Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)(Cl)Cl>[CH3:30][S:31]([O:29][C@H:26]1[CH2:27][CH2:28][C@H:23]([CH2:22][CH2:21][O:20][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:24][CH2:25]1)(=[O:33])=[O:32]
Reactant: O[C@H]1CC[C@H](CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)O[C@H]1CC[C@H](CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
trans-4-[2-(Trityloxy)ethyl]cyclohexanol (1.95 g, 0.00504 mol) was dissolved in chloroform (40.00 mL) and the mixture was cooled to 0° C. To the reaction was added TEA (0.98 mL, 0.0071 mol) and methanesulfonyl chloride (0.47 mL, 0.0060 mol) and this mixture was stirred at 0° C. for 2 hours The reaction was then extracted with ethyl acetate and the organic extracts were washed with water, and saturated NaCl, then dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18].O>CN(C=O)C>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Reactant: CCOC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)n1ncc2ccc([N+](=O)[O-])cc21

Procedure:
6-Nitroindazole (10 g) was dissolved in dry DMF (200cm3) and 50% sodium hydride (2.94 g) added portionwise with stirring. After 20 minutes ethyl 2-bromopropionate (8cm3) was added and the mixture stirred at room temperature for 4 hours, poured into water (1L) and extracted with ethyl acetate four times. The combined organic extracts were washed with water, dried (MgSO4), filtered and the filtrate concentrated under vacuum. The residue was purified by chromatography (SiO2 ; hexane: t-butylmethyl ether, 7:3) to give ethyl 2-(6-nitroindazol-1-yl)propionate (1.3 g) m.p. 99.7°-100.1° C.; M+ =263;
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([NH:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O[N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:13]([NH:20][C@@H:21]1[CH2:22][CH2:23][C@H:24]([O:27][N:29]2[C:33](=[O:34])[C:32]3[C:31](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:30]2=[O:39])[CH2:25][CH2:26]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](ON2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4.1 ml (0.0244 mol) of diethyl azodicarboxylate (93%) are added dropwise to a mixture of 5 g (0.0232 mol) of trans-4-(N-BOC-amino)-cyclohexanol (cf. Example 1c), 3.8 g (0.0232 mol) of N-hydroxyphthalimide, 6.1 g (0.0232 mol) of triphenylphosphine and 100 ml of tetrahydrofuran at 20°-30° C. The reaction mixture is further stirred at room temperature for 15 hours and then evaporated in vacuo. To separate off the diethyl 1,2-hydrazinc dicarboxylate and triphenylphosphine oxide, the oily residue is dissolved in ethyl acetate, the solution is cooled to 0° C. and filtered, the filtrate is evaporated and the same operation is repeated once more, but using diethyl ether. The residue obtained after evaporation of the diethyl ether is purified by means of flash chromatography on silica gel using ethyl acetate/hexane mixtures (1:2 and 1:1). After evaporation of the product-containing fractions, the title compound is obtained as a crystalline residue, m.p. 134°-135° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:9][CH:10]=[CH2:11])[CH2:4][CH2:5][CH2:6][C:7]#[N:8].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:1][CH2:2][CH:3]([CH2:9][CH:10]=[CH2:11])[CH2:4][CH2:5][CH2:6][C:7]#[N:8])(=[O:22])=[O:21]
Reactant: C=CCC(CO)CCCC#N
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC(CCCC#N)COS(C)(=O)=O
Reaction time: 3 h

Procedure:
To a solution of 2679 g of 6-hydroxy-5-(2-propenyl)-hexanenitrile in 25 L of methylene chloride is added 2681 mL of triethylamine. The mixture is cooled to -10° in an ice salt bath and a solution of 2103 g of methanesulfonyl chloride in 2 L of methylene chloride is added dropwise over 3 hours keeping the temperature at -5°. After addition is complete, the mixture is stirred for 3 hours in an ice salt bath and then overnight at 10°. The mixture is washed with water, saturated sodium bicarbonate solution, water and then brine, dried over sodium sulfate, evaporated to dryness, and dried at 45°/3 mm Hg to yield 6-methanesulfonyloxy-5-(2-propenyl)-hexanenitrile.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]#[C:21][CH3:22]>CC(C)=O>[CH2:19]([O:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=1)[C:20]#[C:21][CH3:22]
Reactant: COc1ccc(O)cc1OC
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#CCOc1ccc(OC)c(OC)c1

