Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[O:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([CH:30]=2)[C:26]([NH:28][NH2:29])=[O:27])(=[O:20])=[O:19])[CH2:14][CH2:13]1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](/[C:8](=[N:29]/[NH:28][C:26](=[O:27])[C:25]2[CH:30]=[C:21]([S:18]([N:15]3[CH2:14][CH2:13][O:12][CH2:17][CH2:16]3)(=[O:20])=[O:19])[CH:22]=[N:23][CH:24]=2)/[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: NNC(=O)c1cncc(S(=O)(=O)N2CCOCC2)c1
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cncc(S(=O)(=O)N2CCOCC2)c1)c1cc(Cl)ccc1O
Temperature: 70 °C
Yield: 65.7 %

Procedure:
1-(5-chloro-2-hydroxyphenyl)ethanone (6.55 mg, 0.038 mmol) and 5-(morpholinosulfonyl)nicotinohydrazide (10 mg, 0.035 mmol) was dissolved in Methanol (3 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was refluxed for 12 h at 70° C. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the title compound (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-5-(morpholinosulfonyl)nicotinohydrazide (10 mg, 0.023 mmol, 65.2% yield) as a solid. 1HNMR (400 MHz, DMSO-d6): δ 11.82 (bs, 1H), 9.35 (s, 1H), 9.08 (s, 1H), 8.52 (s, 1H), 7.66 (s, 1H), 7.34 (d, 1H, J=8.4 Hz), 6.94 (d, 1H, J=8.8 Hz), 3.63 (m, 4H), 2.99 (m, 4H), 2.50 (s, 3H). ESI-MS: 439.1 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:45]=[CH:44][C:5]([CH2:6][N:7]([CH:27]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)[CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[C:8](=[O:26])[C@@H:9]([NH:17][C:18](=O)N(C)C(C)(C)C)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH:27]([CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=2)[CH2:36][CH2:37][C:38]2[CH:39]=[CH:40][N:41]=[CH:42][CH:43]=2)[C:8](=[O:26])[C@@H:9]([NH:17][CH3:18])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:44][CH:45]=1
Reactant: CN(C(=O)N[C@@H](Cc1ccccc1)C(=O)N(Cc1ccc(F)cc1)C(CCc1ccncc1)CCc1ccncc1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H](Cc1ccccc1)C(=O)N(Cc1ccc(F)cc1)C(CCc1ccncc1)CCc1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Compound 4 was dissolved in methylene chloride (10 mL) and treated with trifluoroacetic acid (4.0 mL). After stirring at room temperature for 1.5 h, the reaction was concentrated in vacuo. The residue was neutralized with saturated potassium carbonate and extracted with ethyl acetate (2×). The extracts were combined, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to provide Compound 5.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[C:4]([CH3:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.C([Li:15])CCC>CCCCCC>[CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][Li:15]
Reactant: Cc1ccccc1N(C)C
Reactant: [Li]CCCC
Solvent: CCCCCC
Product: [Li]Cc1ccccc1N(C)C
Reaction time: 48 h
Yield: 100 %

Procedure:
A mixture of 96.0 g of N,N-dimethyl-o-toluidine and 444 ml of a 1.6 M solution of butyllithium in hexane was stirred for two days. Stirring was stopped and the orange solution was cooled in ice until it became cloudy, whereupon stirring was resumed with continuing cooling. A yellow solid separated. Volatile materials were removed, about 50 ml of ethyl ether was added, and the solution was stirred for another 24 hours. During this time a large amount of solid separated. It was washed from the flask with pentane to give 2-dimethylaminobenzyllithium in 100% yield (mp above 200° C with decomposition). The infrared absorption spectrum of the product was in agreement with its assigned structure.
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=1)C(OCC)=O)C.[OH-].[K+]>C(O)C.O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH:5]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:29][CH:30]=2)[C:4]([OH:37])=[O:3])=[CH:13][CH:14]=1)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)C(Cc1ccc(C(=O)C(C)(C)C)cc1)(Cc1ccc(C(=O)C(C)(C)C)cc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)C(=O)c1ccc(CC(Cc2ccc(C(=O)C(C)(C)C)cc2)C(=O)O)cc1

