Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C@@H:5]1[CH2:10][C:9]2[C:11]([O:15][CH3:16])=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6]1)([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].[Br:22]Br.Cl>C(O)(=O)C.C(OCC)C>[Br:22][C:14]1[C:8]2[O:7][CH2:6][C@H:5]([NH:4][CH:1]([CH3:3])[CH3:2])[CH2:10][C:9]=2[C:11]([O:15][CH3:16])=[CH:12][CH:13]=1
Reactant: BrBr
Reactant: COc1cccc2c1C[C@@H](NC(C)C)CO2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1ccc(Br)c2c1C[C@@H](NC(C)C)CO2
Yield: 62 %

Procedure:
(R)-3-(N-Isopropylamino)-5-methoxy-3,4-dihydro-2H-1-benzopyran (4.02 g, 18.2 mmol) and anhydrous sodium acetate were dissolved in acetic acid (80 mL). To the stirred mixture was bromine (0.93 mL, 18.2 mmol) dissolved in acetic acid (40 mL) added dropwise under 1.5 h. The solvent was removed in vacuo, taken into a 2M NaOH solution and extracted twice with diethyl ether. The combined ether portions were treated with brine, dried (Na2SO4), filtered, and the solvent was removed in vacuo to give the crude residue. The hydrochloride salt was made by dissolving the pure base in diethyl ether and adding an excess of an ethereal HCl solution to give a white solid. The salt was recrystallized twice from ethanol/diethyl ether to give 3.8 g (62% yield) Mp: 257°-8° C. [α]21D =-97.7° (C=0.1 CHCl3). The free base was made from the hydrochloride salt to give an oil. GC-MS (70 eV) M=301 (100%).
Reaction SMILES: [CH3:1][C:2](OC(C)=O)=[O:3].[CH2:8]1[O:17][C:16]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=2[O:9]1.CO>O1CCOCC1>[O:17]1[C:16]2[CH:15]=[CH:14][C:12]([NH:13][C:2](=[O:3])[CH3:1])=[CH:11][C:10]=2[O:9][CH2:8]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: CC(=O)OC(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)Nc1ccc2c(c1)OCO2
Temperature: 16 °C
Reaction time: 16 h
Yield: 86.1 %

Procedure:
Ac2O (21.4 mL, 226 mmol) was added dropwise to a stirred solution of 3,4-methylendioxyaniline (217) (25.87 g, 189 mmol) in dioxane (200 mL) at 0° C. and the mixture was stirred at 16° C. for 16 h. MeOH (10 mL) was added to decompose excess Ac2O and the solvent evaporated. The residue was dissolved in EtOAc (200 mL), dried and the solvent evaporated. The residue was filtered through a short column of silica, eluting with a gradient (50-100%) of EtOAc/pet. ether, to give acetamide 218 (29.17 g, 86%) as a white solid: mp 133-135° C. [lit (Krasso, A. & Ramuz, H., U.S. Pat. No. 4,599,347, 1986) mp (toluene) 138-139° C.]; 1H NMR δ 7.09 (d, J=1.8 Hz, 1H, H-4), 7.06 (br s, 1H, NH), 6.77 (dd, J=8.3, 1.8 Hz, 1H, H-6), 6.72 (d, J=8.3 Hz, 1H, H-7), 5.94 (s, 2H, H-2), 2.14 (s, 3H, CH3).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([O:10]C)=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1)[CH3:2].[Cl:18]N1C(=O)CCC1=O.[OH-].[Na+]>O1CCCC1>[Cl:18][C:13]1[CH:14]=[N:15][N:16]([CH3:17])[C:12]=1[C:4]1[CH:5]=[C:6]([C:8]([OH:10])=[O:9])[S:7][C:3]=1[CH2:1][CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCc1sc(C(=O)OC)cc1-c1ccnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (300 mg, 1.2 mmol) [Prepared in Example 98] and N-chlorosuccinimide (160 mg, 1.2 mmol) in tetrahydrofuran (6 ml) was stirred in a sealed tube for 1 h at 70° C. 6N sodium hydroxide (1 ml, 5.99 mmol) was added in one portion and the solution stirred an additional 1 h. The reaction mixture was then partitioned between H2O-DCM and the pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated then purified via column chromatography (silica, 20% EtOAC in hexanes) yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (325 mg, 1.20 mmol, 100% yield) as a yellow oil: LCMS (ES) m/e 271, 273 (M, M+2)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[CH:7][NH:6][N:5]=1.[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][C:15](F)=[C:14](C)[C:13]=1[C:20]([F:23])([F:22])[F:21]>CCCCCC.CN(C)C=O>[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][C:15]([N:6]2[CH:7]=[CH:8][C:4]([CH3:3])=[N:5]2)=[CH:14][C:13]=1[C:20]([F:21])([F:23])[F:22]
Reactant: COC(=O)c1ccc(F)c(C)c1C(F)(F)F
Reactant: Cc1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2ccc(C)n2)cc1C(F)(F)F
Yield: 59.7 %