Procedure:
Following the same procedure as in Example 2, 15.4 g (0.1 mole) of 1-hydroxy-3,4-dimethoxybenzene, 13.8 g (0.1mole) of anhydrous potassium carbonate in ml 50 of acetone and 13.3 g (0.1 mole) of 1-bromo-2-butyne were reacted. After work up and evaporation of the mixture u.v. (20° C./21 mbar), a residue was obtained, that after purification on silica gel column (eluant n-hexane:ethyl acetate 5:1 v/v) gave a thick oil that after some time solidified with low melting point (28-30° C.), whose NMR and MS analyses corresponded to those of the aforementioned compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12]Br)=[CH:4][CH:3]=1.C[O-].[Na+].O.[C:18](OCC)(=[O:20])C>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:20][CH3:18])=[CH:4][CH:3]=1
Reactant: BrCCCCOc1ccc(Br)cc1
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCCCCOc1ccc(Br)cc1

Procedure:
A solution of 1-bromo-4-(4-bromobutoxy)benzene (3.05 g) in methanol (30 ml) was treated with 28% sodium methoxide in methanol (2.43 ml), and the solution was refluxed for 5 hours. After cooling, the reaction mixture was added to a mixture of water and ethyl acetate. The organic layer was washed with brine. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (10:1 hexane-ethyl acetate elution) to give 1-bromo-4-(4-methoxybutoxy)benzene (1.95 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]2[CH:12]=[C:13](I)[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH2:19][F:20])([CH2:17][F:18])[CH:7]=1)=[O:5])[CH3:2].[F:21][C:22]([F:30])([F:29])[C:23]([F:28])([F:27])C([O-])=O.[K+]>>[CH2:1]([O:3][C:4]([C:6]1[C:11]2[CH:12]=[C:13]([C:23]([F:28])([F:27])[C:22]([F:30])([F:29])[F:21])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH2:19][F:20])([CH2:17][F:18])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(I)cc21
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Agent: [K+]
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc21

