Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22](=[O:36])[CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)[CH3:25])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6]1)=[O:4].COC(C1CN(CC2C=CC(OCC3C4C=C(Cl)C=CC=4OC=3)=CC=2)C1)=O>>[F:35][C:32]([F:33])([F:34])[C:28]1[CH:27]=[C:26]([C:24]([CH3:25])=[CH:23][C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:13]3[CH:14]=[CH:15][C:10]([CH2:9][N:7]4[CH2:8][CH:5]([C:3]([OH:4])=[O:2])[CH2:6]4)=[CH:11][CH:12]=3)=[CH:21][CH:20]=2)=[O:36])[CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)C1CN(Cc2ccc(-c3ccc(C(=O)C=C(C)c4cccc(C(F)(F)F)c4)cc3)cc2)C1
Agent: COC(=O)C1CN(Cc2ccc(OCc3coc4ccc(Cl)cc34)cc2)C1
Product: CC(=CC(=O)c1ccc(-c2ccc(CN3CC(C(=O)O)C3)cc2)cc1)c1cccc(C(F)(F)F)c1
Yield: 62 %

Procedure:
When the product of Step E was substituted for methyl-1-(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl)azetidine-3-carboxylate in Example 25, Step E, the similar process afforded the title compound in 62% yield, as a light yellow solid. 1H-NMR (CDCl3+CD3OD) 7.84 (d, 2H, J=8.34 Hz); 7.59-7.33 (m, 6H); 4.7 (d, 2H); 3.96-3.92 (m, 4H); 3.19-3.14 (m, 1H); 2.36 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C:3]#[C:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[NH:14][CH3:15].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:2]([C:3]1[N:14]([CH3:15])[C:6]2[C:5]([CH:4]=1)=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[CH:8][CH:7]=2)([CH3:17])([CH3:16])[CH3:1]
Reactant: CNc1ccc([N+](=O)[O-])cc1C#CC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1c(C(C)(C)C)cc2cc([N+](=O)[O-])ccc21
Yield: 94 %

Procedure:
A solution of [2-(3,3-dimethyl-but-1-ynyl)-4-nitro-phenyl]-methyl-amine (5.0 g, 22.9 mmol) and TBAF (23.9 g, 91.6 mmol) in THF (50 mL) was heated at reflux overnight. The solvent was removed by evaporation under vacuum and the residue was dissolved in brine (100 mL) and EtOAc (100 mL). The organic phase was separated, dried over Na2SO4 and evaporated under vacuum to give 2-tert-butyl-1-methyl-5-nitro-1H-indole (5.0 g, 99%), which was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 8.47 (d, J=2.4 Hz, 1H), 8.07 (dd, J=2.4, 9.2 Hz, 1H), 7.26-7.28 (m, 1H), 6.47 (s, 1H), 3.94 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[C:19]3[CH2:20][CH2:21][CH2:22][C:23](=O)[C:18]=3[O:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C(O)C.[BH4-].[Na+]>C1COCC1>[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][CH:23]2[C:18]3[O:17][N:16]=[C:15]([C:5]4[CH:6]=[CH:7][C:8]([N:9]5[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[C:19]=3[CH2:20][CH2:21][CH2:22]2)=[CH:28][CH:27]=1
Reactant: COc1cc(-c2noc3c2CCCC3=O)ccc1-n1cnc(C)c1
Reactant: Nc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(-c2noc3c2CCCC3Nc2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a mixture of 3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5,6-dihydrobenzo[d]isoxazol-7(4H)-one (850 mg, 2.6 mmol) and 4-fluoroaniline (877 mg, 7.89 mmol) in THF (10 mL) was added Ti(OPr-i)4 (823 mg, 2.9 mmol) and the reaction mixture was stirred at 60° C. overnight. The mixture was cooled to 0° C., and 10.0 mL of dry ethanol was added, followed by NaBH4 (149 mg, 3.4 mmol). The mixture was stirred for 1 hr, precipitate was removed by filtration and washed with ethyl acetate. The filtrate was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography using a gradient of 0-7% of MeOH in DCM to afford the 660 mg of the title product.
