Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Cl[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CCCl
Reactant: Sc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCSc1ccccc1Br
Yield: 80.7 %

Procedure:
A mixture of 2-bromobenzenethiol (6 g, 30 mmol), ethyl 3-chloropropanoate (13 g, 96 mmol), K2CO3 (8.8 g, 64 mmol) and acetone (150 mL) was refluxed for 15 h. The reaction mixture was filtered and the filter cake washed with acetone (50 mL). The filtrate was concentrated to dryness and subjected to FCC to give ethyl 3-(2-bromophenylthio)propanoate (7 g, 78%). MS (ESI): mass calcd. for C11H13O2S, 287.98; m/z found, 288.8 [M+H]+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][O:31][CH3:32])[CH:24]=1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:32][O:31][CH2:30][O:29][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH2:13][CH:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH3:6])[CH:28]=[CH:27][CH:26]=1
Reactant: COCOc1cccc(CCc2ccccc2OCC2CCCN2C(=O)OC(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCOc1cccc(CCc2ccccc2OCC2CCCN2C)c1
Yield: 8.4 %

Procedure:
Following a procedure similar to that described in Example 38, 1.00 g of 1-t-butoxycarbonyl-2-{2-[2-(3-methoxymethoxyphenyl)ethyl]phenoxymethyl}pyrrolidine [prepared in a similar manner to that described in Example 40(a)] was reacted with a dispersion of 88.1 mg of lithium aluminum hydride in 10 ml of tetrahydrofuran. The mixture was then worked up as described in Example 38, and the crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 68 mg (yield 83%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].S(=O)(=O)(O)O.[CH2:10]([OH:12])[CH3:11]>>[CH:11]1([NH:1][C:2]([NH2:4])=[O:3])[NH:4][C:2](=[O:3])[NH:1][C:10]1=[O:12]
Reactant: NC(N)=O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: NC(=O)NC1NC(=O)NC1=O
Temperature: 25 °C

Procedure:
A mixture of 22.2 g of glyoxylic acid ethyl ester ethyl hemiacetal (0.15 mol), 30.0 g of urea (0.5 mol), 90 g of ethanol and 7.5 g of 8% strength ethanolic sulfuric acid was heated under reflux for 4 hours. Thereafter, the reaction had ended and the reaction mixture was cooled to room temperature, whereupon a colorless precipitate separated out, which was filtered off, washed three times with ethanol and dried in vacuo at 70° C. 24.5 g, that is to say 80% of theory, of allantoin acid ethyl ester were obtained by this reaction.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[C:11]([C:20]#[N:21])=[CH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[CH:9]=1)([CH3:3])[CH3:2].[OH-:24].[K+]>O.CC(O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[C:11]([C:20]([NH2:21])=[O:24])=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C#N
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C(N)=O

Procedure:
A solution of 5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile (727 mg, 2.28 mmol) and KOH (767 mg, 13.7 mmol) in H2O (7.70 mL) and i-PrOH (11.55 mL) was subjected to microwave irradiation (300 W 130° C., 4 h) in a sealed tube. The reaction mixture was concentrated in vacuo to remove the i-PrOH. The aqueous slurry obtained was diluted with water (50 mL) and extracted with EtOAc (50 mL). The organic extract was dried (Na2SO4) and concentrated in vacuo to afford 5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carboxamide. The aqueous layer was acidified with concentrated HCl and extracted with EtOAc (3×50 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give 5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carboxylic acid as a colorless solid. 1H NMR (CDCl3, 500 MHz) δ 8.01 (s, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.14 (d, J=8.1 Hz, 1H), 7.04 (s, 1H), 6.77 (d, J=8.1, 1H), 3.68 (s, 3H), 2.84 (septet, J=6.7 Hz, 1H), 1.19 (d, J=6.7 Hz, 6H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C([N:14]1[CH2:19][CH2:18][O:17][CH:16]([CH:20]=[C:21]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH2:25][CH2:24][C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]2=3)[CH2:15]1)C1C=CC=CC=1>C1C=CC=CC=1>[CH2:5]([O:4][C:2]([N:14]1[CH2:19][CH2:18][O:17][CH:16]([CH:20]=[C:21]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH2:25][CH2:24][C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]2=3)[CH2:15]1)=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: C(=C1c2ccccc2CCc2ccccc21)C1CN(Cc2ccccc2)CCO1
Solvent: c1ccccc1
Product: CCOC(=O)N1CCOC(C=C2c3ccccc3CCc3ccccc32)C1