Procedure:
Using 2,2-bis(fluoromethyl)-6-iodo-2H-1-benzopyran-4-carboxylic acid ethyl ester and potassium pentafluoropropionate, an oily product of 6-pentafluoroethyl-2,2-bis(fluoromethyl)-2H-1-benzopyran-4-carboxylic acid ethyl ester was obtained according to the same method as in Example 23 (4).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]2[CH:11]=[C:12]([C@@H:14]([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH3:15])[N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)=[O:4].[I:27]N1C(=O)CCC1=O>C(#N)C.O>[CH2:20]([O:19][C:17]([NH:16][C@H:14]([C:12]1[N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[N:10]2[C:11]=1[I:27])[CH3:15])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1cccc2nc([C@H](C)NC(=O)OCc3ccccc3)cn12
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cccc2nc([C@H](C)NC(=O)OCc3ccccc3)c(I)n12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-methyl-2-(1-(((benzyloxy)carbonyl)amino)ethyl)imidazo[1,2-a]pyridine-5-carboxylate (5.5 g, 7.93 mmol) in acetonitrile (50 mL) was added N-iodosuccinimide (2.3 g, 10.3 mmol) at 25° C. The reaction mixture was stirred at 25° C. overnight. After completion of the reaction, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with satd. sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 0-50% EtOAc in hexane to provide (S)-methyl 2-(1-(((benzyloxy)carbonyl)amino)ethyl)-3-iodoimidazo[1,2-a]pyridine-5-carboxylate: 1H NMR (CDCl3, 400 MHz) δ 1.547 (d, J=6.8 Hz, 3H), 4.048 (s, 3H), 5.067-5.200 (m, 3H), 5.805 (d, J=7.2 Hz, 1H), 7.229-7.260 (m, 2H), 7.292-7.350 (m, 5H), 7.675-7.708 (m, 1H); LC-MS (ESI) m/z 479.9 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH:10]=2)=[CH:5][CH:4]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][CH:12]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(C2=CCC(=O)CC2)cc1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: CSc1ccc(C2=CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
The title compound was prepared as a white solid by the reductive amination of 4-(4-methylsulfanyl-phenyl)-cyclohex-3-enone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: O[CH:2]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:3]([F:6])([F:5])[F:4].P(Cl)(Cl)[Cl:18]>P(Cl)(Cl)(Cl)=O.CCCCCCC>[Cl:18][CH:2]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: ClP(Cl)Cl
Reactant: O=C(NC(O)C(F)(F)F)c1ccc(Cl)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCCCCCC
Product: O=C(NC(Cl)C(F)(F)F)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
A mixture of N-(1-hydroxy-2,2,2-trifluoroethyl)-4-chlorobenzamide (2.53 g, 0.01 mol) in phosphorus oxychloride (2 mL) is treated with phosphorus trichloride (1.57 g, 0.012 mol), heated to and held at 80° C. for 30 minutes, and concentrated in vacuo to obtain a residue. The residue is dissolved in hot heptane, decanted from the waxy phosphorus products, and crystallized to give the title product as a white crystalline solid (2.43 g, 89.3% yield): mp 119.0-121.0° C.; IR (Nujol) 3266, 1668 cm−1; 1H NMR (CDCl3) δ7.76 and 7.46 (AB with fine splitting, ArH), 6.86 (d, J=8.5 Hz, NH, moves to 10.24 in DMSO-d6), 6.55(m, CH); 19F NMR δ−77.7(d, J=5 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.[C:17](Cl)(=O)[C:18](Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:17][CH2:18][C:9](=[O:11])[CH2:8]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (3-bromophenyl)acetic acid (˜10 g, 50 mmol) in 200 mL of DCM was added DMF (183 mg, 2.5 mmol) and then oxalyl dichloride (6.3 g, 50 mmol) was added dropwise over 30 min. The resulting mixture was stirred at room temperature for 6 hr and then concentrated under reduced pressure. A mixture of prepared acid chloride in 200 mL of DCM was added AlCl3 (13.2 g, 100 mmol) portion-wise at 0° C. After the mixture was stirred at 0° C. for 30 min, the solution was bubbled with ethene gas for 2 h and the resulting mixture was warmed to room temperature and stirred overnight. Then 300 mL of water was added dropwise over 30 min with stirring. Then separated the organic layer and extracted the aqueous layer with 200 mL of DCM. The combined organic layers were washed with 1N HCl (200 mL), saturated NaHCO3 (200 mL) and brine (200 mL) and then dried over Na2SO4. Then the organic layer was concentrated under reduced pressure to remove the solvent. The crude product was purified via chromatography (EtOAc/petrol ether 1:20 to 1:5) to give the desired 7-bromo-3,4-dihydronaphthalen-2(1H)-one along with the isomeric side product 5-bromo-3,4-dihydronaphthalen-2(1/1)-one. 1H-NMR (400 MHz, CDCl3) δ 7.33 (d, J=8.0 Hz, 1H), 7.27 (s, 1H), 7.10 (d, J=8.0 Hz, 1H), 3.01 (t, J=6.8 Hz, 2H), 2.54 (t, J=6.8 Hz, 2H); MS m/e 225 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12]O)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.C(N(CC)CC)C.S(Cl)([Cl:23])=O>ClCCl>[Cl:23][CH2:12][C:4]1[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=[C:2]([F:1])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(F)cc2c1OCCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1cc(CCl)c2c(c1)OCCO2

Procedure:
A solution of (7-fluoro-2,3-dihydro-1,4-benzodioxine-5-yl)methanol (436 mg, 2.36 mmol) and triethylamine (400 μL, 2.83 mmol) in dichloromethane (20 mL) was cooled to 0° C. and then slowly added thionyl chloride (260 μL, 3.55 mmol) and stirred for 45 min. The reaction mixture was partitioned with water (100 mL) and ethyl acetate (100 mL). The organic layer was washed with aqueous saturated sodium bicarbonate, brine, and then dried over anhydrous magnesium sulfate and concentrated to give crude 5-(chloromethyl)-7-fluoro-2,3-dihydro-1,4-benzodioxine as a colorless oil. The crude residue was taken up in N,N-dimethylformamide (10 mL) and was added potassium cyanide (460 mg, 7.08 mmol). The reaction mixture was heated to 60° C. and stirred for 5 h, at which time it was cooled to room temperature and partitioned with water (100 mL) and ethyl acetate (150 mL). The organic layer was washed with 10% citric acid (3×100 mL) and then aqueous saturated sodium bicarbonate (2×100 mL). The organic solution was further washed with brine, dried over anhydrous magnesium sulfate and concentrated to give 430 mg (94% over 2 steps) of (7-fluoro-2,3-dihydro-1,4-benzodioxin-5-yl)acetonitrile as an off-white powder. GCMS for C10H8FNO2: 193 (M+).
Reaction SMILES: [ClH:1].Cl.[N+:3]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].C(N(CC)CC)C.[Cl:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29]>C1C=CC=CC=1>[ClH:26].[ClH:1].[N+:3]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH2:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:29])[CH2:13][CH2:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=C(CCl)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(CN2CCNCC2)cc1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1)c1ccccc1
Yield: 42 %

