Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])=[CH:11][CH:10]=1)(O)[CH3:7])C.O.O.Cl[Sn]Cl.Cl.[OH-].[Na+].S>C(O)(=O)C>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([CH:6]([CH3:7])[CH2:5][C:4]([OH:23])=[O:3])=[CH:10][CH:11]=1
Reactant: CCOC(=O)CC(C)(O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: S
Solvent: CC(=O)O
Solvent: O
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
3.2 g. of 3-(2',4'-difluoro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester are dissolved in 40 ml. of acetic acid. The solution is poured into a solution of 9 g. of SnCl2.2H2O in 20 ml. of concentrated hydrochloric acid. The mixture is heated under reflux for 3 hours and adjusted to pH 2 with sodium hydroxide solution. Hydrogen sulfide is passed in until no more SnS precipitates and the mixture is filtered and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]([CH3:28])[C@@H:13]2[CH2:22][CH2:21][C:16]3(OCC[O:17]3)[CH2:15][C@H:14]2[N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]([CH3:28])[C@@H:13]2[CH2:22][CH2:21][C:16](=[O:17])[CH2:15][C@H:14]2[N:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C(=O)Cc1ccc(Cl)c(Cl)c1)[C@@H]1CCC2(C[C@H]1N1CCCC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: CN(C(=O)Cc1ccc(Cl)c(Cl)c1)[C@@H]1CCC(=O)C[C@H]1N1CCCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
A mixture of trans-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]dec-8-yl]benzeneacetamide (12.3 g, 0.029 mol) from Example 1, 3 N HCl solution (288 ml), and 432 ml of acetone was stirred at 60° C. under N2 atmosphere for one hour. Acetone was removed on a rotary evaporator and the mixture was extracted with chloroform. The chloro-form extracts were dried (Na2SO4), concentrated in vacuo and diluted with ether. Refrigeration overnight gave white crystals which were dried at 60° C. in vacuo for two days to give 10.5 g (87%) of the titled compound, mp 148.0°-148.9° C. The mass spectrum indicated ion fragments at m/e 382/384 (M+, chlorine isotopic peaks). The ir and nmr spectra were consistent with the structure assignment.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][NH2:5].[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][NH:5][C:12]1[S:11][CH2:17][C:15](=[O:16])[N:14]=1
Reactant: O=C1CSC(=S)N1
Reactant: Cc1cccc(Cl)c1CN
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Cl)c1CNC1=NC(=O)CS1

Procedure:
Similar procedure as described in example 15a was used, starting with 2-chloro-6-methyl-benzylamine, rhodanine, mercuric chloride and DIEA to give 2-(2-chloro-6-methyl-benzylamino)-thiazol-4-one. LC-MS m/e 259 (MH+).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2C(=O)NCC[C:6]3=[C:7](C4C=CC(C=O)=CC=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.C1(C2NC3C=CC=C4C(=[O:43])NCCC=2C=34)C=CC=CC=1.BrC1N(F)C2C=C(F)C=C3C(=O)NCCC=1C=23.C(C1C=CC(B(O)O)=CC=1)=O.N1CCCC1>>[N:8]1[C:9]2[C:5]([CH:4]=[CH:3][C:2](=[O:43])[CH:10]=2)=[CH:6][CH:7]=1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: O=Cc1ccc(-c2[nH]c3cc(F)cc4c3c2CCNC4=O)cc1
Agent: O=C1NCCc2c(Br)n(F)c3cc(F)cc1c23
Agent: O=Cc1ccc(B(O)O)cc1
Solvent: C1CCNC1
Product: O=C1C=CC2=CC=NC2=C1