Procedure:
Sodium hydride (60% suspension in oil, 3.85 g, 96.3 mmol) was washed with hexane, dried under nitrogen and resuspended in dry dimethylformamide (150 mL). A solution of 3-methylpyrazole (7.75 mL, 96.3 mmol) in dimethylformamide (50 mL) was added dropwise at ambient temperature. Stirring was continued until the gas evolution subsided, and then a solution of methyl 4-fluoro-2-trifluoromethylbenzoic acid methyl ester of Step A (17.8 g, 80.1 mmol) in dimethylformamide (50 mL) was added dropwise to the clear solution. After stirring for 30 min at room temperature, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and evaporated to dryness. The residue was dissolved in 1:1 mixture of dichloromethane and hexane and absorbed onto a silica Merck-60 flash column. Elution with a dichloromethane-hexane gradient (from 1:1 to 4:1) provided the title compound (13.6 g) as a white solid, m.p. 59-61° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2.[N+:14]([O-])([O-:16])=[O:15].[K+]>OS(O)(=O)=O>[CH3:1][C:2]1[C:10]([N+:14]([O-:16])=[O:15])=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(C)c2c(c1)NC(=O)C2=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc2c(c(C)c1[N+](=O)[O-])C(=O)C(=O)N2
Temperature: 0 °C
Yield: 77.2 %

Procedure:
The method of Cheesman, G. W. H.; J. Chem. Soc. 1170 (1962), was adapted. 4,6-Dimethylisatin (89 mg, 0.50 mmol) was dissolved in concentrated H2SO4 (1.0 mL) at 0° C. for 30 min with stirring, then KNO3 (55 mg, 0.55 mmol, Baker) was added to this solution. The mixture was stirred at 25° C. for 24 h. It was then poured into ice water (5 g). The resulting precipitate was collected by filtration. The precipitate was dissolved in 1N KOH (5 mL) and the small amount of solid was removed by filtration, then the filtrate was acidified to pH 2 with 4N HCl (~1 mL) to give a yellow precipitate. The solid was collected by filtration and was washed with water (2×1 mL), then it was dried in the air at 50° C. for 4 h affording pure (by NMR) title compound (85 mg, 77%) as a yellow powder. Crystallization from acetone/water gave crystals. Mp 278°-80° C. (dec.). IR (KBr, cm-1): 3452, 3225, 2931, 1780, 1742, 1635, 1608, 1535. 1H NMR (DMSO-d6): δ 11.357 (s, 1H), 6.771 (s, 1H), 2.389 (s, 3H), 2.305 (s, 3H). Purity >97.5% by HPLC.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:17][CH2:18][C:19]([NH:21][C@H:22]([C:30]([NH:32][CH3:33])=[O:31])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:20])=[O:16])[C:10](=[O:34])[CH:9]1[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42]CC2C=CC=CC=2)=[CH:38][CH:37]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:17][CH2:18][C:19]([NH:21][C@H:22]([C:30]([NH:32][CH3:33])=[O:31])[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:20])=[O:16])[C:10](=[O:34])[CH:9]1[CH2:35][C:36]1[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][CH:41]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CN1CCN(C(=O)OC(C)(C)C)C(Cc2ccc(OCc3ccccc3)cc2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CN1CCN(C(=O)OC(C)(C)C)C(Cc2ccc(O)cc2)C1=O