Procedure:
A mixture of N-(4-nitrobenzyl)piperazine dihydrochloride (7.73 g, 30 mmol), triethylamine (8.37 ml, 60 mmol) and 2-chloro-1-phenylethanone (6.12 g, 39 mmol) in 100 ml of benzene was refluxed for 5 hours, and then treated according to general preparation 2 to give 5.2 g of compound (IV-4), yield 59.51%, mp 236-238° C. M+ 339.
Reaction SMILES: [Br:1]Br.[C:3]1([C:9](=[O:21])[CH2:10][C:11](=[O:20])[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(Cl)(Cl)Cl>[Br:1][C:12]1[C:11](=[O:20])[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:21][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: BrBr
Reactant: CCOC(=O)C(=O)CC(=O)CC(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1oc(-c2ccccc2)cc(=O)c1Br
Reaction time: 3 h

Procedure:
A solution of bromine (10.25 ml, 0.198 mol) in chloroform (50 ml) was added dropwise over 30 minutes to a stirred solution of ethyl 6-phenyl-2,4,6-trioxohexanoate (52.0 g) in chloroform (400 ml) at -10° to -20° C. The pale solution was stirred for a further 3 hours without cooling, washed with water and evaporated. The residual solid was recrystallised from ethanol-water to give ethyl 3-bromo-4-oxo-6-phenyl-4H-pyran-2-carboxylate (mp 135° C.). This ester was hydrolysed as in Example 33 to give the title product (mp 247° C. with decomposition).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:10]1[C:11]([CH3:17])=[N:12][CH:13]=[C:14]([CH3:16])[N:15]=1>C1COCC1>[CH3:17][C:11]1[C:10]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:15][C:14]([CH3:16])=[CH:13][N:12]=1
Reactant: Br[Mg]c1ccccc1
Reactant: Cc1cnc(C)c(Cl)n1
Solvent: C1CCOC1
Product: Cc1cnc(C)c(-c2ccccc2)n1
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
A solution of phenylmagnesium bromide (1M in THF, 5.6 mL, 5.6 mmol) is added to a solution of 3-chloro-2,5-dimethylpyrazine (346 mg, 2.42 mmol) and Fe(acac)3 (43 mg, 0.12 mmol) in THF (10 mL) at −30° C. After stirring for 30 min at that temperature, the reaction is quenched with brine, the aqueous layer is extracted with Et2O, the combined organic phases are dried over Na2SO4 and evaporated, and the residue is purified by flash chromatography (hexane/ethyl acetate, 10:1). After eluting a first fraction containing biphenyl (212 mg), one obtains 2,5-dimethyl-3-phenylpyrazine as a pale yellow syrup (287 mg, 64%). 1H NMR (300 MHz, CD2Cl2) δ 8.31 (s, 1H), 7.55–7.59 (m, 2H), 7.43–7.51 (m, 3H), 2.55 (s, 3H), 2.54 (s, 3H). 13C NMR (75 MHz, CD2Cl2) δ 152.7, 150.6, 148.4, 142.1, 139.5, 129.3, 128.7, 128.6, 22.7, 21.2.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][OH:13])[CH:6]=1)[CH2:3][NH2:4].[C:14]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](=O)[CH3:32])=[CH:26][CH:25]=1)([O:16]CC1C=CC=CC=1)=[O:15].O>C1(C)C(C)=CC=CC=1>[C:14]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][OH:13])[CH:6]=2)[CH3:32])=[CH:26][CH:25]=1)([OH:16])=[O:15]
Reactant: CC(=O)Cc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: NCC(O)c1ccc(O)c(CO)c1
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(Cc1ccc(C(=O)O)cc1)NCC(O)c1ccc(O)c(CO)c1
Reaction time: 3 h

