Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[C:15]([CH3:22])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:12]([CH3:14])[CH3:13])[CH:6]=1>C(O)C.CCOC(C)=O.[Pd]>[NH2:19][C:17]1[CH:18]=[C:2]([CH3:1])[C:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:12]([CH3:14])[CH3:13])[CH:6]=2)=[C:15]([CH3:22])[CH:16]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(C(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(N)cc(C)c1Oc1ccc(O)c(C(C)C)c1
Reaction time: 2 h
Yield: 106.2 %

Procedure:
To a solution of 4-(2,6-dimethyl-4-nitro-phenoxy)-2-isopropyl-phenol (478 mg, 1.59 mmol) in a mixture of ethanol (10 mL) and EtOAc (30 mL) was added catalyst (10% Pd/C, 100 mg). The mixture was hydrogenated under 50 psi at RT for 2 h. The mixture was filtered through Celite® and concentrated to give the title compound of Step C (458 mg) as a brown solid. The title product of Step C was used without further purification in the next step. MS (APCl−) Calc.: 271.2, Found: 270.2 (M−1).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([O:8][C:9]([C:11]1[C:15]([CH3:16])=[CH:14][NH:13][CH:12]=1)=[O:10])[CH3:7].[OH-].[Na+].CN([CH:22]=[O:23])C>O>[CH2:6]([O:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14]([CH:22]=[O:23])[NH:13][CH:12]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1c[nH]cc1C
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)c1c[nH]c(C=O)c1C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
POCl3 (4 mL, 1.1 eq) added to 9 mL (3 eq) of DMF cooled in an ice bath. After 15 mins, a solution of the 4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (6 g, 39.2 mmol) in DMF (2M, 20 mL) was added to the reaction and stirring continued at rt. After 2 hr, the reaction mixture was diluted with water (100 mL) and basified to pH=11 with 1N NaOH. The aqueous layer was extracted into DCM (2×250 mL), washing the combined organic layers with water (2×400 mL), dried (MgSO4), filtered through a plug of silica and concentrated to afford a pinkish solid. Trituration with hexanes afforded 3.3 g (46%) of 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester as a tan solid
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.C(N(C(C)C)CC)(C)C.P([O-])([O-])(O)=O.[Na+].[Na+].P([O-])(O)(O)=O.[Na+].[P:29]([O-:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32]>CN(C=O)C>[CH2:31]([O:30][P:29]([C:2]1[CH:6]=[CH:5][S:4][CH:3]=1)([O:33][CH2:34][CH3:35])=[O:36])[CH3:32]
Reactant: CCOP([O-])OCC
Reactant: Brc1ccsc1
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)c1ccsc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
Under nitrogen, 0.0815 g (0.5 mmols) of 3-bromothiophene and 0.0231 g (0.02 mmols) of commercially available tetrakistriphenylphosphine palladium were dissolved in DMF, to which 0.0829 g (0.6 mmols) of commercially available diethyl phosphite and 0.0776 g (0.6 mmols) of diisopropylethylamine were added at room temperature. Thereafter, the reaction mixture was heated to 110° C. and stirred for 4 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a disodium hydrogen phosphate/sodium dihydrogen phosphate buffer solution, adjusted to pH=7, was added to the reaction mixture, followed by extraction with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a silica gel column (ethyl acetate:hexane=1:1) to obtain the specified substance in the form of a yellow oil at a yield of 0.0782 g (yield: 71%).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N+:27]([O-:29])=[O:28])=[C:19]([NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24])[CH:20]=1.CC(C)=O>C(O)(C)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N+:27]([O-:29])=[O:28])=[C:19]([NH:21][C:22]([CH3:26])([C:23]([OH:3])=[O:24])[CH3:25])[CH:20]=1
Reactant: CC(C)(CO)Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(C)(Nc1cc(Cl)ccc1[N+](=O)[O-])C(=O)O

