Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[Br:9][C:10]1[CH:11]=[C:12]([CH:16]=[O:17])[CH:13]=[N:14][CH:15]=1>CS(C)=O>[Br:9][C:10]1[CH:15]=[N:14][CH:13]=[C:12]([CH:16]2[CH2:2][O:17]2)[CH:11]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Brc1cncc(C2CO2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of trimethylsulfoxonium iodide (CAS#1774-47-6, 11.83 g, 53.8 mmol) in methyl sulfoxide (80 mL), was added slowly sodium hydride (60% dispersion in oil, 1.989 g, 49.7 mmol). The reaction was permitted to stir for 15 min at room temperature. A solution of 5-bromo-pyridine-3-carbaldehyde (CAS#135124-70-8, 5.0 g, 26.9 mmol) in dimethylsulfoxide (20 mL) was added slowly to the reaction mixture. The reaction permitted to stir for 10 minutes after the addition was complete. The reaction was cooled to 0° C., quenched with brine, and diluted with diethyl ether. The layers were separated and the aqueous layer was extracted two additional times with diethyl ether. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane, 0 to 60%) to afford 3-bromo-5-oxiranyl-pyridine; MS: (ES+) m/z 200.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[O:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.[NH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[N:22]=1>>[N:5]1[C:4]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[O:10][C:3]=2[C:2]([NH:17][CH2:18][CH2:19][NH:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[N:22]=2)=[N:7][CH:6]=1
Reactant: NCCNc1ccnc(N)n1
Reactant: Clc1ncnc2c1oc1ccccc12
Agent: Cl
Product: Nc1nccc(NCCNc2ncnc3c2oc2ccccc23)n1

Procedure:
4-Chloro-benzo[4,5]furo[3,2-d]pyrimidine (50 mg, 0.244 mmol) and the product of Example 1E (72 mg, 0.318 mmol) were treated under the conditions of Example 1F to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.59-3.85 (m, 4H) 6.03 (d, J=7.12 Hz, 1H) 7.52 (t, J=7.46 Hz, 1H) 7.58-7.67 (m, 1H) 7.67-7.88 (m, 4H) 8.11 (d, J=7.12 Hz, 1H) 8.28-8.44 (m, 1H) 8.82 (t, J=5.43 Hz, 1H) 11.69 (s, 1H); MS (ESI+) m/z 322.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])=[O:4].[C:14]([CH:16]1[CH2:18][CH2:17]1)#[CH:15].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>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.[Cu]I.C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:15]#[C:14][CH:16]2[CH2:18][CH2:17]2)=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])=[O:4]
Reactant: COC(=O)c1sc(Br)cc1[N+](=O)[O-]
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C#CC2CC2)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
Firstly bis(triphenylphosphine)palladium(II) chloride (17.6 mg) and then copper(I) iodide (19 mg) were added to a mixture of 5-bromo-3-nitrothiophene-2-carboxylic acid methyl ester (133 mg), ethynylcyclopropane (66 mg), triethylamine (51 mg), triphenylphosphine (3.3 mg) and THF (14 mL). After one hour, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC. The product with the molecular weight of 251.26 (C11H9NO4S) was obtained in this way; MS (ESI): 252 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=2)=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:22][NH:23][CH3:24]>>[CH3:1][O:2][C:3]([C:5]1([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:23]([CH3:24])[CH3:22])=[CH:16][CH:15]=2)=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: CNC
Reactant: COC(=O)C1(NC(=O)c2ccc(CCl)cc2)CCCCC1
Product: COC(=O)C1(NC(=O)c2ccc(CN(C)C)cc2)CCCCC1
Reaction time: 8 h
Yield: 50 %