Procedure:
2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl) ethanamine (1.09 g) and 1-(4-carbobenzyloxyphenyl) propan-2-one (1.6 g) were refluxed in xylene in a Dean and Stark apparatus until the theoretical amount of water had been collected. The solvent was removed, ethanol added and the mixture hydrogenated at 70 psi and 50° for 3 hours using 10% Pd/c as catalyst. Filtration of the catalyst and evaporation of the solvent gave the title compound as a foam τ(d6DMSO) 8.95 (3H, d, J=7 Hz), 6.8-7.4 (5H, m), 5.5 (2H, s+1H, t), 3.65 (5H, broad), 2.3-3.3 (5H, m), 2.0 (2H, d, J=8 Hz).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]([OH:30])[CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:7]1)=[O:5])C.[OH-].[Na+].O>C(O)C>[CH:26]1[C:17]2[CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:15]([CH2:14][CH:13]([OH:30])[CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:16]=2[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CC(O)CN2c3ccccc3CCc3ccccc32)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)[C@@H]1CCCN(CC(O)CN2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
The above ester (0.38 g, 0.93 mmol) was dissolved in ethanol (5 ml), 2 N sodium hydroxide (1.54 ml, 3.07 mmol) was added and the homogeneous mixture was stirred at room temperature for 24 h. Water (15 ml) was added and the ethanol was removed in vacuo. The aqueous solution was washed with ether (2×10 ml) and pH was adjusted to 6 by addition of 1N hydrochloric acid. The acidic mixture was extracted with dichloromethane (2×15 ml). The combined organic extracts were washed with water (20 ml), dried (MgSO4) and concentrated in vacuo. The residue was triturated with ether and the product collected by filtration to give 0.23 g (66%) of the title compound as a powder.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Cl[CH2:15][CH2:16][O:17][CH2:18][CH2:19]Cl.O>CS(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:12]#[N:13])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: ClCCOCCCl
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC1(c2ccc(Cl)c(Cl)c2)CCOCC1
Reaction time: 1 h
Yield: 35.1 %

Procedure:
NaH (420 mg, 10.5 mmol, 60%, w/w) was added to a solution of 2-(3,4-dichlorophenyl)acetonitrile (930 mg, 5 mmol) in DMSO (20 ml) at room temperature. After stirring for 40 minutes at room temperature (15° C.), 1-chloro-2-(2-chloroethoxy)ethane (786.5 mg, 5.5 mmol) was added. The mixture was stirred for another 1 hour, then poured into water (5.0 mL), and the mixture was extracted with EtOAc-toluene (2:1, 3×30 mL). The combined organic extracts were washed with 2N aq. HCl (30 mL), water (30 mL) and brine (30 mL), dried over MgSO4, filtered, and concentrated to 5 mL. The precipitated solids were collected by filtration and washed with cold diethylether (10 mL) to afford the title compound (450 mg, yield 35%). 1H NMR (400 MHz, CDCl3): 7.58 (d, J=2.0 Hz, 1H), 7.52 (d, J=1.6 Hz, 1H), 7.34 (dd, J=2.0 Hz, J=8.8 Hz, 1H), 4.08-4.12 (m, 2H), 3.85-3.92 (m, 2H), 2.2.02-2.13 (m, 4H). LC-MS (M+H): m/z 229.1 (M-CN).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.C([Li])CCC.C1(C)C=CC(S[C:24]#[N:25])=CC=1>C1COCC1.[Cl-].[NH4+]>[Cl:11][C:9]1[C:10]2[C:2]([C:24]#[N:25])=[CH:3][NH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Reactant: Cc1ccc(SC#N)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#Cc1c[nH]c2ncnc(Cl)c12
Reaction time: 1 h
Yield: 22.4 %

Procedure:
To 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.31 g, 1.3 mmol) in dry THF (4 ml), cooled in a dry ice-acetone bath, was added dropwise n-butyllithium (1.3 ml, 3.3 mmol, 2.5 M In hexanes). The reaction mixture was stirred for 1 hour, then p-toluenesulphenyl cyanide (0.44 g, 2.4 mmol) suspended in dry THF (7 ml) was added. The solution was stirred for 18 hours at ambient temperature then diluted with aqueous ammonium chloride. The phases were separated and the organic phase washed with water and aqueous NaCl. The organic phase was dried over sodium sulfate, and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (15 g, 40 mm mesh) using 3% methanol/methylene chloride to afford 4-chloro5-cyano-7H-pyrrolo[2,3-d]pyrimidine as a yellow solid (52 mg).