Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O.C1(C)C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>CCOC(C)=O>[O:12]=[C:10]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: O=C(O)CCCCc1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1CCCCc2sccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
To a mixture of 5-(2-thienyl)pentanoic acid (5.04 g) and toluene (50 ml) was dropwise added trifluoroacetic anhydride (6.95 ml) over 1 minute with ice-water cooling. The reaction mixture was stirred at room temperature (r.t.) overnight, and was poured into a mixture of a saturated aqueous solution of sodium hydrogen carbonate (NaHCO3) and AcOEt. The organic layer was washed with water and brine, and dried over MgSO4, and evaporated. The resulting oil was purified by chromatography on silica gel (SiO2) (20% AcOEt in n-hexane as eluent). The fractions including the object compound were combined and evaporated to give 4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene (1.57 g) as an oil.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[Li+].CCC[CH2-].[CH2:13]([N:20]([CH3:32])[S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Br)=[CH:26][CH:25]=1)(=[O:23])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1.O.Cl>[CH2:13]([N:20]([CH3:32])[S:21]([C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH:5]2[S:1][C:2](=[O:7])[NH:3][C:4]2=[O:6])=[CH:28][CH:29]=1)(=[O:23])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN(Cc1ccccc1)S(=O)(=O)c1ccc(CBr)cc1
Reactant: O=C1CSC(=O)N1
Agent: Cl
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1ccccc1)S(=O)(=O)c1ccc(CC2SC(=O)NC2=O)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 76.8 %

Procedure:
2,4-Thiazolidinedione (11 mmol, 1.3 g) was dissolved in tetrahydrofuran (50 ml) and cooled to -78° C. N-Butyllithium (22 mmol, 13.8 ml of 1.6M in hexane) was added over 15 minutes. The cooling bath was removed and the reaction mixture was stirred for 20 minutes. N-Benzyl-N-methyl-4-(bromomethyl)benzenesulfonamide (10 mmol, 3.5 g) dissolved in tetrahydrofuran (50 ml) was added over 20 minutes. The reaction mixture was heated to reflux for 15 hours, cooled and diluted with water (50 ml) and 6N HCl (10 ml). The mixture was extracted with ethyl acetate (75 ml) and the organic layer was dried (Na2SO4) and removed in vacuo. The residue was purified on silica gel using 1:1 hexane:ethyl acetate to afford 3.0 g of title product as a gum; MS 390 (m+), 269, 205.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:18])[C:14]=1[O:15][CH2:16][CH3:17])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:19][C:20]1[N:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:18][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][CH:27]=[N:28][C:20]=3[CH3:19])[C:14]=1[O:15][CH2:16][CH3:17])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CCOc1c(Cl)cc2c([nH]c3cnccc32)c1N
Reactant: Cc1ncccc1C(=O)O
Product: CCOc1c(Cl)cc2c([nH]c3cnccc32)c1NC(=O)c1cccnc1C
Yield: 40 %

Procedure:
The desired compound was prepared according to Method A from 6-chloro-7-ethoxy-9H-β-carbolin-8-ylamine and 2-methylnicotinic acid in 40% yield. 1H-NMR (300 MHz, MeOH-d4): δ 1.39 (t, 3H), 2.76 (s, 3H), 4.14 (q, 2H), 7.43 (dd, 1H), 8.05 (d, 1H), 8.26 (m, 3H), 8.55 (d, 1H), 8.79 (s, 1H).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([CH3:17])[C:10]=1[CH3:18]>C(OCC)(=O)C>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([NH:8][C:5](=[O:7])[CH3:6])=[C:10]([CH3:18])[C:11]=1[CH3:17])#[N:14]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(N)ccc(C#N)c1C
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(C#N)c(C)c1C
Reaction time: 4 h
Yield: 81.8 %

Procedure:
Acetic anhydride (1.36 ml, 14.4 mmol) was added to a solution of 4-amino-2,3-dimethylbenzonitrile (1.32 g, 9.03 mmol) in ethyl acetate (10 ml) at room temperature, and then the reaction was carried out for 4 hours under reflux conditions. After the reaction mixture was cooled, the precipitate obtained was collected by filtration and dried to obtain N-(4-cyano-2,3-dimethylphenyl)acetamide (1.39 g, 81.8%).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])C>Cl>[C:7]1(=[O:16])[N:6]([CH2:5][CH:4]=[O:3])[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]12
Reactant: CCOC(CN1C(=O)c2ccccc2C1=O)OCC
Agent: Cl
Product: O=CCN1C(=O)c2ccccc2C1=O
Yield: 88.1 %