Procedure:
In a manner similar to that described for Compound PPP, 4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl) benzaldehyde (100 mg, 0.32 mmol; prepared in a manner similar to that described for compound 12 from 2-bromo-8-fluoro-fluoro-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one and 4-formylphenylboronic acid) was reacted with pyrrolidine (115 mg, 1.62 mmol) to yield 8-fluoro-2-(4-pyrrolidin-1-ylmethyl-phenyl)-1,3,4,5-tetrahydro-azepinop5,4,3-cd]indol-6-one, 16 mg (14%) as a yellow solid: m.p. 264-265° C. (dec), 1H NMR (300 MHz, d6-DMSO) δ 1.72 (m, 4H), 2.49 (m, 4H), 3.04 (m, 2H), 3.39 (m, 2H), 3.64 (br s, 2H), 7.31 (dd, J=9.3, 2.4 Hz, 1H), 7.43 (m, 3H), 7.58 (d, J=8.1 Hz, 2H), 8.25 (br t, 1H), 11.66 (br s, 1H). HRMS (MALDI MH+) Calcd for C22H22N3OF: 362.1825. Found: 364.1810. Anal. (C22H22N3OF.0.5 H2O) C, H, N.
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[C:13](=[O:15])[CH3:14].C(Cl)Cl>C(O)C.O.[Fe]>[NH2:10][C:8]1[CH:7]=[CH:6][C:5]([C:13](=[O:15])[CH3:14])=[C:4]([Cl:3])[CH:9]=1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CC(=O)c1ccc(N)cc1Cl
Reaction time: 0.03 h

Procedure:
Iron (2.7 g) and ammonium chloride (2.6 g) were added to a solution of 2′-chloro-4′-nitroacetophenone (CAS Reg. No. 67818-41-1, 960 mg) in ethanol (68 ml) and water (8.1 ml). The mixture was heated for 1 h under reflux. DCM (35 ml) was added and stirred for 2 min. The mixture was filtered over Celite. Water (100 ml) was added and extracted with DCM (200 ml, and 2×150 ml). The combined organic layers were dried over Na2SO4 and concentrated to give the title compound (837 mg) as light yellow oil. MS (m/e)=170.1 [M+H+].
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=1[O:38][CH3:39].CN(C)C=O>O>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=4[O:38][CH3:39])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 90 °C
Yield: 58.6 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (5.1 g, 20 mmol), K2CO3 (5.2 g, 40 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), and dimethylformamide (60 ml) was heated at 90° C. for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4) and concentrated to afford a moist solid. Recrystallization (twice) from ethyl alcohol afforded 5.0 g (58%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-ethanone as a beige solid, m.p.=118°-120° C.
Reaction SMILES: ClCCl.[CH2:4]([C@H:6]1[O:8][CH2:7]1)[Cl:5].[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(OC)(C)(C)C.CS(O)(=O)=O>[Cl:5][CH2:4][C@@H:6]([OH:8])[CH2:7][O:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1ccccc1
Reactant: ClC[C@@H]1CO1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: O[C@H](CCl)COc1ccccc1
Reaction time: 1 h
Yield: 122 %

