O)=NC(N(C)C)=O.C(P(CCCC)CCCC)CCC>C1COCC1.C1(C)C=CC=CC=1>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:33][CH2:32][N:30]3[CH:31]=[C:26]([CH:25]([C:22]4[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=4)[C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)[CH:27]=[CH:28][C:29]3=[O:35])[C:10]=2[N:9]=[C:8]1[CH3:11])[CH3:17]
Reactant: O=c1ccc(C(c2ccc(F)cc2)c2ccc(F)cc2)cn1CCO
Reactant: CCOC(=O)Cn1c(C)nc2c(O)cccc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)Cn1c(C)nc2c(OCCn3cc(C(c4ccc(F)cc4)c4ccc(F)cc4)ccc3=O)cccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.4 %

Procedure:
To a mixture of ethyl (4-hydroxy-2-methyl-1H-benzimidazol-1-yl)acetate (476 mg), 5-[bis(4-fluorophenyl)methyl]-1-(2-hydroxyethyl)pyridin-2(1H)-one (694 mg), 1,1′-azobis(N,N-dimethylformamide) (385 mg) and toluene (9.5 mL) was added tributylphosphine (452 mg) at ambient temperature. The mixture was stirred at ambient temperature for 20 hours. The reaction mixture was diluted with a mixture of EtoAc (50 mL) and THF (20 mL), and washed with water (30 mL) and brine (30 mL). The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo to give crude oil. The crude oil was crystallized from solvent(EtOAc and n-hexane) to give ethyl[4-(2-{5-[bis(4-fluorophenyl)methyl]-2-oxopyridin-1(2H)-yl}ethoxy)-2-methyl-1H-benzimidazol-1-yl]acetate (1.07 g) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][NH:14][C:15](=O)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O.C(#N)C>CN(C=O)C>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([Cl:21])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2c1CN(Cc1ccccc1)CC2
Solvent: CC#N
Solvent: CN(C)C=O
Product: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Temperature: 70 °C
Yield: 57.8 %

Procedure:
A mixture of 6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one (5.0 g, 0.02 mol), phosphoryl chloride (3.30 mL, 0.035 mol) and acetonitrile (80 mL) and DMF (catalytic amount) was heated at 70° C. for 1 hour. The mixture was concentrated in vacuo and the remaining black residue was taken up in dichloromethane (250 mL) and poured over ice. The mixture was carefully neutralized with the addition of solid sodium bicarbonate. The organic layer was separated and dried over sodium sulfate and concentrated in vacuo. The mixture was purified by silica gel column with EtOAc/hexane (0-100%) to yield the title compound as a yellow oil (3 g, 57.8%). LC-MS: 260 [M+1]+; 1H NMR (400 MHz, DMSO-d6): δ 8.80 (s, 1H), 7.40-7.24 (m, 5H), 3.76 (s, 2H), 3.57 (s, 2H), 2.92 (t, 2H), 2.80 (t, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.B(O)(O)[C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[Cl:8][C:7]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Clc1cccnc1Cl
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: O
Solvent: COCCOC
Product: Cc1ccc(-c2ncccc2Cl)cc1
Yield: 84 %

Procedure:
{circle around (1)} 100 g (0.676 mol) of 2,3-dichloropyridine, 91.87 g (0.676 mol) of p-tolylboronic acid, and 86 g (0.811 mol) of sodium carbonate were dissolved in 500 mL of 1,2-dimethoxyethane and 500 mL of distilled water, after which 78 g (0.0676 mol) of Pd(PPh3)4 was added. The mixture was heated to reflux for 18 hours so that it was allowed to react. After completion of the reaction, the reaction solution was concentrated under reduced pressure to remove 1,2-dimethoxyethane, and then extracted with ethyl acetate. The extract was treated with magnesium sulfate, filtered, and concentrated under reduced pressure, yielding 3-chloro-2-para-tolylpyridine as represented below in a 84% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][C@H:16]2[C@H:13]([CH2:14][NH:15]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:20](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][C@H:16]2[C@H:13]([CH2:14][N:15]2[CH3:20])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C(OCc1ccccc1)N1C[C@H]2CN[C@H]2C1
Agent: C=O
Agent: [Na+]
Solvent: O
Product: CN1C[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]21
Temperature: 25 °C
Yield: 90.4 %

Procedure:
To a solution of (1R,5R)-3,6-diazabicyclo[3.2.0]heptane-3-carboxylic acid benzyl ester (14.2 g, 61.2 mmol; prepared according to patent WO 2001081347) and aqueous formaldehyde (38%, 100 mL, 1.38 mol; Fisher) in water (100 mL) was added sodium triacetoxyborohydride (25.8 g, 122 mmol; Aldrich). The mixture was stirred at room temperature until the reaction was complete according to HPLC analysis. The mixture was extracted with chloroform (3×100 mL) and the organic phase was washed with brine (100 mL) and concentrated under reduced pressure to afford the title compound (13.6 g, 55.3 mmol; 90% yield): 1H NMR (300 MHz, CD3OD) δ ppm 7.26-7.42 (5H, m), 5.15 (2H, s), 3.85 (1H, dd, J=7, 4 Hz), 3.69-3.79 (1H, m), 3.42-3.55 (1H, m), 3.13-3.25 (4H, m), 2.98-3.09 (1H, m), 2.32 (3H, s); MS (DCI/NH3) m/z 247 (M+H)+.