Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=O.[Cl:11][C:12]1[CH:13]=[C:14]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=[O:25].[Na+].[Na+].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([N:18]2[CH2:23][CH2:22][N:21]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:9][CH2:8][C:7](=[O:25])[CH2:6]3)[CH2:20][CH2:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: O=C1CCCN1CCCCl
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=C1CCN(CCCN2CCN(c3cccc(Cl)c3)CC2)C1
Temperature: 150 °C
Reaction time: 14 h

Procedure:
A mixture of 1-chloro-3-[2-oxopyrrolidin-1-yl]propane (1 g, 6.2 mmcl), 1-(3-chlorophenyl)piperazine (1.22 g, 6.2 minol) anhydrous Na2CO3 (0.33 g, 3.1 mmol) and Nal (0.093 g, 0.6 mmcl) in dry xylene (15 ml) was stirred at 150° C. for 14 hours. The solvent was removed at reduced pressure and residue was poured on water (30 ml). The separated residue was extracted with dichloromethane (2×25 ml), dried over Na2SO4 and concentrated to give 1-[4-(3-chlorophenyl)piperazin-1-yl]-3-[3-oxopyrrolidin-1-yl]propane as an oil which was purified by flash column chromatography over silica gel using chloroform as fluent, yield 0.72 g (36%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([S:8](O)(=[O:10])=[O:9])[CH:7]=1.O=S(Cl)[Cl:17]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([S:8]([Cl:17])(=[O:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1S(=O)(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(F)cc1S(=O)(=O)Cl

Procedure:
In a similar fashion using route 39 general procedure 96, 5-fluoro-2-nitro-benzenesulfonic acid 450 (0.6 g, 2.71 mmol), SOCl2 (3.1 ml) and DMF (0.06 ml) at 90° C. for 3 h gave the title compound (3.4 g) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: C([O:9][C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[O:17][CH3:18])(=O)C1C=CC=CC=1.[OH-].[Na+]>O.C(O)C>[Br:16][C:14]1[CH:13]=[CH:12][C:11]([O:17][CH3:18])=[C:10]([OH:9])[CH:15]=1
Reactant: COc1ccc(Br)cc1OC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(Br)cc1O
Yield: 98.3 %

Procedure:
A solution of 2-benzoyloxy-4-bromoanisole (5 g) and sodium hydroxide (3 g) in water (5 mL) and ethanol (50 mL) is heated at reflux for 1 hour 30 minutes. It is then evaporated and the residue is triturated with water (20 mL) and concentrated hydrochloric acid (10 mL) and extracted with dichloromethane (150 mL). The organic solution is washed with saturated aqueous sodium bicarbonate solution (3×25 mL), dried, and concentrated, to give 5-bromo-2-methoxyphenol (3.25 g), in the form of a white crystalline solid, m.p. 67°-68° C.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](Cl)=[O:14])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.[C:33]([CH:38]([CH:40]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[OH:41])[OH:39])([O:35][CH2:36][CH3:37])=[O:34]>CCOCC>[CH:18]1([CH2:17][CH2:16][NH:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:41][CH:40]([CH:38]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[OH:39])[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:14])=[CH:8][CH:7]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)C(O)C(O)C(=O)OCC
Reactant: O=C(Cl)Cc1ccc(N(CCC2CCCCC2)C(=O)C(F)(F)F)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C(O)C(OC(=O)Cc1ccc(NCCC2CCCCC2)cc1)C(=O)OCC

Procedure:
A mixture of 4-[N-trifluoroacetyl-(2-cyclohexylethylamino)]phenylacetyl chloride and 1.2 g. triethylamine in 100 ml. warm ether is treated with 2.5 g. diethyl tartrate and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields diethyl O-[4-(2-cyclohexylethylamino)phenylacetyl]tartrate as a white, crystalline solid.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[C:19]([O:24][CH3:25])(=[O:23])[CH:20]([CH3:22])[CH3:21].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]=[O:33]>C1COCC1>[OH:33][CH:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=1)[C:20]([CH3:22])([CH3:21])[C:19]([O:24][CH3:25])=[O:23]
Reactant: O=Cc1ccccn1
Reactant: COC(=O)C(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)C(O)c1ccccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 48.8 %