Procedure:
Jones reagent (2.67 M) is added in aliquots (40 ml, 20 ml, 20 ml, 20 ml and 10 ml) every 15 min to a solution of 2-[N-(5-Chloro-2-nitrophenyl)]amino-2-methyl-1-propanol (IX,EXAMPLE 9, 26.9 g) and acetone (2.05 l) at 0° until the reaction is done as measured by TLC. Isopropanol (150 ml) is added and the mixture is allowed to warm to 20°-25°. The mixture is filtered and the solids are washed with acetone several tunes. The combined filtrates are concentrated and partitioned between ether (800 ml) and potassium hydroxide (10%, 3×100 ml). The basic layers are acidified (3 N hydrochloric acid) and extracted with methylene chloride (3×180 ml). The methylene chloride layers are dried over magnesium sulfate, filtered, and concentrated to provide the title compound, mp 146°-147°; IR (mineral oil) 3363, 2953, 2924, 2855, 1707, 1613, 1573, 1495, 1336, 1272, 1241 and 753 cm-1 ; NMR (CDCl3) 8.48, 8.16, 6.68, 6.64 and 1.74 δ; MS (EI, m/z) 258 and 213.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[O:9])[CH:3]=1.[CH:10]1([Mg]Br)[CH2:12][CH2:11]1>>[OH:9][CH:8]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1)[CH:10]1[CH2:12][CH2:11]1
Reactant: Cc1ccnc(C=O)c1
Reactant: Br[Mg]C1CC1
Product: Cc1ccnc(C(O)C2CC2)c1
Yield: 87 %

Procedure:
The Grignard reaction of 4-methyl-2-pyridinecarboxaldehyde (1.21 g, 10.0 mmol) and cyclopropylmagnesium bromide (24 ml, 15.0 mmol, 1.5 equiv., 1.6 ml/mmol) provided 1.42 g (87%) of 2-(1-hydroxy-1-cyclopropylmethyl)-4-methyl-pyridine. TLC (silica gel GF): Rf =0.21 acetone-methylene chloride (1:6). 1H NMR (CDCl3,TMS): δ 8.47 (d, 1H, J=5.08 Hz), 7.30 (s, 1H), 7.12 (d, 1H, J=5.14 Hz), 4.70 (brs, 1H), 4.16 (d, 1H, J=7.92 Hz), 2.47 (s, 3H), 1.26-1.12 (m, 1H), 0.74-0.57 (m, 4H). Mass Spectrum: M/Z (relative intensity %): 163 (34), 162 (51), 146 (51), 135 (70), 122 (100), 107 (57), 92 (98).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][C@H:11]3[NH:22][CH2:21][CH2:20][C@@:17]4([C:18]=2[CH:19]=1)[C@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16]4.Cl.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][C@H:11]3[N:22]([C:31](=[O:33])[CH3:32])[CH2:21][CH2:20][C@@:17]4([C:18]=2[CH:19]=1)[C@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16]4
Reactant: ClCCCOc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OCCCCl)cc13
Temperature: 25 °C
Yield: 82 %

Procedure:
To a stirred solution of 3-(3-chloropropyloxy)morphinan.HCl 54 (3 mg, 0.008 mmol) and triethylamine (7 μL, 0.050 mmol) in dry dichloromethane (0.3 mL) was added acetyl chloride (1.8 μL, 0.025 mmol) and the mixture was stirred at room temperature. After starting material disappeared on TLC, solvent was concentrated and column chromatography gave 2.5 mg (82%) of the title compound: 1H NMR (300 MHz, CDCl3) δ6.96 (1H, t); 6.83 (1H, d); 6.75 (1H, d. d.); 4.92 (1H, m); 4.15 (2H, t); 3.81 (2H, t); 3.75 (1H, m); 3.12 (1H, m); 2.95 (1H, m); 2.62 (1H, m); 2.30 (1H, m); 2.18 (2H, m); 2.05 (3H, s); 1.00˜1.80 (10H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1.[Br:14]N1C(=O)CCC1=O>O1CCCC1>[Br:14][C:12]1[CH:11]=[N:10][N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-n2cccn2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-n2cc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
To a solution of 1-(4-methoxyphenyl)-1H-pyrazole (7.2 g, 0.042 mol) in tetrahydrofuran (100 mL) was added N-bromosuccinimide (7.3 g, 0.042 mol). The reaction was stirred at room temperature for 3 hours. The reaction was concentrated and purification by column chromatography gave 4-bromo-1-(4-methoxyphenyl)-1H-pyrazole (8.9 g, 84%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 7.83 (s, 1H), 7.63 (s, 1H), 7.52 (d, J=8.8 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 3.84 (s, 3H).
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[C:17]=1[O:18][CH3:19])[CH:13]=[O:14].S(=O)(=O)(O)O>O1CCCC1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[C:17]=1[O:18][CH3:19])[CH:13]([OH:14])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1OC
Reactant: [Li]c1ccccc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: COc1cc(C(O)c2ccccc2)cc([N+](=O)[O-])c1OC
Reaction time: 2 h