Procedure:
Phthalimidoacetaldehyde diethyl acetal (100 g, 0.38 mol) and 1 N hydrochloric acid (600 ml) was mixture was stirred at reflux temperature for 5 min. or until a homogeneous solution is obtained. The reaction mixture was cooled and the precipitate was filtered off and dried in vacuo at 50° C. for 16 hours, which afforded 63.3 g (88%) of phthalimido-acetaldehyde as a solid.
Reaction SMILES: [CH:1]1[C:6]([CH2:7]Cl)=[CH:5][CH:4]=[C:3]([Cl:9])[CH:2]=1.[CH3:10][NH:11][CH3:12]>O1CCCC1.C(OCC)C>[CH3:10][N:11]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([Cl:9])=[CH:2][CH:1]=1)[CH3:12]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
The starting material is prepared as follows: The solution of 141 g of α,p-dichlorotoluene in 200 ml tetrahydrofuran is added dropwise to an ice-cold saturated solution of dimethylamine in 1 liter of tetrahydrofuran and the mixture stirred for 2 days at 25°. It is diluted with diethyl ether, washed with 2N aqueous sodium hydroxide, the organic layer dried, evaporated, the residue distilled and the fraction boiling at 106°/12 mm Hg collected, to yield the N,N-dimethyl-4-chlorobenzylamine.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][OH:14])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:17](/B(O)O)=[CH:18]\[CH2:19][CH2:20][CH2:21][CH3:22]>>[CH:17](/[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][OH:14])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[CH:18]\[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCC/C=C/B(O)O
Reactant: CCC(CO)Nc1ccc2ncc(Br)n2n1
Product: CCCC/C=C/c1cnc2ccc(NC(CC)CO)nn12
Yield: 38 %

Procedure:
Prepared from the product of step A and (E)-1-hexeneboronic acid according to general procedure 2 providing the title compound (27 mg, 38%) as an off-white solid; 1H NMR (500 MHz, CD3OD) δ 7.51 (d, J=9.7 Hz, 1H), 7.40 (s, 1H), 6.76-6.70 (m, 1H), 6.66 (d, J=9.7 Hz, 1H), 6.61 (d, J=16.1 Hz, 1H), 3.93-3.89 (m, 1H), 3.70-3.67 (m, 2H), 2.35-2.30 (m, 2H), 1.81-1.76 (m, 1H), 1.69-1.65 (m, 1H), 1.53-1.48 (m, 2H), 1.45-1.40 (m, 2H), 1.04-1.01 (t, J=7.3 Hz, 3H), 0.55 (t, J=7.3 Hz, 3H); 13C NMR (75 MHz, CD3OD) δ 155.6, 138.2, 133.3, 129.1, 128.9, 125.8, 117.2, 114.1, 64.2, 56.1, 34.8, 33.2, 35.4, 23.7, 14.7, 11.4; HPLC tR=12.9 min (Luna), 95.1%; ES-MS: (M+H)=289 m/z.
Reaction SMILES: CS[C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[N:9][C:5]=2[N:6]=[CH:7][N:8]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>>[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH:17][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[N:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CSc1ncnc2ncccc12
Reactant: Nc1cccc(Br)c1
Product: Brc1cccc(Nc2ncnc3ncccc23)c1
Temperature: 100 °C