Procedure:
30 ml of 40% aqueous dimethylamine solution was added to 4.5 g (14.5 mmol) of 1-[[[4-(chloromethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acid methyl ester, and the mixture was heated under reflux for 3 hours. The reaction solution was distilled off under reduced pressure, a saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the residue, and the mixture was stirred overnight. The precipitated solid was collected by filtration to obtain 2.3 g (50%) of the title compound.
Reaction SMILES: NC(N)=O.[C:5]([O:9][C:10]([NH:12][CH:13]([C:31]([OH:33])=[O:32])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][S:19]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[C:24]([NH2:29])[C:23]=1[OH:30])(=[O:21])=[O:20])=[O:11])([CH3:8])([CH3:7])[CH3:6].[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]=[C:42]=[O:43]>>[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH:41][C:42]([NH:29][C:24]1[CH:25]=[CH:26][C:27]([Cl:28])=[C:22]([S:19]([NH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:13]([NH:12][C:10]([O:9][C:5]([CH3:8])([CH3:6])[CH3:7])=[O:11])[C:31]([OH:33])=[O:32])(=[O:20])=[O:21])[C:23]=1[OH:30])=[O:43]
Reactant: O=C=Nc1ccccc1Br
Reactant: CC(C)(C)OC(=O)NC(CCCCNS(=O)(=O)c1c(Cl)ccc(N)c1O)C(=O)O
Agent: NC(N)=O
Product: CC(C)(C)OC(=O)NC(CCCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Br)c1O)C(=O)O
Yield: 7.3 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-[5-(tert-butoxycarbonylamino)-5-carboxypentyl]-3-amino-6-chloro-2-hydroxybenzenesulfonamide (189 mg, 0.42 mmol) and 2-bromophenylisocyanate (84 mg, 0.42 mmol) were coupled to form the desired urea (20 mg, 7%). LC-MS (m/z) 651.2 (M+).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]([CH3:14])([CH3:13])[C:11]#N.CC(C[AlH]CC(C)C)C.C(O)(=O)[C@@H]([C@H](C(O)=O)O)[OH:26]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]([CH3:14])([CH3:13])[CH:11]=[O:26]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: COc1cccc(C(C)(C)C#N)c1F
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: COc1cccc(C(C)(C)C=O)c1F
Temperature: -65 °C

Procedure:
4.66 g (24.12 mmol) of 2-(2-fluoro-3-methoxyphenyl)-2-methylpropanenitrile is dissolved in 96 ml of toluene. At −65° C. to −60° C., 30 ml (36.18 mmol) of a 1.2 molar solution of DIBAH in toluene is added in drops. After three and one-half hours of stirring at −65° C., 276 ml of a 10% L(+)-tartaric acid solution is added in drops at this temperature. In this case, the temperature rises to 0° C. The cold bath is removed, and the batch is stirred vigorously at room temperature for one hour. The reaction mixture is extracted three times with 300 ml each of diethyl ether. The combined organic extracts are treated as usual (water, brine, drying). After the solvent is spun off, 4.78 g (slightly above 100%) of the desired compound remains.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.Cl[CH2:13][C:14]1[N:18]([CH2:19][CH2:20][CH3:21])[CH:17]=[N:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH3:21])[CH:17]=[N:16][N:15]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CCCn1cnnc1CCl
Reactant: O=[N+]([O-])c1ccc(S)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1cnnc1CSc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
2-mercapto-5-nitropyridine (5.0 g), 3-chloromethyl-4-propyl-4H-1,2,4-triazole hydrochloride (6.3 g) and potassium carbonate (11 g) was added to N,N-dimethylformamide (100 ml), and the mixture was stirred overnight at room temperature. The solvent was distilled off, and to the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 5-nitro-2-(4-propyl-4H-1,2,4-triazol-3-yl)methylthiopyridine (8.0 g) as brown crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:29][CH3:30])=[C:4]([NH:10][C@H:11]([C@@H:26]([OH:28])[CH3:27])[C:12]([NH:14][NH:15][C:16](=O)[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(NP1(N(CC)CC)N(C)CCCN1C)(C)(C)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:29][CH3:30])=[C:4]([NH:10][C@@H:11]([C:12]2[O:13][C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=3)=[N:15][N:14]=2)[C@H:26]([OH:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@H](C)O)ccc(C#N)c1Cl
Agent: CCN(CC)[PH]1(NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: CCc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@@H](C)O)ccc(C#N)c1Cl
Reaction time: 1 h
Yield: 16.8 %