Reaction SMILES: Cl[Si](C)(C)C.[F:6][C:7]1[CH:8]=[C:9]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:10][CH:11]([C:13]([OH:15])=[O:14])[NH2:12].C(N(C(C)C)C(C)C)C.[C:29](Cl)(=[O:36])/[CH:30]=[CH:31]/[CH2:32][CH2:33][CH2:34][CH3:35]>ClCCl>[F:6][C:7]1[CH:8]=[C:9]([CH2:10][CH:11]([NH:12][C:29](=[O:36])/[CH:30]=[CH:31]/[CH2:32][CH2:33][CH2:34][CH3:35])[C:13]([OH:15])=[O:14])[CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: CCCC/C=C/C(=O)Cl
Reactant: NC(Cc1cc(F)cc(F)c1)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC/C=C/C(=O)NC(Cc1cc(F)cc(F)c1)C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
6.3 ml (49.7 mmol) of chlorotrimethylsilane are added to a solution of 5.0 g (24.9 mmol) of 3,5-difluoro-DL-phenylalanine in dichloromethane (150 ml) and the reaction mixture is heated to reflux for 1 h. After cooling to 0° C., 9.7 ml (55.9 mmol) of ethyldiisopropylamine are added slowly and then, dropwise, 3.64 g (24.9 mmol) of trans-2-heptenoyl chloride. The reaction mixture is stirred overnight with slow warming to RT and remains standing at RT for 2 days. For working up, it is evaporated to dryness in vacuo, the residue is taken up using diethyl ether and extracted with 2.5 pc. aqueous sodium hydrogencarbonate solution (250 ml). The aqueous phase is extracted twice with ether, and the combined organic phases are extracted a further three times with sodium hydrogencarbonate solution. The combined aqueous phases are brought to pH=2 using 1N aqueous hydrochloric acid and extracted three times with ethyl acetate. The combined ethyl acetate phases are dried over sodium sulfate, filtered, and the solvent is concentrated in vacuo. The residue is washed by stirring with diethyl ether and filtered. The filter residue is isolated, the filtrate is concentrated and again treated with diethyl ether. After repetition twice, a total of 6.12 g (79% of th.) of product are obtained as a colorless solid.
Reaction SMILES: [CH3:1][SH:2].[Na].[CH2:4]([O:6][C:7](=[O:12])[C:8]([CH2:10]Br)=[CH2:9])[CH3:5]>C(O)C.O>[CH2:4]([O:6][C:7](=[O:12])[C:8]([CH2:10][S:2][CH3:1])=[CH2:9])[CH3:5]
Reactant: C=C(CBr)C(=O)OCC
Reactant: CS
Agent: [Na]
Solvent: O
Solvent: CCO
Product: C=C(CSC)C(=O)OCC
Reaction time: 2 h

Procedure:
A solution of methylmercaptan 4.8 g.) and sodium (2.3 g.) in absolute ethanol (75 ml.) is added dropwise to a solution of ethyl-2-bromomethylacrylate (19.3 g.) in ethanol (25 ml.). After two hours, it is diluted with water (400 ml.) and extracted with methylene chloride. The organic layer is dried and concentrated to dryness in vacuo to yield ethyl-2-methylthiomethylacrylate.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]1[CH2:26][O:25][CH:24]2[CH:9]([C@@H:10]([C@@H:22]([CH2:27][CH2:28][CH:29]([OH:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:23]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:8]1>[O-2].[O-2].[O-2].[Cr+6].C(Cl)Cl>[CH2:7]1[CH2:26][O:25][CH:24]2[CH:9]([C@@H:10]([C@@H:22]([CH2:27][CH2:28][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:23]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:8]1
Reactant: CCCCCC(O)CC[C@H]1CC2OCCOC2[C@@H]1CCCCCCC(=O)OCC
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCC(=O)CC[C@H]1CC2OCCOC2[C@@H]1CCCCCCC(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 8.7 g. of dry pyridine in 140 ml. of dry methylene chloride, stirred in a tap water bath is treated with 5.5 g. of dry chromium trioxide. The resulting deep red suspension is stirred at ambient temperature for 15 minutes. A solution of 3.78 g. of ethyl-9-ethylenedioxy-15-hydroxy-prostanoate (Example 55) in 15 ml. of methylene chloride is added, all at once, to the suspension. A black, tarry deposit is formed immediately. After stirring for 15 minutes at ambient temperature, the methylene chloride solution is decanted from the tarry deposit which is triturated with several portions of ether. The combined organic phases are washed with 5% aqueous sodium hydroxide, water, ice-cold 5% aqueous hydrochloric acid, saturated sodium bicarbonate solution, and saturated sodium chloride solution, dried with anhydros magnesium sulfate and taken to dryness to give 3.29 g. (88%) of a viscous oil; λ max 5.78 and 5.86 μ (carbonyl groups).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5].[OH-].[Na+].[C:22]1([CH2:28][C:29](Cl)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>C(OCC)(=O)C>[C:22]1([CH2:28][C:29]([NH:2][CH:3]([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([OH:6])=[O:5])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC(C(=O)O)C(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)NC(C(=O)O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.1 %

Procedure:
An aqueous solution (14 mL) of 2-amino-3,3-diphenylpropanoic acid hydrochloride (2.0 g, 7.2 mmol) was adjusted to pH 12 with 1M aqueous sodium hydroxide solution. Phenylacetyl chloride (1.05 mL, 7.9 mmol) was added dropwise at 0-10° C. while adjusting the mixture to pH 11-12 with 1M aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 4 hrs. Ethyl acetate (40 mL) was added to the reaction mixture, and the mixture was adjusted to pH 1.1 with concentrated hydrochloric acid and partitioned. The obtained organic layer was warmed to 50° C. and hexane (30 mL) was added. The mixture was cooled in an ice bath to allow solid precipitation. The solid was collected by filtration and dried to give the title compound (2.41 g).