Procedure:
To a solution of 10g (0.03 mole) of bis-(p-pivaloylbenzyl) malonic acid diethyl ester in 45 ml of ethanol and 45 ml of water, there is added 8.4 g (0.15 mole) potassium hydroxide which is refluxed for 5 hours. The solvents are removed in vacuo and the residue partitioned between ether and water. The aqueous layer is made acidic at 0°C with concentrated hydrochloric acid, extracted with ether, dried and evaporated. The resulting oil is treated with 200 ml of concentrated hydrochloric acid and the mixture is refluxed for 20 hours. The cooled mixture is extracted with ether, the ether extracted with 2N sodium hydroxide and the basic solution is made acidic at 0°C with concentrated hydrochloric acid, extracted with ether, and the ether is then dried and evaporated. The resulting residue is crystallized from ether/petroleum ether to give bis-(p-pivaloylbenzyl) acetic acid, m.p. 107°-109°C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[C:15](=[O:21])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:22]([OH:24])=[O:23])[CH2:3]1.Cl.[CH2:26](O)[CH3:27]>>[CH2:26]([O:23][C:22]([C@H:11]1[CH2:10][CH2:9][C@H:8]2[C@H:7]3[C@H:16]([C:15](=[O:21])[CH2:14][C@:12]12[CH3:13])[C@:17]1([CH3:20])[C@H:4]([CH2:3][C@H:2]([OH:1])[CH2:19][CH2:18]1)[CH2:5][CH2:6]3)=[O:24])[CH3:27]
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=O)[C@@H]12
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
A solution of 3α-hydroxy-11-oxo-5α-androstane-17β-carboxylic acid (500 mg.) in dry ethanol containing 3.3%, by weight, of hydrogen chloride (100 ml.) was refluxed for 2 hours.
Reaction SMILES: [N:1]1([CH:5]2[CH2:10][CH2:9][CH:8]([NH:11]C(=O)OC(C)(C)C)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([CH:5]2[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)NC1CCC(N2CCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCC(N2CCC2)CC1

Procedure:
tert-butyl N-[4-(azetidin-1-yl)cyclohexyl]carbamate (Intermediate 227; 260 mg, 1.01 mmol) was taken up in DCM (3 mL) and TFA (2 mL) and stirred at ambient temperature for 3 hours.
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][O:9][C:10]2[C:11]([CH:18]3[O:22][CH2:21][CH2:20][O:19]3)=[CH:12][C:13]([O:16][CH3:17])=[N:14][CH:15]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:23][N:24](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:19]1[CH2:20][CH2:21][O:22][CH:18]1[C:11]1[CH:12]=[C:13]([O:16][CH3:17])[N:14]=[CH:15][C:10]=1[O:9][CH2:8][C:7]1[C:2]([C:23]#[N:24])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: COc1cc(C2OCCO2)c(OCc2cccnc2Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COc1cc(C2OCCO2)c(OCc2cccnc2C#N)cn1
Temperature: 125 °C
Yield: 84 %

Procedure:
A mixture of 5-((2-bromopyridin-3-yl)methoxy)-4-(1,3-dioxolan-2-yl)-2-methoxypyridine (1.1 g, 3.0 mmol, 1 eq.), Zn (CN)2 (704 mg, 6.0 mmol, 2.0 eq.), and Pd(PPh3)4 (346 mg, 0.3 mmol, 0.2 eq.) in DMF (10 mL) was heated at 125° C. for 2 h under N2. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)picolinonitrile (820 mg, 84%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J=4.6 Hz, 1H), 8.12 (dd, J=8.0, 0.7 Hz, 1H), 7.88 (s, 1H), 7.60 (dd, J=8.0, 4.7 Hz, 1H), 6.95 (s, 1H), 6.16 (s, 1H), 5.37 (s, 2H), 4.18-4.00 (m, 4H), 3.92 (s, 3H). LRMS (M+H+) m/z 314.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]=[CH:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>C(O)C.O=[Pt]=O>[C:1]([O:5][C:6]([NH:8][NH:9][CH2:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC=NNC(=O)OC(C)(C)C
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CC(=O)O
Product: CCNNC(=O)OC(C)(C)C
Yield: 97.5 %