Procedure:
Ethyl chloroformate (3.6 g) was added to 5-(4-benzylmorpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (3.13 g) in anhydrous benzene at room temperature, and the resulting mixture was heated under reflux for 5.5 hours. After cooling, the mixture was washed with a saturated aqueous sodium bicarbonate solution and water, dried and evaporated to afford 5-(4-ethoxycarbonylmorpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]-cycloheptene as oily material.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]([O:13][CH3:14])=[O:12].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]=[C:24]=[O:25])=[CH:18][C:17]=1[Cl:26].CCCCCC>C1COCC1>[Cl:26][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][C:16]=1[Cl:15])[CH2:22][NH:23][C:24]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]([O:13][CH3:14])=[O:12])=[O:25]
Reactant: COC(=O)n1ncc2c(N)cccc21
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)n1ncc2c(NC(=O)NCc3ccc(Cl)c(Cl)c3)cccc21
Reaction time: 3 h

Procedure:
The product of Example 90B (0.19 g, 1 mmol) in THF (3 mL) was treated with 1,2-dichloro-4-(isocyanatomethyl)benzene (0.22 g, 1.1 mmol) at ambient temperature. After stirring for 3 hours, hexane was added to the reaction mixture to precipitate the title compound as a tan solid (0.25 g). 1H NMR (300 MHz, DMSO-d6) δ 4.38 (d, 2H), 6.97 (t, 1H), 7.36 (dd, 1H), 7.48 (t, 1H), 7.6 (m, 2H), 7.7 (d, 1H), 7.8 (d, 1H), 8.45 (s, 1H), 9.16 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH2:18])[CH2:3]1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl.O>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH:18][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:3]1
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(C(F)(F)F)cc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC1(C)CC(c2ccccc2NS(C)(=O)=O)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4,4-dimethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl)aniline (150 mg) and pyridine (1 mL) in anhydrous dichloromethane (3 mL) was added methanesulfonyl chloride (36 μL) at ice-bath under nitrogen. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, concentrated. The residue was purified by HPLC to give N-[2-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-methanesulfonamide LC/MS m/e obsd. (ESI+) [(M+H)+] 399.6.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]([F:22])([F:21])[F:20])[C:10]=1[N+:23]([O-])=[O:24])([C:3]([O:5]CC)=O)=[O:2].CN(C)C=O.N>O1CCCC1.[Pd]>[F:16][C:15]([F:17])([F:18])[C:13]1[CH:14]=[C:9]2[C:10](=[C:11]([C:19]([F:20])([F:21])[F:22])[CH:12]=1)[N:23]([OH:24])[C:3](=[O:5])[C:1](=[O:2])[NH:8]2
Reactant: CCOC(=O)C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1[N+](=O)[O-]
Agent: [Pd]
Agent: N
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(C(F)(F)F)cc(C(F)(F)F)c2n(O)c1=O
Yield: 70 %

Procedure:
0.20 g (0.5 mmol) N-ethoxalyl-3,5-bistrifluoromethyl-2-nitroaniline in 10 ml tetrahydrofuran:dimethylformamide:25% aqueous ammonia (30:10:0.7) was hydrogenated at atm. pressure by using 5% Pd-C (0.02 g) as a catalyst. The reaction mixture was filtered and evaporated in vacuo. The residue was stirred with water, and the precipitate was filtered off to give 0.11 g (84%) of 6,8-bistrifluoromethyl-1-hydroxyquinoxaline- 2,3(1H,4H)-dione. M.p. decomp. 1H-NMR (DMSO-d6): 8.1 (s). MS (m/e): 314 (M+, 40%), 173 (45%), 69 (100%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][CH2:12][NH2:13])[CH:7]=[CH:8][CH:9]=1.[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([Cl:22])=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:14][C:15]1[N:20]=[C:19]([NH:13][CH2:12][CH2:11][CH2:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=2)[C:18]([Cl:22])=[CH:17][N:16]=1
Reactant: COc1cccc(CCCN)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(CCCNc2nc(Cl)ncc2Cl)c1
Yield: 91.1 %