Procedure:
25 ml of 2M phenyl lithium solution (in benzene/ether (7:3)) are added dropwise within 15 minutes to 10.0 g of 3,4-dimethoxy-5-nitrobenzaldehyde dissolved in 150 ml of tetrahydrofuran and the mixture is stirred at 0° for 1 hour and at 20° for 2 hours. The mixture is subsequently treated with 150 ml of 2N sulfuric acid and extracted three times with 150 ml of ether. The combined ether phases are washed with sodium chloride solution, dried over sodium sulfate and evaporated. The thus-obtained residue is chromato graphed on 180 g of silica gel with methylene chloride. There is obtained 3,4-dimethoxy-5-nitrobenzhydrol as an amorphous solid.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(N(C)C)=O.[CH2:20]([N:27]([CH2:31][CH2:32][CH2:33][CH3:34])[C:28](Cl)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H-].[Na+]>O>[CH2:20]([N:27]([CH2:31][CH2:32][CH2:33][CH3:34])[C:28]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: CCCCN(Cc1ccccc1)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCCN(Cc1ccccc1)C(=O)N(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of 3.89 g. of diphenylamine in 25 ml. of dimethylacetamide is added during one hour to a stirred mixture of 5.19 g. of N-benzyl-N-(n-butyl)carbamyl chloride, 0.685 g. of sodium hydride, and 65 ml. of dimethylacetamide under a nitrogen atmosphere at 45°-50° C. The mixture is stirred for 2 hours at 50° C. and then poured into water. The mixture is extracted with methylene chloride and the extract is evaporated. The residue is purified by chromatography using silica gel as the adsorbant and acetone-hexane as the eluent. After evaporation of the eluent, the residue is evaporatively distilled at 165° C. under reduced pressure (150 microns) to yield 1-benzyl-1-(n-butyl)-3,3-diphenylurea as a viscous, clear, clorless liquid.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:20]=[CH:19][C:18]([C:21]2[O:25][CH:24]=[N:23][CH:22]=2)=[CH:17][C:12]=1[C:13]([O:15]C)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCOCC1>[CH2:3]([O:10][C:11]1[CH:20]=[CH:19][C:18]([C:21]2[O:25][CH:24]=[N:23][CH:22]=2)=[CH:17][C:12]=1[C:13]([OH:15])=[O:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cc(-c2cnco2)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2cnco2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 87.6 %

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (4.5 mL) was added to a dioxane (5 mL) solution of the obtained methyl 2-(benzyloxy)-5-(oxazol-5-yl)benzoate (0.55 g), followed by stirring at room temperature for 2 hours and 40 minutes. The solvent was evaporated under reduced pressure, and water was added to the residue. After adjusting the pH to 4.0 with 6 mol/L hydrochloric acid, the solid substance was collected by filtration to obtain 0.46 g of 2-(benzyloxy)-5-(oxazol-5-yl)benzoic acid as a light yellow solid.
Reaction SMILES: [C:1]([C:9]#[N:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N+:12]=[N-:13]>>[C:1]([C:9]1[N:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]=[N:13][N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: N#CC(=O)c1ccccc1
Product: CCOC(=O)Cn1nnnc1C(=O)c1ccccc1
Temperature: 105 °C

Procedure:
A mixture of benzoyl cyanide (5.1 grams, 39 mmol.) and ethyl azidoacetate (5.0 grams, 39 mmol.) was heated at 105°C. for 20 hours. The solution was cooled. The crystalline product [6.5 g. (64 percent), m.p. 63°-67°C.] was separated and washed with a mixture of ethyl ether and hexane. The yield of the title product was 6.5 grams (64 percent of theoretical). The melting point was 63°-67°C. The analysis was as follows:
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[C:4]([F:21])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]2=[O:20].[CH2:23]([Sn](CCCC)(CCCC)C#CC)[CH2:24][CH2:25]C>C1(C)C=CC=CC=1.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>[CH:12]1([N:10]2[C:11]3[C:6](=[CH:5][C:4]([F:21])=[C:3]([F:22])[C:2]=3[C:23]#[C:24][CH3:25])[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9]2)[CH2:14][CH2:13]1
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1cn(C2CC2)c2c(Br)c(F)c(F)cc2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC#Cc1c(F)c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c12
Yield: 30.7 %