Procedure:
To a solution of N′-((2R,3S)-2-(3-chloro-4-cyano-2-ethylphenylamino)-3-hydroxybutanoyl)-4-cyanobenzohydrazide (310 mg, 0.73 mmol) in anhydrous THF (20 mL) at room temperature was added 2-tert-butylamino-2-diethylamino-1,3-dimethyl perhydro-1,3,2-diazaphosphorine on polystyrene (2.2 mmol base/g) (1.0 g) followed by p-TSCl (167 mg, 0.88 mmol) and the mixture was stirred for 1 h. The mixture was filtered and the residue washed with acetone (200 mL) followed by MeOH (200 mL). The filtrate was then concentrated and subjected to flash column chromatography [EtOAc-Hexanes (1:12)] to give two fractions. The second-eluted material was the desired product (50 mg, 17%): 1H NMR (500 MHz, acetone-d6, δ in ppm) 8.20 (d, J=8.6 Hz, 2H), 7.99 (d, J=8.6 Hz, 2H), 7.48 (d, J=8.6 Hz, 1H), 6.86 (d, J=8.6 Hz, 1H), 5.99 (d, J=8.7 Hz, 1H), 5.12 (dd, J=4.5 Hz, 8.7 Hz, 1H), 4.71 (d, J=6.4 Hz, 1H), 4.57-4.49 (m, 1H), 2.97-2.82 (m, 2H), 1.41 (d, J=6.4 Hz, 3H), 1.20 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH:6]([C@H:8]([NH:14][CH:15]=[O:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][C@@H:4]([CH3:17])[O:3]1.C(Cl)Cl.C(N(CC)C(C)C)(C)C.[C:30](Cl)(=O)[O:31]C>C(O)C.Cl>[CH3:17][C@@H:4]1[CH2:5][CH:6]([C@H:8]([NH:14][C:15]([O:31][CH3:30])=[O:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][C@@H:2]([CH3:1])[O:3]1
Reactant: CCOC(=O)[C@@H](NC=O)C1C[C@@H](C)O[C@H](C)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)[C@@H](NC(=O)OC)C1C[C@@H](C)O[C@H](C)C1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 69.8 %