Procedure:
To a mixture of N′,N′-disalicylidene ethylenediaminatocobalt(II) (138 mg, 0.425 mmol) and dichloromethane (10 ml) was added methanesulfonic acid (3 μl, 0.510 mmol) and the reaction system was stirred for 1 hour while being filled with air. The reaction solution was evaporated to dryness under reduced pressure to give a crude blackish (dark) brown cobalt (III) complex. Thereto was added tert-butylmethyl ether (4 ml) to disperse the crude cobalt (III) complex and then thereto were added (S)-epichlorohydrin (2.00 ml, 25.5 mmol, optical purity 99% e.e.) and phenol (2.00 g, 21.3 mmol) in order. The mixture was stirred for 24 hours under nitrogen atmosphere at room temperature. After the reaction, the reaction mixture was diluted with tert-butylmethyl ether (20 ml), the solution was washed with a 6% aqueous sodium hydroxide solution (10 ml) and a saturated sodium chloride solution (10 ml) in order, and the organic layer was condensed under reduced pressure to give crude (S)-1-chloro-3-phenoxy-2-propanol (4.85 g). This crude compound (4.85 g) was dissolved in isopropanol (10 ml) and thereto was added a 24% aqueous sodium hydroxide solution (4.50 g, 25.5 mmol) under ice-cooling. The mixture was stirred for 1 hour at room temperature. After the reaction, the reaction mixture was diluted with tert-butylmethyl ether (50 ml) and the solution was washed with water (20 ml), a saturated aqueous ammonium solution (20 ml) and a saturated aqueous sodium chloride solution (20 ml) in order. The organic layer was condensed under reduced pressure to give crude (R)-glycidylphenyl ether (3.24 g). Quantitative analysis by gas chromatography and optical purity measurement by HLPC were conducted on the compound. As a result the subject compound, (R)-glycidylphenyl ether (3.07 g, 96.1%) was produced with optical purity at. 99% e.e.
Reaction SMILES: [CH2:1]([C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1)[CH3:2].[C:8]([C-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)#[CH:9].[Fe+2:15].[I:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=1>C1COCC1.CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH2:1]([C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1)[CH3:2].[I:16][C:17]1[CH:22]=[CH:21][C:20]([C:9]#[C:8][C-:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)=[CH:19][CH:18]=1.[Fe+2:15]
Reactant: Ic1ccc(I)cc1
Reactant: C#C[c-]1cccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Ic1ccc(C#C[c-]2cccc2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 97.4 %

Procedure:
Following the procedure for preparing 6, samples of 13 (1.0 g, 4.2 mmol), 1,4-diiodobenzene (2.8 g, 8.5 mmol), PdCL2(PPh3)2 (30 mg, 43 μmol) and CuI (5.0 mg, 26 μmol) were reacted in THF (20 mL) and Et3N (20 mL). The reaction mixture was stirred at 50° C. for 5 h and worked up. The resulting residue was purified by column chromatography (silica, petroleum ether) to afford 1.8 g (95%) of a red-brown solid. mp 55–57° C.; 1H NMR δ 1.17 (t, J=7.5 Hz, 3H), 2.35 (q, J=7.5 Hz, 2H), 4.10 (s, 4H), 4.18 (t, J=2.1 Hz, 2H), 4.40 (t, J=2.1 Hz, 2H), 7.18, 7.64 (AA′BB′, J=8.1 Hz, 2×2H); 13C NMR δ 15.5, 22.3, 67.0, 68.9, 69.5, 70.2, 74.5, 91.2, 123.3, 133.5, 134.0, 135.8; FAB-MS obsd 439.8721, calcd exact mass 439.8724 (C20H17FeI).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[C:5]([CH3:11])[CH:4]=1)#[CH:2].[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1)[CH3:13]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[C:5]([CH3:11])[CH:4]=2)=[CH:18][CH:17]=1)[CH3:13]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(CO)c(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(CO)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
Using General Procedure F; (4-ethynyl-2-methyl-phenyl)-methanol (Intermediate 136, 100.0 mg, 0.44 mmol) and ethyl-4-iodo benzoate (Reagent A, 125.0 mg, 0.45 mmol) in triethylamine (4 mL) was treated with copper(I)iodide (29 mg, 0.15 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (102 mg, 0.15 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (20-40% EtOAc-hexanes) afforded 130.0 mg (99%) of the title compound as an orange solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:19])=[C:8](C(OC(C)(C)C)=O)[NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].Cl>C(O)(C)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:19])=[CH:8][NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)[nH]c(C(=O)OC(C)(C)C)c1C
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)c1c(C)c[nH]c1C
Temperature: 47.5 °C