Procedure:
A slurry of N′-ethylidene-hydrazinecarboxylic acid tert-butyl ester (5.0 g, 32 mmol), acetic acid (48 μL) and PtO2 (250 mg) in ethanol (50 mL) was shaken under a 40 psi pressure of H2 in a Parr hydrogenator for 24 h. The mixture was filtered through Celite to provide N′-ethylhydrazinecarboxylic acid tert-butyl ester (5 g) as a clear oil. MS (ESI+) for C7H16N2O2 m/z 161.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].[Cl:16][C:17]1[C:27]([Cl:28])=[CH:26][C:20]2[NH:21][C:22](CCl)=[N:23][C:19]=2[CH:18]=1>CN(C)C=O>[Cl:28][C:27]1[C:17]([Cl:16])=[CH:18][C:19]2[N:23]=[C:22]([CH2:11][O:10][C:8]3[C:7]([O:12][CH3:13])=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[CH:9]=3)[NH:21][C:20]=2[CH:26]=1
Reactant: COc1cc(F)c(C=O)cc1OC
Reactant: ClCc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(F)cc1OCc1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
2-Fluoro-4-hydroxy-5-methoxy-benzaldehyde (38, 0.364 g, 2.14 mmol) was dissolved in N,N-dimethylformamide (10.0 mL) and sodium hydride (60% dispersion in mineral oil, 100 mg, 2.50 mmol) was added. After 20 minutes, 5,6-dichloro-2-chloromethyl-1H-benzoimidazole (208, 0.420 g, 1.78 mmol) was added. The reaction was stirred at 80° C. overnight. The reaction was concentrated, then washed with ethyl acetate and saturated sodium bicarbonate. The organic portions were dried with anhydrous sodium sulfate, filtered and the filtrate was adsorbed onto silica. The mixture was purified by silica gel chromatography, eluting with methanol/dichloromethane, to provide the desired compound, consistent by 1H-NMR (209, 140 mg, 21%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9][C:10]#N)[CH:6]=[CH:5][C:4]=1[OH:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9][CH3:10])[CH:6]=[CH:5][C:4]=1[OH:12]
Reactant: COc1cc(SC#N)ccc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: COc1cc(SC)ccc1O

Procedure:
2-Methoxy-4-thiocyanatophenol (10.2 g) and triphenylphosphine (14.8 g) in dry methanol (150 ml) were heated at reflux under nitrogen for 2 hours. Removal of solvent in vacuo followed by column chromatography on silica gel eluting with diethyl ether/petroleum ether (bp 40°-60°) mixtures (gradient 10 to 50% v/v diethyl ether) gave the phenol as a white solid, m.p. 47°-49°.
Reaction SMILES: [CH3:1][C:2]1([C:10]([OH:12])=[O:11])[NH:6][CH:5]([C:7]([OH:9])=[O:8])[CH2:4][S:3]1.N[CH:14]([C:17](O)=[O:18])CS>>[C:17]([N:6]1[CH:5]([C:7]([OH:9])=[O:8])[CH2:4][S:3][C:2]1([CH3:1])[C:10]([OH:12])=[O:11])(=[O:18])[CH3:14]
Reactant: NC(CS)C(=O)O
Reactant: CC1(C(=O)O)NC(C(=O)O)CS1
Product: CC(=O)N1C(C(=O)O)CSC1(C)C(=O)O
Yield: 44 %

Procedure:
By an operation similar to that in Synthetic Example 16 and using 2-methylthiazolidine-2,4-dicarboxylic acid synthesized from DL-cysteine by a method similar to that in Reference Example 1, N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid (cis form) was obtained as an amorphous substance (yield 44%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][CH2:10][OH:11])=[CH:6][CH:5]=1)([O-])=O.O.NN>C1COCC1.CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][CH2:10][OH:11])=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(C=CCO)cc1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Nc1ccc(C=CCO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a solution of 1.5 g (8.37 mmol) of 4-nitrocinnamyl alcohol in THF/methanol (60 mL, 1:1 v/v) was added a catalytic amount of Raney Nickel and hydrazine monohydrate (1.22 mL, 25.1 mmol). The mixture was stirred at room temperature for 3 h, additional hydrazine monohydrate (1.22 mL) being added after 1.5 h. The reaction mixture was filtered over HFLO and concentrated under reduced pressure to 5 mL. Dichloromethane (100 mL) was added and the resultant solution was washed with water, dried over Na2SO4, filtered, and concentrated, which gave 10 (1.24 g, 8.31 mmol, 99%).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=CC(O)=C[CH:5]=1.N[C@H](C(O)=O)CCCCN.N[C@H](C(O)=O)CCCNC(=N)N>>[NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][CH:4]([CH3:9])[CH3:5]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Agent: NCCCC[C@H](N)C(=O)O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
Tyr 0.90 (1); Lys 0.17 (1); Arg 0.96 (1)
Reaction SMILES: C([O:5][C:6]([C:8]1([CH3:29])[N:12]2[C:13](=[O:28])[C:14]([NH:17][C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[CH:15][N:16]=[C:11]2[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>O>[CH2:21]([O:20][C:18]([NH:17][C:14]1[C:13](=[O:28])[N:12]2[C:8]([CH3:29])([C:6]([OH:7])=[O:5])[CH2:9][CH2:10][C:11]2=[N:16][CH:15]=1)=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)C1(C)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC1(C(=O)O)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Yield: 105.5 %