Procedure:
In a 1 L flask equipped with a condenser which was stoppered with a septum and vented with a needle, a solution of (S)-ethyl 2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-formamidoacetate (17.6 g, 72.3 mmol) in ethanol (409 mL) and 1.5 N HCl (aq) (409 mL) was heated in a pre-equilibrated oil bath at 52° C. for 7.5 h. The volatile component was removed under vacuum and the residue was azeotroped with EtOH (2×50 mL) and dried under vacuum overnight to afford a white foam. The white foam was dissolved into DCM (409 mL) and N,N-diisopropylethylamine (38.0 mL, 218 mmol) was added dropwise over 10 min followed by methyl chlorocarbonate (8.40 mL, 109 mmol), also added dropwise over 10 min. The reaction mixture was stirred at ambient temperature for 4.5 h and then quenched carefully with 1 N HCl (100 mL). The layers were separated and the organic layer was washed with 1 N HCl (50 mL) and then with an aqueous basic solution (50 mL water+2 mL sat. NaHCO3). The organic layer was dried (MgSO4), filtered, and concentrated. The residue was purified with a Biotage® (300 g SiO2; sample was loaded onto column with a minimal amount of chloroform, and eluted with 30% EtOAc/hexanes) to yield (S)-ethyl 2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-(methoxycarbonyl-amino)acetate (13.8 g) as a viscous yellow oil. 1H-NMR (400 MHz, CDCl3) δ 5.23 (d, J=8.8 Hz, 1H), 4.34-4.15 (m, 4H), 3.81-3.72 (m, 1H), 3.70 (s, 3H), 2.35-2.23 (m, 1H), 1.63-1.51 (m, 2H), 1.34-1.27 (‘m’ & ‘t’ overlapped, J=7.0 Hz, 1H & 3H), 1.25 (d, J=6.8 Hz, 3H), 1.14 (d, J=6.0 Hz, 3H), 1.11-0.99 (m, 1H). LC-MS retention time 2.89 min; m/z 296.23 (M+Na)+. LC data were recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3μ C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min. Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid, and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data were determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:26]=[CH:25][C:16]4[C:17]([C:21]([NH:23][CH3:24])=[O:22])=[C:18]([CH3:20])[O:19][C:15]=4[CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:28][CH2:29][CH2:30][C:31]([O:33]C)=[O:32].C([O-])([O-])=O.[Cs+].[Cs+].CC#N>CN(C=O)C>[CH3:20][C:18]1[O:19][C:15]2[CH:14]=[C:13]([O:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([O:1][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:3][CH:4]=4)[N:9]=[CH:8][CH:7]=3)[CH:26]=[CH:25][C:16]=2[C:17]=1[C:21]([NH:23][CH3:24])=[O:22]
Reactant: CNC(=O)c1c(C)oc2cc(Oc3ccnc4cc(O)ccc34)ccc12
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CNC(=O)c1c(C)oc2cc(Oc3ccnc4cc(OCCCC(=O)O)ccc34)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 6-[(7-hydroxyquinolin-4-yl)oxy]-N,2-dimethyl-1-benzofuran-3-carboxamide 119-A (200 mg, 0.57 mmol), methyl 4-bromobutanoate (155 mg, 0.85 mmol), and Cs2CO3 (433 mg, 1.14 mmol) in a mixed solvent of CH3CN (4 mL)/DMF (1 mL) was heated to 65° C. overnight. The reaction mixture was extracted with EtOAc, concentrated and dissolved in 5 mL of MeOH. To the solution was added 1N NaOH (1 mL). The solution was stirred at room temperature for 2 hours and then heated to 60° C. for 2 hours. The solution was acidified with AcOH to a pH of about 6 and extracted with EtOAc. The concentrated residue was purified by HPLC using 20-60% CH3CN/H2O over 30 min. to give 4-{[4-({2-methyl-3-[(methylamino)carbonyl]-1-benzofuran-6-yl}oxy)quinolin-7-yl]oxy}butanoic acid 119.
Reaction SMILES: [O:1]=[C:2]([CH2:49][CH2:50][CH2:51][C:52](=[O:72])[NH:53][C:54]1[CH:55]=[N:56][C:57]([C:60]2[N:61]=[N:62][C:63]([C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][N:67]=3)=[N:64][N:65]=2)=[CH:58][CH:59]=1)[NH:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][C:42]([O:44]C(C)(C)C)=[O:43].C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]=[C:2]([CH2:49][CH2:50][CH2:51][C:52](=[O:72])[NH:53][C:54]1[CH:55]=[N:56][C:57]([C:60]2[N:61]=[N:62][C:63]([C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][N:67]=3)=[N:64][N:65]=2)=[CH:58][CH:59]=1)[NH:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43]
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCNC(=O)CCCC(=O)Nc1ccc(-c2nnc(-c3ccccn3)nn2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCNC(=O)CCCC(=O)Nc1ccc(-c2nnc(-c3ccccn3)nn2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3 (160 mg, 0.157 mmol) in anhydrous DCM (2 mL) under nitrogen atmosphere was added TFA (2 mL). The reaction mixture was stirred for 2 hours at room temperature and evaporated to dryness. The residue was redissolved in dry DCM (2 ml) and again treated with TFA (2 mL) for 2 hours. This process was repeated once more. Finally, the reaction mixture was evaporated to dryness and co-evaporated twice with DCM furnishing the deprotected product 4 in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][C:7](=O)[C:5]=2[CH:6]=1.C([SiH](CC)CC)C.O>ClCCl>[Cl:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[CH:6]=1
Reactant: O=C1CCCc2sc(Cl)cc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O
Product: Clc1cc2c(s1)CCCC2
Temperature: 25 °C
Reaction time: 84 h

Procedure:
111 g (594 mmol) of 2-chloro-6,7-dihydro-1-benzothiophen-4(5H)-one together with 414 g (3.57 mol) of triethylsilane are initially charged in 1.25 ml of dichloromethane, and 506 g (3.57 mol) of boron trifluoride/ether complex are added at room temperature. The reaction mixture is stirred at room temperature for 84 h and then added to water. The organic phase is dried over sodium sulphate and concentrated under reduced pressure. This gives 90.0 g of 2-chloro-4,5,6,7-tetrahydro-1-benzothiophene.
Reaction SMILES: [OH:1][CH:2]([C:12]1[CH:13]=[C:14]([C:18]#[C:19][CH2:20][CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:15]=[CH:16][CH:17]=1)[CH2:3][CH2:4][NH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8]>CCO>[OH:1][CH:2]([C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:15]=[CH:16][CH:17]=1)[CH2:3][CH2:4][NH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8]
Reactant: CN(C)C(=O)CCC#Cc1cccc(C(O)CCNC(=O)C(F)(F)F)c1
Solvent: CCO
Product: CN(C)C(=O)CCCCc1cccc(C(O)CCNC(=O)C(F)(F)F)c1