Procedure:
To a solution of diisopropylamine (1.675 mL, 11.75 mmol) in THF (10 mL) was added n-BuLi/hexane (4.70 mL, 11.75 mmol) dropwise at −78° C. The reaction mixture was stirred in the bath for 5 min and then stirred in ice bath for 30 min. The reaction mixture was added dropwise a solution of methyl isobutyrate (1 g, 9.79 mmol) in THF (5 mL) at −78° C. The reaction mixture was stirred at −78° C. for 2 hr. The solution of picolinaldehyde (1.258 g, 11.75 mmol) in THF (2 mL) was added dropwise at −78° C. Then the solution was allowed to warm to room temperature and stirred for 1 hr. The reaction was quenched with NH4Cl, then diluted with EtOAc. Then organic phase was washed with sat. NaHCO3, water, sat. NaCl, dried over anhydrous Na2SO4, and concentrated to yield an oil. The crude was purified by silica chromatography with 0-100% EtOAc/Hex to yield methyl 3-hydroxy-2,2-dimethyl-3-(pyridin-2-yl)propanoate (1.0 g) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) ppm 8.61-8.44 (m, 1H), 7.66 (td, J=7.7, 1.8 Hz, 1H), 7.26-7.12 (m, 2H), 4.96 (d, J=7.5 Hz, 1H), 4.67 (d, J=7.5 Hz, 1H), 3.74 (s, 3H), 1.18 (s, 3H), 1.10 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])C#N)=[CH:4][CH:3]=1.[C:12]1([CH2:18][CH2:19][CH2:20]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][N:29](C)C=O>C(OCC)C>[C:12]1([CH2:18][CH2:19][CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:11][C:28]#[N:29])=[CH:6][CH:7]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)C=O
Reactant: CC(C#N)c1ccc(O)cc1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: N#CCCc1ccc(OCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-hydroxyphenylpropanenitrile (5.25 g) in N,N-dimethyl formamide (40 mL), 3-phenylpropyl bromide (7.1 g) and potassium carbonate (14.79 g) were added, followed by stirring at room temperature for 16 hours. Then, the reaction mixture was diluted with diethyl ether and an organic layer was successively washed with water and brine. After the organic layer was dried, the solvent was concentrated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the title compound (8.54 g) having the following physical properties.
Reaction SMILES: [CH2:1]([N:6]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][C:8]([C:17]([O:19]CC)=[O:18])=[N:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].O.[OH-].[Li+].Cl>O1CCCC1.C(OCC)C>[CH2:1]([N:6]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][C:8]([C:17]([OH:19])=[O:18])=[N:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN1N=C(C(=O)OCC)CC1c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCN1N=C(C(=O)O)CC1c1ccccc1
Temperature: 70 °C
Yield: 74 %

Procedure:
To a magnetically stirred solution of ethyl 1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylate (Intermediate (V-1) (11.76 g, 38.74 mmol) in tetrahydrofuran (100 ml) and water (100 ml) was added lithium hydroxide (1.86 g, 77.5 mmol) and the resulting mixture was heated at 70° C. for 1 hour. The reaction mixture was allowed to attain room temperature and diethyl ether (200 ml) and concentrated hydrochloric acid (7 ml) were added. The organic layer was separated, washed three times with water and with brine and subsequently dried over Na2SO4, filtered and concentrated in vacuo to give 1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylic acid (Intermediate (VI-1) (7.9 g, 74% yield) as an oil. 1H-NMR (400 MHz, CDCl3) δ 0.84 (t, J=7, 3H), 1.15-1.28 (m, 4H), 1.53-1.65 (m, 2H), 2.92 (dd, J=17 and 13, 1H), 3.02-3.11 (m, 1H), 3.18-3.27 (m, 1H), 3.44 (dd, J=17 and 13, 1H), 4.75 t, J=13, 1H), 7.31-7.41 (m, 5H), 7.42-9.00 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][NH:7][C:6]2=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:34].[C:38]([C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43])#[CH:39]>ClCCCl.C(O)(C)(C)C>[ClH:34].[C:38]([C:40]1[CH:41]=[C:42]([NH:43][C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH:44]=[CH:45][CH:46]=1)#[CH:39]
Reactant: C#Cc1cccc(N)c1
Reactant: ClC(Cl)(Cl)Cl
Reactant: COc1ccc2nc[nH]c(=O)c2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: C#Cc1cccc(Nc2ncnc3ccc(OC)cc23)c1
Product: Cl
Temperature: 60 °C
Reaction time: 21 h
Yield: 73 %