Procedure:
A mixture of 4-methylthiopyrido[2,3-d]pyrimidine (157 mg, 0.89 mmol, and 3-bromoaniline (1 mL) is heated to 100° C. for 2 h. On cooling a precipitate forms which is filtered then washed with EtOH and air dried to yield 4-(3-bromoanilino)pyrido[2,3-d]pyrimidine (55.5 mg, 20%. 1H NMR (DMSO) δ 10.13 (1H, s), 9.11 (1H, dd, J=1.7, 4.3 Hz), 9.01 (1H, dd, J=1.7, 8.2 Hz), 8.81 (1H, s), 8.22 (1H, s), 7.90 (1H, d, J=7.7 Hz), 7.71 (1H, dd, J=4.3, 8.0 Hz), 7.40 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[O:25][CH2:24][CH2:23][NH:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)COc4ccccc4Cl)cc3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCOc4ccccc4Cl)cc3)c2cc1OC
Temperature: 0 °C
Yield: 79.9 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-2-(2-chlorophenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%). Mass spectrometry value (ESI-MS, m/z): 452 (M++1)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[Cl:36][C:37]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:38]=1[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[NH2:46]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:46][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[O:39][C:38]2[CH:47]=[CH:48][C:49]([Cl:51])=[CH:50][C:37]=2[Cl:36])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Nc1ccccc1Oc1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
A solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (489 mg, 2.13 mmol) in dry DCM (10 mL) was stirred under nitrogen, and 4-dimethylaminopyridine (DMPA, 40 mg, 0.327 mmol), (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 1.116 g, 5.82 mmol) and triethylamine (0.3 mL) were added. The resulting mixture was stirred for 30 min under nitrogen and 2-(2,4-dichlorophenoxy)phenylamine (AMR01026, 491 mg, 1.93 mmol) in dry DCM (5 mL) was added. After stirring at room temperature for 72 h, the mixture was diluted with DCM, washed with HCl 1M (3×25 mL), water, saturated NaHCO3 (2×25 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated to give 4-[2-(2,4-Dichlorophenoxy)phenylcarbamoyl]piperidine-1-carboxylic acid tert-butyl ester (754 mg, 84%) as a white solid (mp 120-121° C. from hexane), which was used in the next step without further purification. Rf: 0.31 (Hexane/EtOAc 7:3) LC/MS (APCI) tr=1.39 min, m/z 464.96 (21), 462.94 (M−−H, 32), 253.90 (66), 251.89 (100). 1H NMR (270 MHz, CDCl3) δ 1.44 (9H, s, 3CH3), 1.70 (2H, m, CH2), 1.86 (2H, br d, CH2), 2.40 (1H, tt, J=11.3, 3.7 Hz, CH), 2.77 (2H, br t, CH2), 4.14 (2H, m, CH2), 6.71 (1H, dd, J=8.2, 1.7 Hz, ArH), 6.94 (1H, d, J=8.9 Hz, ArH), 7.01 (1H, td, J=8.2, 1.5, ArH), 7.12 (1H, td, J=8.2, 1.5 Hz, ArH), 7.21 (1H, dd, J=8.9, 2.5 Hz, ArH), 7.48 (1H, d, J=2.5 Hz, ArH), 7.76 (1H, br s, NH) and 8.40 (1H, dd, J=7.9, 1.5 Hz, ArH).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1COCC1.[Br:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[C:33]([F:40])[CH:32]=1.Cl.[CH3:42][O:43][C:44](=[O:48])[CH2:45][CH2:46][NH2:47]>CCOC(C)=O.Cl>[Br:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:47][CH2:46][CH2:45][C:44]([O:43][CH3:42])=[O:48])=[O:37])=[C:33]([F:40])[CH:32]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: COC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCNC(=O)c1ccc(Br)cc1F
Temperature: 25 °C

Procedure:
Solid HATU (1.6 g, 4.2 mmol) was added to a THF solution (7 mL) of 4-bromo-2-fluorobenzoic acid (750 mg, 3.2 mmol), i-Pr2Net (1.1 mL, 6.4 mmol), and β-alanine methyl ester hydrochloride (584 mg, 4.2 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture was diluted with EtOAc and 1N aqueous HCl. The organic layer was separated, washed with brine, dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C@@H:12]([OH:23])[CH2:11][C@H:10]1[OH:24].C[Si](N(CC)CC)(C)C.C(OCC)(=O)C.CCCCCC>CC(C)=O.CCOCC>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:12](=[O:23])[CH2:11][C@H:10]1[OH:24]
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Agent: CCN(CC)[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O