Procedure:
To a solution of 3-(3-methoxyphenyl)propan-1-amine hydrochloride (2.00 g, 9.92 mmol) and 2,4,5-trichloropyrimidine (1.19 mL, 10.4 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (4.80 g, 34.7 mmol). The resultant mixture was stirred overnight at room temperature. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and brine successively, then dried (Na2SO4), filtered, and concentrated (then triturated with cold EtOAc) to give the desired product as a light brown gel (2.82 g, 91%). LCMS for C14H16Cl2N3O (M+H)+: m/z=312.0, 314.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]([OH:24])([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[CH2:17][CH3:18])[CH:5]=[C:6]([O:8]CC2C=CC=CC=2)[CH:7]=1.C([O-])=O.[NH4+]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:16]([OH:24])([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[CH2:17][CH3:18])[CH:5]=[C:6]([OH:8])[CH:7]=1
Reactant: CCC(O)(c1cc(F)cc(OCc2ccccc2)c1)c1nccs1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCC(O)(c1cc(O)cc(F)c1)c1nccs1
Yield: 79 %

Procedure:
To a solution of 5-fluoro-3-[1-hydroxy-1-(thiazol-2-yl)propyl](O-benzyl)phenol (200 mg, 0.58 mmol) in MeOH (9 mL) was added 10% Pd on charcoal (200 mg) and ammonium formate (180 mg, 2.9 mmol). The reaction mixture was refluxed for 2 h and then filtrated through a pad of celite and washed with EtOAc. After evaporation of the solvent, the residue was purified by chromatography on silica gel using a mixture of hexane:EtOAc 7:3 to give 116 mg (79%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][CH2:13][CH2:14][N:15]3CCN(C(OC(C)(C)C)=O)CC3)=[CH:8][C:7]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([F:36])[CH:29]=3)=[N:6]2)[CH2:3][CH2:2]1.C1(CN2C(=O)C(CCCOS(C)(=O)=O)=CC(C3C=CC(OC)=C(F)C=3)=N2)CC1>>[NH2:15][CH2:14][CH2:13][CH2:12][C:9]1[C:10](=[O:11])[N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:6]=[C:7]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([F:36])[CH:29]=2)[CH:8]=1
Reactant: COc1ccc(-c2cc(CCCN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CC3CC3)n2)cc1F
Agent: COc1ccc(-c2cc(CCCOS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Product: COc1ccc(-c2cc(CCCN)c(=O)n(CC3CC3)n2)cc1F
Yield: 67.8 %

Procedure:
Following the procedure of Example 24 (1), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one was reacted to yield a crude product. Without purification, the crude product was reacted further in accordance with the procedure of Example 24 (2) to yield the title compound as a yellow oil (yield: 67.8%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([C:43]1[CH:44]=[N:45][C:46]([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)=[N:47][CH:48]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].[CH2:56]([O:59][C:60]1[CH:64]=[C:63]([CH2:65]O)[O:62][N:61]=1)[CH2:57][CH3:58]>C1COCC1>[CH2:32]([C:43]1[CH:44]=[N:45][C:46]([C:49]2[CH:50]=[CH:51][C:52]([O:55][CH2:65][C:63]3[O:62][N:61]=[C:60]([O:59][CH2:56][CH2:57][CH3:58])[CH:64]=3)=[CH:53][CH:54]=2)=[N:47][CH:48]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCOc1cc(CO)on1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCc1cnc(-c2ccc(OCc3cc(OCCC)no3)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A fully reacted mixture of equimolar amounts of diethyl azodicarboxylate and triphenylphosphine in THF is admixed with equimolar amounts of 4-(5-undecyl-pyrimidin-2-yl)phenol and 3-propyloxy-isoxazol-5-yl-methanol (prepared by LiAlH4 reduction of methyl 3-propyloxy-isoxazole-5-carboxylate). The mixture is stirred for 24 h at room temperature and then evaporated to dryness under reduced pressure. Purification by chromatography (silica gel, dichloromethane) and recrystallization affords the target compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].C1C=CC=CC=1.N1CCCCC1>O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[C:13]([C:14]([CH3:16])=[O:15])[C:12]([O:18][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][N:24]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:25][CH2:26]1)=[O:17])([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: C1CCNCC1
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of m-nitrobenzaldehyde (1.67 g), 2-(4-benzhydryl-1-piperazinyl)ethyl acetoacetate (4.20 g), benzene (40 ml) and piperidine (0.05 g) was refluxed for 4 hours, during which time the water produced was removed using a Dean-Stark trap. The mixture was washed with water and dried (MgSO4). The solvent was then distilled off and the residue was purified by column chromatography on silica gel (100 g) [eluent: ethyl ether-ethyl acetate (10:1, v/v)] to give 2-(4-benzhydryl-1-piperazinyl)ethyl 2-(3-nitrobenzylidene)acetoacetate as an oil. Yield 4.37 g.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]([C:31](=[O:33])[CH3:32])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=3[O:29][CH3:30])=[CH:17][CH:16]=2)[CH:8]=1)C.O.[OH-].[Li+].O1CCCC1>O>[C:31]([N:6]([CH2:5][C:4]([OH:34])=[O:3])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=3[O:29][CH3:30])=[CH:19][CH:20]=2)[CH:8]=1)(=[O:33])[CH3:32]
Reactant: CCOC(=O)CN(C(C)=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3OC)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc(N(CC(=O)O)C(C)=O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottom flask containing {acetyl-[3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-phenyl]-amino}-acetic acid ethyl ester (10 mg, 0.02 mmol) was added lithium hydroxide hydrate (2 mg, 0.05 mmol), tetrahydrofuran (0.5 mL) and water (0.5 mL). The reaction was stirred at room temperature overnight, diluted with ethyl acetated (25 mL) and washed with aqueous HCl (0.1 M, 25 mL) and brine (25 mL), dried over magnesium sulfate, concentrated and dried from hexanes/methylene chloride mixtures to yield {acetyl-[3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-phenyl]-amino}-acetic acid as an off white solid (12 mg, 127%) LC-MS (ES) calculated for C24H21F2NO5, 441.14; found m/z 442 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([C:17]([O:19]C)=[O:18])[C:14]3[C:9](=[C:10]([O:21][CH3:22])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1>[C:1]1([C:7]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[C:14]3[C:9](=[C:10]([O:21][CH3:22])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc(-c2ccccc2)nc2c(OC)cccc12
Solvent: C1CCOC1
Product: COc1cccc2c(C(=O)O)cc(-c3ccccc3)nc12