Procedure:
7.5 g of ethyl 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 9.1 g of 1-tributylstannyl-prop-1-ine and 1.16 g of tetrakis(triphenylphosphine)palladium(0) are refluxed for 8 hours in 80 ml of absolute toluene under a nitrogen atmosphere. The solid which crystallises out at -18° C. is filtered off with suction and dried. 2.05 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(propin-1-yl)-3-quinolinecarboxylate are obtained (31% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([O:10][CH2:11][CH3:12])=[CH:8][C:7]2[C:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20](=O)[CH3:21])[CH2:15][C:14]=3[C:23](=[O:25])[O:24][C:6]=2[CH:5]=1)[CH3:2].[CH3:26][NH:27][CH3:28].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:41].Cl.Cl>CO>[ClH:41].[ClH:41].[CH3:26][N:27]([CH3:28])[CH:20]([CH3:21])[CH2:19][N:16]1[CH2:17][CH2:18][C:13]2[C:7]3[CH:8]=[C:9]([O:10][CH2:11][CH3:12])[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=3[O:24][C:23](=[O:25])[C:14]=2[CH2:15]1
Reactant: CNC
Reactant: CCOc1cc2oc(=O)c3c(c2cc1OCC)CCN(CC(C)=O)C3
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Product: CCOc1cc2oc(=O)c3c(c2cc1OCC)CCN(CC(C)N(C)C)C3

Procedure:
Prepared by the method described in Example 38 from 1,2,3,4-tetrahydro-8,9-diethoxy-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one (35.9 g, 0.10 moles) and dimethylamine (50 g, 1.11 moles). The product is converted to the dihydrochloride with gaseous hydrogen chloride in methanol. An additional recrystallization from methanol/diethyl ether yielded the final product (6.8 g), mp 210° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14](OS(C(F)(F)F)(=O)=O)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([OH:31])[CH2:27][CH2:28][C:29]#[CH:30].Cl>N1CCCCC1.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.[Cu](I)I>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:30]#[C:29][CH2:28][CH2:27][CH2:26][OH:31])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCCCO
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCCc2cc(C#CCCCO)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To 850 mg (2.2 mmol) 6-Trifluoromethanesulfonyloxy-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester in 5 ml piperidine, 128.0 mg (0.1 mmol) tetrakis(triphenylphosphine)palladium followed by 21.0 mg (0.1 mmol) copper iodide were added. The solution was evaporated and flushed with argon prior to the addition of 210 μl (2.2 mmol) 4-pentynol at 80° C. over a period of 45 min. Further 0.2 ml (2.1 mmol) 4-pentynol were added and the solution was stirred for 2 h. The mixture was added to ice water, acidified with 2M HCl and extracted with ether. The combined organic phases were washed with water and dried over Na2SO4. Purification by column chromatography with CH2Cl2/MeOH 30:1 yielded 650 mg (92%) 6-(5-Hydroxy-pent-1-ynyl)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as light brown oil, MS: 316 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.[C-:12]#[N:13].[K+].Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:12]#[N:13])=[C:10]([C:8]([OH:7])=[O:9])[CH:11]=1
Reactant: [C-]#N
Reactant: O=C1OCc2ccc(Cl)cc21
Agent: Cl
Agent: [K+]
Solvent: O
Product: N#CCc1ccc(Cl)cc1C(=O)O
Temperature: 180 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
A mixture of 6-chlorophthalide (2.0 g) and potassium cyanide (2.0 g) was stirred at a temperature of 180° C. for a period of 4 hours. The solid was cooled, dissolved in water and the solution was acidified with concentrated hydrochloric acid. The dark brown solid was collected, washed with water and dried. The crude solid was dissolved in ethyl acetate, the solution was treated with charcoal, filtered, and the solvent was evaporated to give 4-chloro-2-carboxyphenylacetonitrile (1.70 g) as pale yellow crystals mp 120° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.CN([CH:17]=[O:18])C.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:17]=[O:18])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(Br)cn1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a solution of 2,5-dibromopyridine (1 g) in toluene (50 mL) at −78° C. was slowly added 2.5M n-BuLi (2 mL). The reaction mixture was stirred for 2 h, then DMF (0.5 mL) was added. The solution was stirred for 1 h at −78° C., then warmed to −10° C. Saturated NH4Cl (10 mL) was added and the mixture was allowed to warm to room temperature. The two phases were partitioned and the organic layer dried over sodium sulfate and the solvent concentrated to dryness to afford 0.432 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:9]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 19.1 %