Procedure:
A solution of intermediate 19a (55 mg, 0.138 mmol) in 4 mL 1:1 TFA/CH2Cl2 with 2 drops water was stirred at rt for 12 h. The mixture was concentrated in vacuo, then coevaporated with CCl4 to afford 50 mg of intermediate 19b (quantitative), which was used without further purification in the following step.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([OH:14])=O)[C:6]=2[O:5][CH2:4][C:3]1=[O:15].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[C:19]([Cl:25])[CH:18]=1>[Zn].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>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:12]([C:11]2[C:6]3[O:5][CH2:4][C:3](=[O:15])[N:2]([CH3:1])[C:7]=3[CH:8]=[CH:9][CH:10]=2)=[O:14])=[C:19]([Cl:25])[CH:18]=1
Reactant: CN1C(=O)COc2c(C(=O)O)cccc21
Reactant: Clc1cc(Br)ccc1CBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Zn]
Product: CN1C(=O)COc2c(C(=O)Cc3ccc(Br)cc3Cl)cccc21

Procedure:
In analogy to Example 49, step 1, 4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxylic acid (CAS Reg. No. 1017273-27-6) was converted to the acid chloride and subsequently reacted with 4-bromo-1-bromomethyl-2-chloro-benzene in the presence of zinc and tetrakis(triphenylphosphine)palladium(0) to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=392.1 [M−H+].
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15]C)[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([CH2:23][C:24]#[N:25])[CH:20]=[CH:21][CH:22]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([CH2:23][C:24]#[N:25])[CH:20]=[CH:21][CH:22]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1nccc2c1c(-c1cccc(CC#N)c1)nn2C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#CCc1cccc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
To a solution of (3-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)acetonitrile (120 mg) in acetonitrile (10 mL) were added sodium iodide (108 mg) and chloro(trimethyl)silane (0.366 mL), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate to give the title compound (105 mg).
Reaction SMILES: [Na].Br[CH:3]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH:24]=1)[C:4]([O:6][CH2:7]C)=[O:5].[C:25](O)(=[O:27])C>CO.O>[CH3:25][O:27][CH:3]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH:24]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCOC(=O)C(Br)c1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Reactant: CC(=O)O
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=O)C(OC)c1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Temperature: 25 °C
Reaction time: 68 h

Procedure:
Sodium (0.23 g.) was dissolved in dry methanol (60 ml.) and this solution added to ethyl 2-bromo-2-(p-chlorophenyl-5-benzoxazolyl)acetate (2.8 g.). The resulting solution was stirred for 68 hours at room temperature and then evaporated at 20° C. in vacuo to leave a residual oil. The oil was stirred in water (50 ml.) and the pH adjusted to 4 by the addition of glacial acetic acid. The resulting suspension was extracted with ether (3 × 75 ml.). The extracts were combined and washed with saturated sodium bisulphite solution (3 × 25 ml.). After drying (Na2SO4), the ether solution was evaporated to leave a gummy solid (2.15 g.). 1 Gram was purified by chromatography to yield a waxy solid (0.4 g.), which was subsequently recrystallised from carbon tetrachloride and 40°-60° petroleum ether. The resulting solid was the required product, m.p. 100°-105° C.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[NH:15][C@H:16]([C:18]([OH:20])=[O:19])[CH3:17])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:25]O>>[CH3:25][O:19][C:18](=[O:20])[C@H:16]([CH3:17])[NH:15][C:13]1[C:12]2[C:7]([CH:6]=[C:5]3[C:14]=1[CH:1]=[CH:2][CH:3]=[CH:4]3)=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: CO
Reactant: C[C@H](Nc1c2ccccc2cc2ccccc12)C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H](C)Nc1c2ccccc2cc2ccccc12
Temperature: 0 °C
Yield: 68 %