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:32])[N:14]([N:23]=[CH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:33]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:32])[N:14]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: Cc1ccccc1C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1CNn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 258A (0.026 g, 0.057 mmol) in tetrahydrofuran (1.2 mL) and methanol (0.005 mL, 0.114 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.045 mL, 0.090 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (5.0 mL), and the resulting precipitate was collected by filtration, washed with water and dried. The crude product was triturated with dichloromethane/diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.29 (s, 3 H) 3.97 (s, 2 H) 6.02 (t, J=6.62 Hz, 1 H) 7.08 (t, J=7.35 Hz, 1 H) 7.23 (s, 3 H) 7.29 (t, J=7.54 Hz, 2 H) 7.47 (m, 1 H) 7.55 (d, J=7.72 Hz, 2 H) 7.67 (m, 2 H) 8.10 (d, J=7.72 Hz, 1 H) 16.31 (s, 1 H). MS (ESI−) m/z 459 (M−H)−.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][CH:21]=[C:20]([C:23]([OH:25])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[C:26]([O:30][C:31](=[O:40])[NH:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31](=[O:40])[NH:32][C@H:33]1[CH2:34][CH2:35][C@H:36]([NH:39][C:23]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:7]4[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:15]=3[NH:22][CH:21]=2)=[O:25])[CH2:37][CH2:38]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: COc1ccc(-c2ncnc3c(C(=O)O)c[nH]c23)c(OCC2CC2)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A73) and trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[O:9][C:10]([CH3:14])([CH3:13])[O:11][CH2:12][C:7]=2[CH:6]=1)=[O:4].[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:17]([CH2:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[O:9][C:10]([CH3:14])([CH3:13])[O:11][CH2:12][C:7]=2[CH:6]=1)=[O:4])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)OCc2cc(C(=O)CBr)ccc2O1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc(C(=O)CN=[N+]=[N-])ccc2O1
Temperature: 20 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone (Glaxo DE 3513885, 1985) (52 g) in DMF (300 ml) was treated with sodium azide (12.24 g) and the mixture was stirred for 2 h at 20° C. The reaction mixture was diluted with ethyl acetate and washed with water and dried (MgSO4). The solvent was removed under reduced pressure to give the title compound (39.11 g). TSP+ve 248(MH)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH:12]([CH:13]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:14][CH:15]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:11][CH:10]([OH:38])[CH2:9]1.C(N([CH2:44][CH3:45])CC)C.[CH3:46][C@@H:47]([C@@H:54]1[C@@:58]2([CH3:76])[CH2:59][CH2:60][CH:61]3[C@@:66]4([CH3:75])[CH2:67][CH2:68][CH:69]([O:71][C:72](Cl)=[O:73])[CH2:70][C:65]4=[CH:64][CH2:63][CH:62]3[CH:57]2[CH2:56][CH2:55]1)CCCC(C)C.CO.C(Cl)(Cl)Cl>ClCCl>[CH3:75][C:66]12[CH2:67][CH2:68][CH:69]([O:71][C:72](=[O:73])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]3[CH2:9][CH:10]([OH:38])[CH2:11][CH:12]3[CH:13]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:14][CH:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH2:70][C:65]1=[CH:64][CH2:63][CH:62]1[CH:61]2[CH2:60][CH2:59][C:58]2([CH3:76])[CH:57]1[CH2:56][CH2:55][CH:54]2[CH2:47][CH2:46][CH2:2][CH2:3][CH2:4][CH2:5][CH2:44][CH3:45]
Reactant: CCN(CC)CC
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Reactant: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2CCCCCCN)c2ccc(OC)cc2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCC1CCC2C3CC=C4CC(OC(=O)NCCCCCCN5CC(O)CC5C(OC(c5ccc(OC)cc5)c5ccc(OC)cc5)c5ccccc5)CCC4(C)C3CCC12C
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