Procedure:
Into a 10-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, gas bubbler and an air condenser, were charged 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid 2-tertiary butyl ester 4-ethyl ester (II) (1.5 Kg; 5.6 mole), isopropyl alcohol 4.5 L and stirred while Conc. HCl (2.2 L) was charged with the aid of addition funnel at 25-30° C. After addition, the temperature of the reaction mixture was raised to 45-50° C. and maintained at this temperature until the gas evolution completely ceases. The reaction was monitored by TLC and the solution cooled to 25-30° C. and quenched in a carboy containing ice water under stirring. The product was isolated by filtration and dried at 50° C.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]([CH2:12][NH:13][C:14]2[CH:31]=[CH:30][C:17]([C:18](=[O:29])[NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:16][CH:15]=2)[CH2:10][NH:9][C:8]2[N:7]=[C:6]([NH2:32])[NH:5][C:4](=[O:33])[C:3]1=2.[OH:34][CH:35]1[O:43][C@H:42]([CH2:44][OH:45])[C@@H:40]([OH:41])[C@H:38]([OH:39])[C@H:36]1[NH2:37]>>[OH:34][CH:35]1[O:43][C@H:42]([CH2:44][OH:45])[C@@H:40]([OH:41])[C@H:38]([OH:39])[C@H:36]1[NH2:37].[CH3:1][N:2]1[C@H:11]([CH2:12][NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18](=[O:29])[NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][C:23]([O-:25])=[O:24])=[CH:30][CH:31]=2)[CH2:10][NH:9][C:8]2[N:7]=[C:6]([NH2:32])[NH:5][C:4](=[O:33])[C:3]1=2
Reactant: CN1c2c(nc(N)[nH]c2=O)NC[C@H]1CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Agent: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Product: CN1c2c(nc(N)[nH]c2=O)NC[C@H]1CNc1ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)O)cc1
Yield: 136.8 %

Procedure:
4.60 g (10 mmol) of 5-methyl-(6R,S)-tetrahydrofolic acid were added portion-wise and completely dissolved in 30 ml of an aqueous solution of D-glucosamine (3.58 g, 20 mmol) stirred under nitrogen. The resulting solution (pH 6.53) was freeze-dried, obtaining 8.72 g of the title product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19][CH3:20])[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19]([CH3:20])=[O:31])[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CSc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2o1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2o1
Temperature: 0 °C
Reaction time: 5 h
Yield: 73.6 %

Procedure:
A mixture of 6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole (522 mg, 1.39 mmol) and m-CPBA (282 mg, 1.39 mmol) in DCM (20 mL) was stirred at 0° C. for 5 h. The reaction mixture was washed with aq Na2S2O3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:1 to 1:5 petroleum ether/ethyl acetate to give 6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]oxaz-ole as a light yellow solid (400 mg, 73.7%). 1H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.48 (s, 1H), 8.40 (s, 1H), 7.68 (s, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.34 (d, J=9.3 Hz, 1H), 5.60 (s, 2H), 2.73 (s, 3H). LCMS (ESI) m/z 390 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:8])([CH3:7])[CH:5]([CH2:9][CH:10]=O)[CH2:4][CH:3]=1.[CH:12](=[O:15])[CH2:13][CH3:14]>N1CCCCC1.C(O)(=O)CCCCCCCCCCCCCCCCC.C(O)(=O)C>[CH3:14][C:13](=[CH:10][CH2:9][CH:5]1[CH2:4][CH:3]=[C:2]([CH3:1])[C:6]1([CH3:7])[CH3:8])[CH:12]=[O:15]
Reactant: CCC=O
Reactant: CC1=CCC(CC=O)C1(C)C
Agent: CCCCCCCCCCCCCCCCCC(=O)O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CC(C=O)=CCC1CC=C(C)C1(C)C
Temperature: 100 °C
Yield: 94.9 %