Procedure:
An anhydrous THF (50 ml) solution containing 4.0 g of methyl 2-phenyl-8-methoxyquinoline-4-carboxylate formed from 2-phenyl-8-methoxyquinoline-4-carboxylic acid in a usual manner was added to guanidine formed from 6.50 g of guanidine hydrochloride in the same manner as in [C] of Example 1 at room temperature. Subsequently, the mixture was heat-refluxed for 3 hours, and cooled to room temperature. The reaction mixture was then concentrated under reduced pressure, and ice water was added to the residue. The precipitate formed was collected by filtration, washed with ethyl ether, and dried to obtain 3.59 of the above-mentioned compound as a white crystal. m.p. 232°-235° C. (decomp.)
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([OH:18])[C:5]2[C:6](=O)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1.COC1C=C(OC)C2C(=O)CC3C=CC=CC=3SC=2C=1>>[C:16]1([OH:18])[C:5]2[CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=[C:2]([OH:1])[CH:17]=1
Reactant: O=C1Cc2ccccc2Sc2cc(O)cc(O)c21
Agent: COc1cc(OC)c2c(c1)Sc1ccccc1CC2=O
Product: Oc1cc(O)c2c(c1)Sc1ccccc1CC2

Procedure:
The invention further relates in essence to a process for producing diaryl sulfide derivatives or salts thereof in which 7,9-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one which is the diol compound of the formula (6) or 7,9-dimethoxy-10,11-dihydrodibenzo[b,f]thiepin-10-one which is the dimethoxy compound of the formula (5) is reduced and deprotected to yield 10,11-dihydrodibenzo[b,f]thiepin-1,3-diol of the formula (7):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1ccc(OC2CCNCC2)nc1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCC(Oc2ccc(Cl)cn2)CC1
Yield: 73.6 %

Procedure:
5-Chloro-2-(piperidine-4-yloxy)-pyridine (2.13 g; 10 mmol) (preparation of this compound was made as described in WO 99-GB2801), diisopropylethylamine (2.20 ml; 12.5 mmol) and Methanesulfonyl chloride (1.56 ml; 10.1 mmol) gave 2.14 g (74%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCO.O.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>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH:10]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc(-c2cccnc2)ncn1
Temperature: 125 °C