Compound 31 (4.5 g, 8.67 mmol) was dissolved in anhydrous dichloromethane (100 mL) and cooled to 0° C. To the solution were added triethylamine (2.52 g, 3.36 mL, 25 mmol) and cholesteryl chloroformate (3.89 g, 8.67 mmol) successively. The reaction temperature was brought to ambient temperature and stirred further for 2 h. The completion of the reaction was ascertained by TLC (10% MeOH/CHCl3). The reaction mixture was evaporated under the vacuum to afford the crude product. Compound 32 (3.05 g, 37%) was obtained as a white foamy solid after column chromatography over silica gel.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16]Cl)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:20][C:21]1[CH:22]=[CH:23][C:24]2[C:28]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:27][S:26][C:25]=2[CH:35]=1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][N:32]3[CH2:33][CH2:34][CH:29]([C:28]4[C:24]5[CH:23]=[CH:22][C:21]([F:20])=[CH:35][C:25]=5[S:26][CH:27]=4)[CH2:30][CH2:31]3)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)csc2c1
Reactant: CC(=O)N1CCc2cc(C(=O)CCCCl)sc2C1
Agent: Cl
Product: CC(=O)N1CCc2cc(C(=O)CCCN3CCC(c4csc5cc(F)ccc45)CC3)sc2C1

Procedure:
The reaction and procedure are conducted in a similar manner as in Example 24 using 6-acetyl-2-(4-chlorobutyryl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 4-(6-fluorobenzo(b)thiophen-3-yl)piperidine hydrochloride to give 6-acetyl-2-(4-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH2:12]([O:19][C:20](=[O:26])[CH2:21][CH2:22][C:23]([O-:25])=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cs+]>CN(C=O)C>[C:23]([O:25][CH2:2][CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])(=[O:24])[CH2:22][CH2:21][C:20]([O:19][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:26]
Reactant: O=C([O-])CCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CCCCl
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCCOC(=O)CCC(=O)OCc1ccccc1
Yield: 14.3 %

Procedure:
A solution of tert-butyl 4-chlorobutyrate (8.9 g, 50 mmol) and cesium monobenzylsuccinate (prepared from monobenzyl succinate and CsOH) (50 mmol) in 100 mL of DMF was heated at 80° C. for 2 days. DMF was evaporated and chromatographed on silica (hexane-ethyl acetate) to afford 2.5 g (14%) of the title compound 3 as a colorless liquid. 1H NMR (DMSO-d6) δ 7.35 (s, 5H), 5.09 (s, 2H), 3.99 (t, J=7 Hz, 2H), 2.58 (m, 4H), 2.25 (t, J=7 Hz, 2H), 1.93 (q, 2H), 1.41 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[CH3:8].Cl[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].ClCCl.CO>C(N(CC)CC)C>[CH2:23]([NH:9][C:5]1[C:4]([NH2:10])=[CH:3][C:2]([CH3:1])=[C:7]([CH3:8])[CH:6]=1)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCCl
Reactant: Cc1cc(N)c(N)cc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCCCCCNc1cc(C)c(C)cc1N
Temperature: 130 °C
Reaction time: 6 h
Yield: 59.1 %

Procedure:
A mixture of 4.08 g (30 millimoles (mmol)) of 4,5-dimethyl-benzene-1,2-diamine (hereinafter compound “1”) and 2.04 grams (g) (10 mmol) of 1-chloro-dodecane in 20 milliliters (mL) of triethylamine was stirred at 130° C. for 6 hrs under argon. After cooling and addition of dichloromethane (100 mL), the organic solution was washed with aqueous Na2CO3 solution (10%, 40 mL). The aqueous layer was extracted twice with dichloromethane (2×100 mL). The combined organic extracts were dried over MgSO4 and rotary evaporated to dryness. The thin-layer chromatography retention factor (Rf) of the target compound (2) was 0.55 with dichloromethane (MC):methanol (MeOH) (95:5) mixture. Compound (2) was purified by flash chromatography on silica gel in MC:MeOH (95:5) to produce 1.8 g of reddish crystals (60% yield); mp 53-54° C.; 1H NMR (400 MHz, CDCl3) δ 6.56 (1H, s), 6.50 (1H, s), 3.20 (3H, broad s), 3.1 (2H, t, J=8 Hz), 2.26 (3H, s), 2.21 (3H, s), 1.68 (2H, q, J=7 Hz), 1.46 (2H, m), 1.34 (16H, s), 0.92 (3H, t, J=8 Hz); 13C NMR (100 MHz, CDCl3) δ 136.0, 131.8, 128.1, 125.9, 118.4, 113.93, 44.7, 31.9, 29.9, 29.69, 29.65, 29.5, 29.4; Anal. Calcd. for C20H36N2 (MW=304.51): C, 78.88; H, 11.92; N, 9.20. Found: C, 78.95; H, 12.16; N, 9.32.