Procedure:
A 500 mL four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel was charged with 171 g (0.98 mol) of campholenic aldehyde (purity: 88%), 3.8 g (0.045 mol) of piperidine and 13.1 g (0.046 mol) of stearic acid, and the contents in the flask were stirred while heating at 100° C. Then, 91 g (1.6 mol) of propionaldehyde was gradually dropped into the flask for 6 h, and the resultant mixture was aged for 1 h and then cooled. Thereafter, 3.2 g (0.053 mol) of acetic acid was added to the mixture to remove amines therefrom, thereby separating the mixture into two layers. The thus separated organic layer was washed with water and separated into two layers, thereby obtaining 295 g (0.93 mol) of 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)-but-2-en-1-al (purity as measured by gas chromatography: 60.6%) (yield based on theoretical amount: 95%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:20])[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=2)=[O:11])=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:20])[C:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(C(=O)c1ccc(O)cc1)c1ccc(O)cc1
Temperature: -78 °C
Reaction time: 15 h

Procedure:
1,2-bis(4-methoxyphenyl)ethane-1,2-dione (5 g, 18.52 mmol) was dissolved in CH2Cl2 and cooled to −78° C. (solid occurred again). BBr3 (8.3 m, 87.82 mmol) was added and mixture was allowed to warm to room temperature and stirred for 15 hrs. TLC check showed 1,2-bis(4-methoxyphenyl)ethane-1,2-dione completely disappeared. The reaction mixture was poured into ice, extracted by EtOAc, washed with NaCl solution, dried over MgSO4. The solvent was removed by vacuum, and the residue was purified by column chromatography to give compound 5, 1,2-bis(4-hydroxyphenyl)ethane-1,2-dione, as confirmed by the following nuclear magnetic resonance (NMR) data obtained therefrom: 1H NMR (500 MHz, DMSO): δ 10.8 (s, 2H), 7.71 (d, J=8.8 MHz, 4H), 6.90 (d, J=8.8 MHz, 4H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=O)[CH2:7]Br)=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])O.[Na+]>C(O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]3[CH:7]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccn1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Brc1ccc(-c2cn3ccccc3n2)cc1
Yield: 84.8 %

Procedure:
15 g (54 mmol) of 4-bromophenacyl bromide and 5.2 g (55 mmol) of 2-aminopyridine were dissolved in 100 mL of ethanol. Then, 7.0 g of sodium hydrogen carbonate was added, and the resultant was heated under reflux for 6 hours. After completion of the reaction, generated crystals were filtered out, washed with water and ethanol, whereby 12.5 g (yield 85%) of 2-(4-bromophenyl)-imidazo[1,2-a]pyridine was obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C1CCCCC1.[CH3:19][O:20][C:21](=[O:36])[CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1.[H-].[Na+].[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=[O:47])[C:41]=1[NH:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51]>O1CCCC1>[F:39][C:40]1[C:41]([NH:48][C:49](=[O:54])[C:50]([CH3:52])([CH3:51])[CH3:53])=[C:42]([CH:46]([OH:47])[CH:22]([CH:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:27][CH2:28]2)[C:21]([O:20][CH3:19])=[O:36])[CH:43]=[CH:44][CH:45]=1
Reactant: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)C(=O)Nc1c(F)cccc1C=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: COC(=O)C(C1CCN(C(=O)OC(C)(C)C)CC1)C(O)c1cccc(F)c1NC(=O)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 81 %