Procedure:
0.7 g of 9-anthryl alanine was mixed with 20 ml of anhydrous methanol, cooled to 0° C. 1.5 eq of thionyl chloride was added drop-wise, refluxing overnight. The solvent was removed on a rotary evaporator. The crude product was dissolved in ethyl acetate. The organic phase was washed by 5% of sodium bicarbonate, distilled water, and dried by anhydrous sodium carbonate. The solvent was removed on a rotary evaporator. The product was purified by column chromatography (hexane: ethyl acetate=1:2.5). 0.5 g of oil-like yellow solid was obtained. The yield was 68%. The product decomposes at 180° C.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH2:8][CH:9]([OH:11])[CH3:10])[N:6]=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.P(Br)(Br)([Br:17])=O>C(Cl)(Cl)Cl>[Br:17][CH2:2][C:3]1[N:7]([CH2:8][CH:9]([OH:11])[CH3:10])[N:6]=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: CC(O)Cn1nc([N+](=O)[O-])cc1CO
Reactant: O=P(Br)(Br)Br
Solvent: ClC(Cl)Cl
Product: CC(O)Cn1nc([N+](=O)[O-])cc1CBr
Temperature: 0 °C
Reaction time: 3 h
Yield: 62.5 %

Procedure:
To a mixture of 250a (4.0 g, 20.0 mmol) in chloroform (100 mL) cooled at 0° C. was added the solution of POBr3 (22.9 g, 80 mmol) in chloroform (20 mL) over 30 minutes while maintaining the internal temperature below 5° C. The reaction mixture was warmed to 50° C. and stirred at this temperature for 3 h. It was then cooled to 0° C. and quenched with water. The organic layer was separated and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 250b (3.3 g, 62%) as yellow solid. MS-ESI: [M+H]+ 264.1
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.[F:16][C:17]([F:23])([CH:20]([F:22])[F:21])[CH2:18][OH:19]>CC(N(C)C)=O>[F:16][C:17]([F:23])([CH:20]([F:22])[F:21])[CH2:18][O:19][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1
Reactant: OCC(F)(F)C(F)F
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=Cc1ccc(OCC(F)(F)C(F)F)cc1
Temperature: 20 °C
Yield: 82.2 %

Procedure:
500 ml of dimethylacetamide, 304 g of potassium carbonate, 248 g of 4-fluorobenzaldehyde and 290 g of 2,2,3,3-tetrafluoropropanol are heated for 22.5 hours at 140° C. The reaction mixture is subsequently cooled to 20° C. and filtered. The salt mixture is washed using 300 ml of dimethylacetamide. After the filtrate has been distilled in vacuo at 3 mbar, a bottom temperature of 135° C. and a head temperature of 109° C. to 110° C., 387.95 g of 4-(2,2,3,3-tetrafluoropropoxy) benzaldehyde with a purity (GC) of 98% to 99% are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C(=O)C>[CH2:18]([O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9](=[O:11])[CH3:10])=[CH:3][C:2]=1[OH:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1ccc(O)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(=O)c1ccc(OCc2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3′,4′-dihydroxyacetophenone (25.4 g) in N,N-dimethylacetamide (420 mL) were added potassium carbonate (23.1 g) and benzyl bromide (19.9 mL) under ice-cooling, and the mixture was stirred at room temperature for 90 minutes. An insoluble was filtered, and then diluted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane→n-hexane/ethyl acetate=20/1), and then triturated with ethyl acetate to give 1-[4-(benzyloxy)-3-hydroxyphenyl]ethanone [REx(26-1)] (11.0 g) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)=[CH:8][C:4]=1[C:5]([Cl:20])=[O:6]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(-n2cnnn2)cc1C(=O)Cl
Reaction time: 4 h

Procedure:
Combine 2-methoxy-5-(1H-tetrazol-1-yl)benzoic acid (1.2 g, 5.5 mmol) and dichloromethane (40 mL). Add dropwise oxalyl chloride (0.72 mL, 8.25 mmol) followed by dimethylformamide (3 drops). After 4 hours, evaporate in vacuo and dry to give the title compound.