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[S:3]([O:6][C:7]1[CH:12]=[C:11](I)[C:10](I)=[CH:9][C:8]=1[O:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])(=[O:5])=[O:4].CCN([CH2:30][CH3:31])CC.[CH2:32]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:33][CH2:34][C:35]#[CH:36]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]([F:24])([F:23])[S:3]([O:6][C:7]1[CH:12]=[C:11]([C:36]#[C:35][CH2:34][CH2:33][CH2:32][O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:10]([C:36]#[C:35][CH2:34][CH2:33][CH2:32][O:37][CH2:38][C:31]2[CH:30]=[CH:44][CH:39]=[CH:40][CH:41]=2)=[CH:9][C:8]=1[O:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])(=[O:5])=[O:4]
Reactant: CCN(CC)CC
Reactant: C#CCCCOCc1ccccc1
Reactant: O=S(=O)(Oc1cc(I)c(I)cc1OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=S(=O)(Oc1cc(C#CCCCOCc2ccccc2)c(C#CCCCOCc2ccccc2)cc1OS(=O)(=O)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
A flame-dried 20 mL vial fitted with a screw-cap septa was charged with Pd(PPh3)2Cl2 (0.06 equiv., 0.12 mmol, 84 mg), Cut (0.12 equiv., 0.24 mmol, 45.6 mg), and 4,5-diiodo-1,2-phenylene bis(trifluoromethanesulfonate) (1 equiv., 2 mmol, 1.25 g). The vessel was evacuated and backfilled with nitrogen (3×), followed by the sequential addition of THF (4 mL), Et3N (3 equiv., 6 mmol, 0.85 mL), and ((pent-4-yn-1-yloxy)methyl)benzene (2.3 equiv., 4.6 mmol, 802 mg) in THF (1 mL). The reaction was stirred for 3 h at rt, filtered through a pad of silica and concentrated in vacuo. Purification by flash chromatography (step gradient from Hex to 10% EtOAc/Hex) afforded 4,5-bis(5-(benzyloxy)pent-1-yn-1-yl)-1,2-phenylene bis(trifluoromethanesulfonate) (1.14 g, 1.59 mmol, 79%). TLC Rf=0.27 (10% EtOAc/Hex); 1HNMR (600 MHz): δ 7.42 (s, 2H), 7.27-7.39 (10H), 4.56 (s, 4H), 3.65 (t, 4H, J=6.0 Hz), 2.62 (t, 4H, J=7.1 Hz), 1.92-1.98 (m, 4H); 13CNMR (150 MHz): δ 138.8, 138.3, 128.4, 128.2, 127.59, 127.56, 126.3, 121.7, 119.6, 117.5, 115.3, 98.1, 77.4, 73.0, 68.5, 28.6, 16.5; FTIR: 2859, 2230, 1489, 1433, 1210, 1178, 1135, 1080, 732 cm−1; HRMS-ESI: calc. for C32H28F6O8S2Na (M+Na)+: 741.1027. found: 741.1039.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:2]1[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Oc1ccnc2c(F)cc(F)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1cc(F)c2nccc(Cl)c2c1

Procedure:
(4-Hydroxy-6,8-difluoro-quinoline, 29.1 g, 0.160 mol) was dissolved in POCl3(183 mL) and heated at reflux for 12 h. On complete consumption of starting material (tic) the contents were brought to RT and excess POCl3 was removed under reduced pressure. Crude mass was azeotroped with toluene and product was diluted with ethyl acetate, organics were washed with sodium bicarbonate and solvent removed under reduced pressure. Crude product was purified by column chromatography at 100-200 mesh size silica in 0-2% EtOAc-hexane. Mass: 199.99 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:1][CH:2]1[N:7]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])cc1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
A mixture of (±)-tert-butyl 3-methylpiperazine-1-carboxylate (1.5 g), 1-fluoro-4-nitrobenzene (1.06 g) and potassium carbonate (2.07 g) in dimethyl sulfoxide (15 ml) was stirred at 120° C. for 15 hours. The reaction mixture was cooled to room temperature and poured into water (30 ml). The mixture was extracted with ethyl acetate three times. The combined organic layers were washed successively with water (twice) and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 2:1) to give the title compound as a white solid.