Procedure:
Reduction reaction of 5-(3-(1-hydroxy-3-(2,2,2-trifluoro acetamido) propyl)phenyl)-N,N-dimethylpent-4-ynamide in EtOH gave 5-(3-(1-hydroxy-3-(2,2,2-trifluoroacetamido)propyl)phenyl)-N,N-dimethylpentanamide as yellow oil. Yield (0.63 g, 99%): 1H NMR (400 MHz, CDCl3) δ 7.62 (bs, 1H), 7.24-7.28 (m, 1H), 7.19 (s, 1H), 7.12 (m, 2H), 4.85 (t, J=6.8 Hz, 1H), 3.57-3.65 (m, 1H), 3.35-3.44 (m, 1H), 2.99 (s, 3H), 2.92 (s, 3H), 2.65 (t, J=6.8 Hz, 2H), 2.29 (t, J=6.8 Hz, 2H), 1.98-2.03 (m, 2H), 1.62-1.68 (m, 4H).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=1)[C:13]([O:15][CH3:16])=[O:14]>CO.[Pt](=O)=O>[ClH:1].[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[CH2:11][CH:12]([C:13]([O:15][CH3:16])=[O:14])[CH2:17][CH2:18][NH:19]1
Reactant: COC(=O)c1ccnc(-c2ccc(F)cc2F)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1CCNC(c2ccc(F)cc2F)C1
Reaction time: 2 h
Yield: 58.3 %

Procedure:
Methyl 2-(2,4-difluorophenyl)isonicotinate hydrochloride (3.93 g, 13.76 mmol) was dissolved in MeOH (40 mL) and platinum(IV) oxide (0.312 g, 1.38 mmol) added. The resulting mixture was hydrogenated in a Büchi hydrogenator at room temperature and 5 bar for 2 h. The catalyst was filtered off, washed with MeOH and the eluate evaporated leaving methyl 2-(2,4-difluorophenyl)piperidine-4-carboxylate hydrochloride (2.34 g, 58%) as a slightly yellow solid. MS m/z 256 (M+H)+
Reaction SMILES: [CH2:1]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([NH:60]C(=O)OCC)[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C1(C)C=CC=CC=1.C(O)C.[OH-].[Na+]>C(OCC)(=O)C.CCCCCC.O>[CH2:1]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH:30]([NH2:60])[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[CH:33][CH:32]=2)=[CH:28][CH:29]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(NC(=O)OCC)c2ccc(OCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(N)c2ccc(OCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Temperature: 100 °C
Yield: 98 %

Procedure:
To crude crystals (31.9 g) of ethyl di(4-docosoxyphenyl)methylcarbamate were added toluene (300 mL), ethanol (200 mL), and sodium hydroxide (4.2 g, 105 mmol), and the mixture was refluxed under stirring at 100° C. Sodium hydroxide (total 9.8 g, 245 mmol) was added, and the mixture was stirred for 16 hours. The reaction mixture was cooled to room temperature, and water (300 mL), hexane (200 mL) and ethyl acetate (200 mL) were added for partitioning. The aqueous layer was discarded, and the organic layer and precipitated crystals were washed with water (300 mL×2). The organic layer and crystals were recovered. The solvent was evaporated under reduced pressure. To the residue were added water (150 mL) and acetonitrile (150 mL) to allow crystallization. The crystals were collected by filtration and thoroughly washed with water and acetonitrile to give di(4-docosoxyphenyl)methylamine (28.1 g, 33.7 mmol, 98% vs —OH).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[CH:20]([Sn](CCCC)(CCCC)CCCC)=[CH2:21].[F-].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([CH:20]=[CH2:21])=[C:3]([CH3:19])[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=Cc1c(C)c(-c2ccccn2)nc2cc(F)ccc12

Procedure:
A solution of 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (2.67 g, 9.79 mmol), bis(tri-tert-butylphosphine)palladium (0) (0.600 g, 1.175 mmol), vinyl tributyl tin (3.26 mL, 10.28 mmol), cesium fluoride (1.49 g, 9.79 mmol), and dioxane (20 mL) was stirred at 105° C. under nitrogen for 30 minutes, then concd. The resulting residue was partitioned between EtOAc and water, and the organic phase was dried over magnesium sulfate and concd. This afforded a crude material that was purified by column chromatography (silica; 0-60% EtOAc in hexanes) to yield 7-fluoro-3-methyl-2-(pyridin-2-yl)-4-vinylquinoline as a white amorphous solid. Mass Spectrum (ESI) m/e=265.2 (M+1).