Procedure:
A mixture of 6-chloropyrimidin-4-amine (0.324 g, 2.5 mmol), pyridin-3-ylboronic acid (0.385 g, 3.13 mmol), Na2CO3 (0.795 g, 7.5 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.05 mmol) were suspended in a mixture of dioxane/EtOH/water. The mixture was heated in the microwave synthesizer at 125° C. for 20 min (reaction was run twice) and concentrated. The residue was purified on by silica gel chromatography using a 10-60% ethyl acetate/hexanes gradient, followed by a 5-25% 9:1 methanol:ammonium hydroxide in ethyl acetate gradient. The desired fractions were concentrated to give an off-white solid. MS(LC/MS) R.T.=0.28; (M+H=173.13).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH:5]1[CH2:10][CH2:9][C:8]2([CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[CH2:7][CH2:6]1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:1]([N:5]1[CH2:10][CH2:9][C:8]2([CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: c1ccc2c(c1)CC1(CCNCC1)O2
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCC2(CC1)Cc1ccccc1O2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3 ml of acetyl chloride in 10 ml of chloroform are added dropwise to a stirred suspension of 6.0 g of 2,3-dihydrospiro[benzofuran-2,4'-piperidine], Example 7, and 14.0 g of sodium bicarbonate in 75 ml of chloroform. After total addition, the reaction mixture is successively stirred at ambient temperature for 16 hours, filtered, washed sequentially with water, dilute hydrochloric acid and a saturated sodium chloride solution, dried and the solvent is removed under reduced pressure, leaving a residue which solidifies upon standing. The solid is recrystallized twice from hexane to give the product, 2,3-dihydro-1'-acetylspiro[benzofuran-2,4'-piperidine], mp 94°-97° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH:5]=[O:6].[CH2:7](O)[CH:8]=[CH2:9].S(=O)(=O)(O)O>CCCCCC>[CH2:9]([O:6][CH:5]1[CH2:4][CH2:3][CH2:2][O:1]1)[CH:8]=[CH2:7]
Reactant: C=CCO
Reactant: O=CCCCO
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Product: C=CCOC1CCCO1
Yield: 69.2 %

Procedure:
The procedure of Example 1 is followed with 4-hydroxybutanal (250 g of 11.0 wt. % solution, 0.31 mol, 1.0 eq.), allyl alcohol (13.8 g, 0.24 mol, 0.80 eq.), and hexanes (500 mL). Concentrated sulfuric acid (0.5 mL) is used in place of the ion-exchange resin. After stirring for 18 h at room temperature the hexane phase contains 5.96% of 2-allyloxytetrahydrofuran (21.3 g, 70% yield). The aqueous phase contains 5.3% of 4-hydroxybutanal and 1.9% of allyl alcohol.
Reaction SMILES: C1C2CC3C(=CC=CC=3)C=2C=CC=1.[F:14][C:15]1[C:27]2[C:26]3[C:21](=[CH:22][C:23]([F:28])=[CH:24][CH:25]=3)[C:20](=O)[C:19]=2[CH:18]=[C:17]([NH2:30])[CH:16]=1.I>C(O)(=O)C>[F:14][C:15]1[C:27]2[C:26]3[C:21](=[CH:22][C:23]([F:28])=[CH:24][CH:25]=3)[CH2:20][C:19]=2[CH:18]=[C:17]([NH2:30])[CH:16]=1
Reactant: Nc1cc(F)c2c(c1)C(=O)c1cc(F)ccc1-2
Agent: I
Agent: c1ccc2c(c1)Cc1ccccc1-2
Solvent: CC(=O)O
Product: Nc1cc(F)c2c(c1)Cc1cc(F)ccc1-2
Yield: 85.2 %

Procedure:
(Namkung, M. J.; Fletcher, T. L.; Wetzel, W. H. Derivatives of Fluorene. XX. Fluorofluorenes. V. New Difluoro-2-acetamidofluorenes for the Study of Carcinogenic Mechanisms. J. Med. Chem. 1965, 8, 551-554, the disclosure of which is herein incorporated by reference). To a 25 mL round-bottomed flask containing 4,7-difluoro-9-oxo-2-fluorenamine (EXAMPLE 32) (158.5 mg, 0.686 mmol) in 4.25 mL glacial acetic acid was added red phosphorous (425 mg, 13.7 mmol, 20 equiv) and 57% aqueous HI (0.51 mL). The mixture was heated to reflux for 40 h, then evaporated to near-dryness by distillation. Boiling water (5 mL) was added, and the hot mixture was filtered. Upon addition of 10% NH4OH (20 mL), a white precipitate formed, and was filtered, washed with water, and dried under vacuum to afford 127 mg (85%) of 4,7-difluoro-2-fluorenamine as a white solid, mp 119°-120° C. (lit. mp 119.5°-121° C.). Data for 4,7-difluoro-2-fluorenamine: 1H NMR (400 MHz, CDCl3) 7.70 (dd, J=8.4, 5.2, 1H), 7.15 (dd, J=9.0, 2.0, 1H), 7.03 (app dt, J=9.0, 2.0,1H), 6.63 (s, 1H), 6.39 (dd, J=11.6, 1.7, 1H), 3.83 (s, 2H), 3.80 (br s, 2H).