Procedure:
A solution of 1.07 g of PGF2=, 1,15-lactone in 45 ml of anhydrous acetone was cooled under nitrogen to between -45° and -40° and treated with 4.5 ml of trimethylsilyldiethylamine. After the addition was complete (2-3 min.), the mixture was stirred at -42° ± 2° C. for 2 hours, by which time TLC (25% ethyl acetate/hexane) showd only a trace of starting material. The reaction mixture was then cooled to -78° , diluted with 150 ml of precooled ether (-78° ) and poured into ice/brine. After extraction with hexane, the combined organic layers were washed with aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the mono-trimethylsily derivative of PGE2α, 1,15-lactone.
Reaction SMILES: CON(C)[C:4]([C:6]12[CH2:13][CH2:12][C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.CCOC(C)=O>C1COCC1>[C:14]1([C:9]23[CH2:12][CH2:13][C:6]([CH:4]=[O:5])([CH2:11][CH2:10]2)[CH2:7][CH2:8]3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CON(C)C(=O)C12CCC(c3ccccc3)(CC1)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=CC12CCC(c3ccccc3)(CC1)CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice water cooled solution of N-methoxy-N-methyl-1-phenylbicyclo[2.2.2]octane-4-carboxamide (Intermediate 5; 8.49 g, 31.05 mmol) in anhydrous THF (100 mL) under nitrogen was added lithium aluminium hydride (1M solution in THF, 62 mL) dropwise and the reaction mixture was allowed to stir at 0° C. for 1 hr. Water (25 mL) was added cautiously followed by EtOAc (˜100 mL) and the mixture was filtered through a pad of celite washing with EtOAc (50 mL). The filtrate was washed with brine (150 mL), the organic phase separated, dried (MgSO4) and concentrated to leave the title compound as a colourless oil which formed a solid on standing (6.92 g, 32.28 mmol, 100%); 1H NMR (CDCl3) δ 1.72-1.83 (6H, m), 1.87-1.94 (6H, m), 7.17-7.22 (1H, m), 7.31-7.33 (4H, m), 9.53 (1H, s); GC-MS EI m/e M+ 214.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:11]=2[CH:10]=1)=[O:8].[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>C(Cl)Cl>[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([OH:17])[C:15]([C:22](=[O:23])[C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[F:19])=[CH:16][C:11]=2[CH:10]=1)=[O:8]
Reactant: O=C(Cl)c1ccccc1F
Reactant: COC(=O)C1=Cc2ccc(OC)cc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C1=Cc2cc(C(=O)c3ccccc3F)c(O)cc21

Procedure:
26.6 g of finely pulverised aluminium chloride are suspended in 60 ml of methylene chloride. While stirring and while cooling slightly, 9.61 g of 5-methoxybenzocyclobutene-1-carboxylic acid methyl ester, dissolved in a small amount of methylene chloride, are added dropwise at room temperature. After stirring for 30 minutes at room temperature, 15.85 g of o-fluorobenzoyl chloride are added dropwise thereto and the resulting reaction mixture is heated at reflux for 4 hours. After cooling, the reaction mixture is poured onto ice and extracted thoroughly with methylene chloride. The combined organic phases are washed with water, dried over magnesium sulphate and concentrated by evaporation. The yellow oily residue (20 g) is chromatographed over 400 g of silica gel with methylene chloride. Fractions 7-16 (50 ml fractions) are combined and concentrated. The residue is crystallised from ether/petroleum ether. 4-(o-fluorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid methyl ester is obtained in the form of yellow crystals having a melting point of 59°-61°.
Reaction SMILES: [CH3:1][C:2]1[C:17]([CH3:18])=[C:16]([O:19][CH2:20][C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:15]=[CH:14][C:3]=1[O:4][CH2:5][C:6](C1C=CC=CC=1)=O.BrCC([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=O.O>C1(C)C(C)=CC=CC=1>[CH3:18][C:17]1[C:16]2[O:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]=2[C:14]2[C:6]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:5][O:4][C:3]=2[C:2]=1[CH3:1]
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1c(OCC(=O)c2ccccc2)ccc(OCC(=O)c2ccccc2)c1C
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1c(C)c2occ(-c3ccccc3)c2c2c(-c3ccccc3)coc12