Procedure:
A 25 mM solution of 6-methoxy-3H-quinazolin-4-one in 1,2-dichloroethane was added to polymer-supported triphenylphosphine (from Fluka, about 3 mmol P/g polymer; 2.5 mol equiv) and carbon tetrachloride (100 mole equiv). The reaction mixture was heated, with shaking, at 60° C. for 21 hours, cooled to 22° C., and a 30 mM solution of the 3-ethynylaniline (1.5 mole equiv) in t-butanol was added. The resulting mixture was then heated, with shaking, at 60° C. for 18 hours followed by cooling to 22° C. The polymer was filtered off and washed twice with methanol. The methanol washes were added to the filtrate and the solution was concentrated in vacuo to afford the title product (73%; LC-MS: 276 (MH+); anal. RP18-HPLC RT: 5.82 min). For these cases the analytical RP18-HPLC system consisted of a Waters 717 (trademark) autosampler, Waters 996 Photodiode Array Detector (trademark), and Waters 600 quarternary solvent delivery system, and was controlled by Millennium (trademark) software. The aliquots of samples were chromatographed using a linear gradient of 0% to 100% acetonitrile/0.2M ammonium acetate buffer (pH 4.5) over ten minutes at a flow rate of 3 ml/min. using a Perkin-Elmer Pecosphere (trademark) (3 mm×3 cm) C18 column.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH3:22])([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[N:27][C:26]=1[CH2:35][CH2:36]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:22][C:5]([O:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:36][CH2:35][C:26]2[N:27]=[C:28]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[O:29][C:25]=2[CH3:24])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C)cc1
Product: Cc1ccc(OC(C)(Cc2ccc(OCCc3nc(-c4cccs4)oc3C)cc2)C(=O)O)cc1

Procedure:
The representative procedure (B) was utilized to prepare the title compound from 3-(4-hydroxyphenyl)-2-methyl-2-p-tolyloxypropionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3) δ 10.0 (bs, 1H), 7.59 (dd, 1H, J=3.8, 1.2 Hz), 7.36 (dd, 1H, J=5.0, 1.2 Hz), 7.19 (d, 2H, J=8.4 Hz), 7.05 (dd, 1H, J=5.0, 3.8 Hz), 7.02 (d, 2H, J=8.0 Hz), 6.83-6.80 (m, 4H), 4.17 (t, 2H, J=6.4 Hz), 3.29 and 3.14 (d of Abq, 2H, J=13.8 Hz), 2.96 (t, 2H, J=6.4 Hz), 2.35 (s, 3H), 2.27 (s, 3H), 1.38 (s, 3H). IR (KBr) 3420, 1715, 1509, 1225 cm−1. HRMS (ES+) m/z exact mass calcd for C27H28NO5S 478.1688, found 478.1714.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl.C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:13][S:14]([O:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1)(=[O:16])=[O:15]
Reactant: COC(=O)c1cccc(CO)n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc(COS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 110.5 %