Procedure:
Diisopropylamine (24.2 mmol, 3.40 mL) was dissolved in tetrahydrofuran (70 mL). The mixture was cooled to −78° C. 2N Butyllithium in cyclohexane (24.40 mmoles, 12.20 mL) was added drop-wise to the reaction. The mixture was held at −78° C. with stirring on and held for 20 minutes. A solution of tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (20.21 mmoles, 5.20 g) in 15 mL tetrahydrofuran was added to the mixture drop-wise. The mixture was held at −78° C. with stirring on and held for 45 min. In a seperate flask, 60% Sodium hydride in mineral oil (24.25 mmoles, 970.00 mg) was washed with hexanes then suspended in tetrahydrofuran (50.00 mL). The mixture was cooled to 0° C. A solution of N-(2-Fluoro-6-formylphenyl)pivalamide (20.16 mmoles, 4.50 g) in 20 mL tetrahydrofuran was added to the mixture drop-wise. The mixture was held at 0° C. with stirring on and held for 1 hr. Aldehyde mixture was added to the ester mixture drop-wise over 1.25 hours. The mixture was held at −78° C. with stirring on and held for 1 hr. The reaction was quenched with aq. ammonium chloride. Mixture was warmed to room temperature then diluted with water. The mixture was extracted 2 times with ethyl acetate and the aqueous phase was discarded. The material was dried (magnesium sulfate), filtered, and concentrated to dryness. Silica gel chromatography gave the title compound as white foam in 81% yield. MS m/e (M-C4H8O2+H)+=381.2.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[I:12][C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])I.IC(I)(C(F)(F)F)C(F)(F)F.C([O-])(=O)C>CS(C)=O.[Cu]>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:15]([F:18])([F:17])[C:14]([F:20])([F:19])[C:13]([F:22])([F:21])[I:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(I)cc1
Reactant: FC(F)(I)C(F)(F)C(F)(F)I
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: FC(F)(F)C(I)(I)C(F)(F)F
Solvent: CS(C)=O
Product: CC(=O)Oc1ccc(C(F)(F)C(F)(F)C(F)(F)I)cc1
Reaction time: 3.5 h

Procedure:
The first stage of the process (equation A) involves reacting p-iodophenyl acetate (II) with 1,3-diiodohexafluoropropane (III). The reaction is conducted in anhydrous dimethyl sulfoxide (DMSO) in the presence of copper powder. Equimolar amounts of the reactants can be used, but it is usually preferred to employ an excess of the diiodohexafluoropropane e.g., 1 to 1.5 moles per mole of the acetate. For every mole of acetate, at least 2, e.g., about 2 to 10, gram atoms of copper are utilized. The reaction is carried out in an inert atmosphere at a temperature ranging from about 110° to 130° C. Examples of gases suitable for providing an inert atmosphere include nitrogen, helium and argon. The reaction period usually ranges from about 2 to 5 hours. At the end of the reaction period, the reaction product is recovered from the reaction mixture. In a preferred procedure, the reaction mixture is allowed to cool after which saturated aqueous ammonium chloride and methylene chloride are added. The excess copper and cuprous salts are then filtered off, and the organic layer is separated. After extracting the aqueous layer with additional methylene chloride, the organic extracts are combined, washed with water, dried over anhydrous magnesium sulfate, and finally reduced in volume to a light yellow oil. The oil is refluxed in acetic anhydride for about 30 minutes to one hour followed by removal of excess acetic anhydride and acetic acid by vacuum distillation. Distillation of the residual oil yields crude 4-(perfluoro-3-iodopropyl)phenyl acetate (IV) which is then purified by recrystallization from hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](N)[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8].Cl.N([O-])=O.[Na+].[I-:18].[K+].OS(O)(=O)=O.II>O.C1(C)C=CC=CC=1>[I:18][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: [I-]
Reactant: COc1ccc(C(=O)O)c(N)c1
Agent: Cl
Agent: II
Agent: O=N[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C(=O)O)c(I)c1
Temperature: 75 °C
Yield: 52 %

Procedure:
A mixture of 4-methoxyanthranilic acid (30.5 g, 0.18 mol), water (274.5 ml), and concentrated HCl (36.6 ml) is heated at 75° C. to effect solution and then is cooled to 0° C. The mixture is then treated with NaNO2 (13.3 g) in water (27.5 ml), followed by potassium iodide (45.75 g) in a water (75 ml)/H2SO4 (10.1 ml) solution. The reaction mixture is heated on a steam bath for 2 hours, then excess iodine is steam distilled. The reaction mixture is then cooled, and the product is collected by filtration and dried in an oven at 75° C. to afford 39.28 g (78.6%) of crude product. The crude product is treated with toluene, the mixture is filtered, and the filtrate is concentrated to afford 26.03 g of 2-iodo-4-methoxybenzoic acid.