Procedure:
A mixture of 2-bromophenol (10 g, 57.8 mmol), benzyl bromide (27.5 ml, 0.23 mol) and potassium carbonate (64 g, 0.462 mol) in N,N-dimethylformamide (70 ml) was stirred at room temperature for 72 hours. The suspension was poured into water (500 ml) and extracted with ethyl acetate (2×300 ml). The combined organic fractions were washed with water (300 ml), dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (98:2) to give the title compound as a colourless oil (2.9 g). 1H NMR (250 MHz, CDCl3) δ 7.58-7.19 (8H, m), 6.95-6.81 (2H, m), and 5.16 (2H, m).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[O:16]([C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1ccccc1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Oc1ccccc1
Temperature: 130 °C
Reaction time: 10 h
Yield: 93 %

Procedure:
To a suspension of 2-fluorobenzonitrile (10.0 g, 82.6 mmol) and phenol (7.7 g, 5.1 mmol) in DMF (80 mL) was added K2CO3 (22.8 g, 165 mmol) at rt. The reaction was stirred at 130° C. for 10 h. The reaction mixture was diluted with water, extracted with EtAOAc (100 mL×3), washed with brine (100 mL), dried (Na2SO4), and concentrated to give 15.0 g, (93%) of the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 6.85 (1H, d, J=8.4 Hz), 7.07-7.14 (3H, m), 7.22 (1H, t, J=7.2 Hz), 7.40 (2H, t, J=8.0 Hz), 7.47 (1H, td, J=2.0, 8.4 Hz), 7.65 (1H, dd, J=1.2, 8.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[C@@H:7]([CH3:17])[CH2:6][CH2:5][C:4]=2[C:3]=1[OH:18].Br[CH:20]1[CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Br:1][C:2]1[C:3]([O:18][CH:20]2[CH2:23][CH2:22][CH2:21]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])[C@@H:7]([CH3:17])[CH2:6][CH2:5]2
Reactant: BrC1CCC1
Reactant: C[C@H]1CCc2c(ccc(Br)c2O)N1C(=O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C[C@H]1CCc2c(ccc(Br)c2OC2CCC2)N1C(=O)C1CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 85.1 %

Procedure:
A 250-mL round-bottom flask was charged with (2S)-6-bromo-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol (2.00 g, 6.45 mmol), bromocyclobutane (1.81 mL, 2.60 g, 19.3 mmol), cesium carbonate (6.3 g, 19.34 mmol) and acetonitrile (100 mL). The resulting mixture was stirred for 6 h at 80° C. The reaction mixture was filtered through a pad of Celite and concentrated under vacuum. The residue was purified via column chromatography on silica gel (gradient elution with 0-10% ethyl acetate-petroleum ether) to afford (2S)-6-bromo-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinoline (2.00 g, 85%) as a colorless oil. MS (ES, m/z): 364, 366 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[S:15][CH:16]=1)=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CC(C)=O.O>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][O:21][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20][C:6]=1[C:7](=[O:8])[NH:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[S:15][CH:16]=1)[CH3:34]
Reactant: CCOC(=O)CBr
Reactant: CC(C)c1nc(CCNC(=O)c2cc(Cl)ccc2O)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(Cl)cc1C(=O)NCCc1csc(C(C)C)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 5-chloro-2-hydroxy-N-[2-(2-isopropyl-thiazol-4-yl)-ethyl]-benzamide (400 mg, 1.23 mmol, 1.00 eq.) and potassium carbonate anhydrous (340 mg, 2.46 mmol, 2.00 eq.) in acetone (20 mL), ethyl bromoacetate (0.14 mL, 1.29 mmol, 1.05 eq.) was added. The mixture was stirred at r.t. for 5 hours. The reaction mixture was poured in water (50 mL). The mixture was extracted with AcOEt (2×20 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by flashmaster (column: 25 g, flow: 30 mL/min, 45 fractions of 15 mL, Heptane+20% AcOEt to Heptane+80% AcOEt) to yield the ester as a white solid.