Procedure:
To a solution of methyl 6-(hydroxymethyl)picolinate (2.6 g, 15.5 mmol) in CH2Cl2 (15 mL) were added methanesulfonyl chloride (1.81 mL, 23.3 mmol) and TEA (5.42 mL, 38.9 mmol) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and diluted with CHCl3 and saturated aqueous NaHCO3 solution. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated to give the desired compound (4.2 g, 85%) as a brown oil. 1H NMR (CDCl3) δ 8.15 (d, J=8.0 Hz, 1H), 7.96 (t, J=8.0 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 5.46 (s, 2H), 4.04 (s, 3H), 3.20 (s, 3H). MS (ESI): 246.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:11](=[S:12](=[O:14])=[O:13])[C:10]([O:15][CH3:16])=[C:9]([CH3:17])[CH:8]=[C:4]1[C:5]([OH:7])=O.CC(C)=O.ClC(OCC)=O.[CH:28]1([N:36]2[CH2:40][CH2:39][CH2:38][CH:37]2[CH2:41][NH2:42])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(N(CC)CC)C.O>[CH:28]1([N:36]2[CH2:40][CH2:39][CH2:38][CH:37]2[CH2:41][NH:42][C:5](=[O:7])[C:4]2[CH:3]([O:2][CH3:1])[C:11](=[S:12](=[O:14])=[O:13])[C:10]([O:15][CH3:16])=[C:9]([CH3:17])[CH:8]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: NCC1CCCN1C1CCCCCCC1
Reactant: COC1=C(C)C=C(C(=O)O)C(OC)C1=S(=O)=O
Agent: CCOC(=O)Cl
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC1=C(C)C=C(C(=O)NCC2CCCN2C2CCCCCCC2)C(OC)C1=S(=O)=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
13 g of 2,4-dimethoxy-5-methyl sulphonyl benzoic acid, 150 ml of acetone, 28 ml of water and 7 ml of triethylamine (density 0.726) are placed in a 250 ml flask fitted with an agitator, a thermometer, a condenser and a dropping funnel. The suspension is cooled to from 0° to +5° C., then 5.4 g of ethyl chloroformate is added drop by drop. The mixture is agitated for 45 minutes at room temperature and cooled to about 0° C., then 13.8 g of 1-cyclooctyl-2-aminomethyl-pyrrolidine is added drop by drop. There is complete solubilisation. The reaction medium is agitated at room temperature then left to stand. The solvents are evaporated under vacuum and the residue is dissolved in 100 ml of water and 20 ml of hydrochloric acid (density 1.18). The organic phase is extracted 3 times with 50 ml of methylene chloride, dried over magnesium sulphate, filtered and evaporated to dryness under vacuum. The residue is dissolved in 100 ml of water. The solution is filtered in the presence of carbon black and the filtrate made alkaline with 10 ml of ammonia. A gum is precipitated. This is extracted 3 times with 50 ml of methylene chloride, and the organic solution is washed twice with 50 ml of water and dried over magnesium sulphate. It is filtered, then the solvent is evaporated under vacuum and the residue re-crystallised in 200 ml of isopropanol. The crystals are filtered off, washed twice with a little iced isopropanol and dried in an oven at 50° C.
Reaction SMILES: [C:1]([C:3](=[C:8](SC)[S:9][CH3:10])[C:4]([O:6][CH3:7])=[O:5])#[N:2].[CH3:13][C:14]([CH3:19])([CH3:18])[C:15]([NH2:17])=[O:16].[H-].[Na+].Cl>CC(N(C)C)=O>[C:1]([C:3](=[C:8]([NH:17][C:15](=[O:16])[C:14]([CH3:19])([CH3:18])[CH3:13])[S:9][CH3:10])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: COC(=O)C(C#N)=C(SC)SC
Reactant: CC(C)(C)C(N)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC(=O)C(C#N)=C(NC(=O)C(C)(C)C)SC
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
Methyl 2-cyano-3,3-bis(methylsulfanyl)prop-2-enoate (4.06 g) and 2,2-dimethylpropanamide (2.02 g) were dissolved in DMA (200 ml), and sodium hydride (1.92 g) was added under ice-cooling. The mixture was stirred at room temperature overnight, and poured into ice. The mixture was acidified with 1 N aqueous hydrochloric acid solution. The precipitated crystals were collected by filtration, and dried to give the object compound (2.4 g).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C:6](=[O:8])[CH:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][C@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23].CN1C(=O)N(C)CCC1.C(O[Li])(C)(C)C.[C:39]([CH2:43]OS(C(F)(F)F)(=O)=O)([F:42])([F:41])[F:40]>C1COCC1>[CH3:1][C@H:2]1[N:7]([CH2:43][C:39]([F:42])([F:41])[F:40])[C:6](=[O:8])[CH:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:13])[CH3:14])[CH2:4][C@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]
Reactant: Cc1ccccc1[C@@H]1CC(NC(=O)OC(C)(C)C)C(=O)N[C@@H]1C
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [Li]OC(C)(C)C
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: Cc1ccccc1[C@@H]1CC(NC(=O)OC(C)(C)C)C(=O)N(CC(F)(F)F)[C@@H]1C
Temperature: 22.5 °C
Reaction time: 24 h
Yield: 76.1 %

Procedure:
To a solution of 37 (50 g, 0.164 mol) and DMPU (25 g, 0.2 mol) in THF (500 mL) was added tert-BuOLi (16.5 g, 0.2 mol) in portions at 20° C. for 0.5 h. After the mixture was degassed for 30 min at 20° C., CF3CH2OTf (45.8 g, 0.2 mol) was added at 20-25° C. The reaction was stirred for 24 h at 20-25° C. After the reaction was complete, the mixture was quenched by water, and then partitioned with water and EtOAc. The organic solution was dried over Na2SO4 and concentrated. The crude residual was further purified by flash chromatography on silica gel (2-10% EtOAc/PE) to give product 38 (50 g, 78% yield). 1H NMR (DMSO-d6, 400 MHz): δ 7.18-7.13 (m, 4H), 4.17 (m, 1H), 4.11 (br, 1H), 3.67 (m, 3H), 2.66 (s, 1H), 2.33 (d, 3H), 1.83 (t, 1H), 1.41 (s, 9H), 0.96 (d, 3H); MS (ESI) m/e [M+H]+ 405.17.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CCCCCC.CN(C=O)C>[C:8]([N:3]1[CH:7]=[N:6][CH:5]=[N:4]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1nc[nH]n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2cncn2)cc1
Reaction time: 0.5 h
Yield: 47 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 13.8 g, 345 mmol) was washed with hexane and suspended in DMF (150 ml). At an ice bath temperature, 1,2,4-triazole (total; 20.7 g, 300 mmol) was added thereto in four divisions. After stirring for 30 minutes, to the mixture was added tritylchloride (total; 83.7 g, 300 mmol) in seven divisions and additionally added DMF (50 ml). After stirring for 1.5 hours at room temperature, to the reaction mixture was added water (600 ml). The precipitated crystal was collected by filteration, washed with water, dissolved in CHCl3 (800 ml) and dried. The solvent was evaporated. The obtained residue was chromatographed on silica gel (ethylacetate:CHCl3=1:2, v/v). The fraction of the objective was concentrated to give 1-trityl-1H-1,2,4-triazole (43.9 g). Yield: 47%.
Reaction SMILES: C([Mg]Br)C.[CH2:5]([OH:8])[C:6]#[CH:7].[Cl:9][CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:11]=[O:12].P(O)(O)([O-])=O.[Na+]>O1CCCC1>[Cl:9][CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:11]([OH:12])[C:7]#[C:6][CH2:5][OH:8]
Reactant: CCCCCC(Cl)C=O
Reactant: C#CCO
Agent: CC[Mg]Br
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCC(Cl)C(O)C#CCO
Reaction time: 2 h
Yield: 50.5 %