Procedure:
A mixture of 2-[2,3-Dimethyl-4-(2-oxo-2-phenyl-ethoxy)-phenoxy]-1-phenyl-ethanone (480 mg, 1.28 mmol) synthesized as described in Example 11, an excess of bromoacetophenone, and polyphosphoric acid (PPA, 100 mg) in xylene (10 mL) was stirred at 150° C. for 10 h. The mixture was then poured into water, extracted with EtOAc, the organic layer was washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column eluting with 10-20% EtOAc in hexane to give 190 mg of 4,5-dimethyl-1,8-diphenyl-benzo[1,2-b;4,3-b′]difuran (250 mg). 1H NMR (CDCl3, 300 MHz) δ: 7.60 (s, 2H), 7.05 (m, 4H), 6.90 (m, 2H), 6.85 (m, 4H), 2.60 (s, 6H) ppm. 13C NMR (CDCl3, 75 MHz) δ: 152.57,141.48, 133.19, 128.42, 127.52, 126.87, 124.05, 117.40, 116.29, 11.80 ppm. MS (m/z): 339 (M+H+).
Reaction SMILES: S([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(O)(=O)=O.[OH-:14].[Na+]>>[OH:14][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cccc(S(=O)(=O)O)c1
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)c1cccc(O)c1

Procedure:
The technical 3-sulphobenzoic acid melt, preferably not diluted, and the concentrated aqueous sodium hydroxide solution are pumped simultaneously into a mixing tube, the mixing tube being so designed that complete mixing takes place solely as a result of the turbulent flow produced. If desired the mixing process can also be assisted by internal fitments in the mixing tube, but this measure is not absolutely necessary. For example, 2,000 to 5,000 ml per hour of technical sulphonation melt can be mixed with corresponding quantities of sodium hydroxide solution in a mixing tube 500 mm in length and 5 mm in diameter, and can be conveyed into the reaction vessel for the subsequent pressure hydrolysis. This variant also can be carried out under normal pressure or under an elevated pressure, this elevated pressure being limited, if desired. If the initial temperatures of the components are suitably chosen, for example 150° to 180° C. for the sulphonation melt and 100° to 180° C. for the sodium hydroxide solution, a reaction temperature which is advantageous for the reaction to give 3-hydroxybenzoic acid, for example 270° to 320° C., will be reached at the end of the mixing tube. It can also be advantageous to carry out the mixing operation at a lower temperature or to limit the resulting steam pressure by blowing off steam. This process constitutes a partially continuous process in which the mixing operation in the mixing tube constitutes the continuous part of the process and the subsequent completion of the reaction in an autoclave constitutes the discontinuous part. However, since the reaction between the 3-sulphobenzoic acid and the alkali metal hydroxide becomes increasingly rapid in the upper part of the temperature range of 220° to 450° C. mentioned, it is also possible to complete the conversion into 3-hydroxybenzoic acid and thus the total reaction in a continuous form in the mixing tube itself, if the temperature is sufficiently high, for example in the region of 400° C. and if the corresponding pressure is maintained.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=3)=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1>>[CH2:1]([NH:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[O:24])=[CH:20][N:19]=3)=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: NCc1ccccn1
Reactant: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Product: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCc3ccccn3)cn2)CC1
Yield: 70 %

Procedure:
By the same procedure as described in the example 73, synthesis was carried out starting with 6-[1-[3-(ethylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using 2-(aminomethyl)pyridine. And then, the product was chromatographed on column (hexane/methylene chloride/ethyl acetate=2/1/1, v/v/v) and crystallized with ether to give a desired compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]/[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]>CO.[Pd]>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18]
Reactant: CC(C)(C)OC(=O)NC/C=C/c1ccccc1CO
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCc1ccccc1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 33-3 (0.987 g, 3.19 mmol) in MeOH (32 ml) was treated with Pd/C (0.339 g, 0.319 mmol) under an atmosphere of nitrogen in a three-necked round bottomed flask. The vessel was then briefly evacuated, then backfilled with a balloon containing Hydrogen gas. The reaction was stirred at RT for 2 hours, then filtered through celite, washed with MeOH, followed by dichloromethane. Filtrate was concentrated in vacuo and purified by reverse phase chromatography (C18 column, 5-95% MeCN in water with 0.1% TFA) to yield 33-4.