Procedure:
460 ml of a solution of ethyl magnesium bromide in tetrahydrofuran titrating 0.71 moles per liter were added dropwise to a solution of 9 g of propargyl alcohol in 100 ml of tetrahydrofuran and after stirring the mixture for 11/2 hours, a solution of 35.6 g of α-chloro-heptanal in 100 ml of tetrahydrofuran was added thereto. The mixture was stirred for one hour and was then poured into a saturated aqueous monosodium phosphate solution. The mixture was extracted with ether and the organic phase was washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure at 100°C. The residue was chromatographed over silica gel and was eluted with a 4-1 benzene-ethyl acetate mixture to obtain 16.6 g of 5-chloro-4-hydroxy-2-decynol in the form of a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:22][CH2:23][CH2:24][CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[C:16]([N+:19]([O-])=O)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C.[OH-].[Na+]>O.C(O)C.[Fe]>[NH2:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1)[N:12]=[CH:11][N:10]=[C:9]2[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CN1CCC(CCCOc2cc3ncnc(Nc4cccc(Br)c4)c3cc2[N+](=O)[O-])CC1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CN1CCC(CCCOc2cc3ncnc(Nc4cccc(Br)c4)c3cc2N)CC1

Procedure:
1.00 g of 4-[(3-bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]-6-nitroquinazoline is dissolved in 16 ml of water, 35 ml of ethanol and 1.3 ml of glacial acetic acid and heated to boiling. Then 540 mg of iron powder are added with stirring. The reaction mixture is refluxed for about another 35 minutes. For working up the cooled reaction mixture is diluted with 15 ml of ethanol, made alkaline with 15 N sodium hydroxide solution, combined with 20 g of Extrelute and stirred for about 20 minutes. The precipitate formed is suction filtered and washed with 200 ml of warm ethanol. The filtrate is concentrated by evaporation, mixed with about 30 ml of water and extracted 3× with 70 ml of methylene chloride/methanol (9:1) each time. The combined extracts are dried over sodium sulfate and concentrated by evaporation, leaving a beige solid. Yield: 716 mg (76% of theory); melting point: 191° C.–198° C.; mass spectrum (ESI+): m/z=470, 472 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21]Br)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C)C=O.O.C(OCC)(=O)C>[N:33]([CH2:21][C@@H:20]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:19])[NH:17]2)[O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[N+:34]=[N-:35]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 25 °C
Yield: 88.3 %

Procedure:
(R)-8-(Benzyloxy)-5-(2-bromo-1-((tert-butyldimethylsilyl)oxy)ethyl)quinolin-2(1H)-one (10.0 g, 20.5 mmol) was dissolved in dimethyl formamide (180 mL) and water (20 mL). Sodium iodide (3.39 g, 22.6 mmol) and sodium azide (1.47 g, 22.6 mmol) were added sequentially. The reaction mixture was stirred at RT until all the solid was in solution. The solution was heated at 80° C. for 40 hours then cooled to RT and diluted with ethyl acetate (300 mL). The mixture was washed with water, brine (×2) and the organic extract was dried (magnesium sulfate), filtered and concentrated under reduced pressure. The crude residue was triturated with iso-hexane to afford the desired compound (8.16 g, 88%). Used without further purification in the next step.