Procedure:
Protected-piperazinoneacetyl-gly-phe-NHCH3, 10a, (6.71 g, 1.00×10-2 mole) in ethanol (100 ml) is hydrogenated in a Parr apparatus at 40 psi over 10% Pd/C (0.5 g). After the reaction has absorbed one equivalent of hydrogen, the catalyst is filtered and washed with ethanol. The filtrate is evaporated at reduced pressure, affording 11a.
Reaction SMILES: C[N:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:14][CH:13]=2)[CH:5]=[CH:4][CH:3]1[C:28](O)=[O:29].Cl.[CH2:32]([NH2:34])[CH3:33]>>[CH2:32]([NH:34][C:28]([C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:14][CH:13]=3)[CH:9]=[N:8][CH:7]=2)[N:2]=1)=[O:29])[CH3:33]
Reactant: CCN
Reactant: CN1c2c(cncc2-c2ccc(OCCOC3CCOCC3)cc2)C=CC1C(=O)O
Agent: Cl
Product: CCNC(=O)c1ccc2cncc(-c3ccc(OCCOC4CCOCC4)cc3)c2n1
Yield: 31.2 %

Procedure:
Using N-methyl-8-{4-[2-(tetrahydro-2H-pyran-4-yloxy)ethoxy]phenyl}-1,6-naphthyridine-2-carboxylic acid (300 mg, 0.76 mmol) produced in the synthetic process in Example 9 (9a) and ethylamine hydrochloride (616 mg, 7.61 mmol), the desired title compound (100 mg, yield 31%) was obtained by the same method as in Example 10.
Reaction SMILES: [C:1]1([CH3:33])[CH:6]=[CH:5][C:4]([N:7]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]3([CH2:29][C:30](O)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:17][CH2:16]2)[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:3][CH:2]=1.[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:34][S:35]([NH:38][C:30]([CH2:29][C:23]1([CH2:22][CH2:21][N:18]2[CH2:19][CH2:20][CH:15]([N:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:33])=[CH:6][CH:5]=3)[C:8]([C:10]3[O:11][CH:12]=[CH:13][CH:14]=3)=[O:9])[CH2:16][CH2:17]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:31])(=[O:37])=[O:36]
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC(=O)O)CCCCC3)CC2)cc1
Reactant: CS(N)(=O)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC(=O)NS(C)(=O)=O)CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 98.1 %

Procedure:
[1-[2-[4-[N-(p-Tolyl)-2-furancarboxamido]-piperidin-1-yl]ethyl]cyclohexyl]acetic acid (synthesized in Example 3B-1) (203 mg), methanesulfonamide (84 mg), 1,3-dicyclohexylcarbodiimide (101 mg) and 4-dimethylaminopyridine (59 mg) were dissolved in dichloromethane (5 mL). The solution was stirred at room temperature for 4 days. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, dichloromethane-methanol (10:1)] to give the title compound (233 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:4]1=[O:18])[CH3:2].[O:19]=[S:20]1(=[O:35])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22](=[O:29])[N:21]1[CH2:30][CH2:31][CH2:32][CH2:33]Br.C(OCC)C>O>[O:19]=[S:20]1(=[O:35])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22](=[O:29])[N:21]1[CH2:30][CH2:31][CH2:32][CH2:33][N:15]1[CH2:16][CH2:17][CH:12]([N:5]2[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:3]([CH2:1][CH3:2])[C:4]2=[O:18])[CH2:13][CH2:14]1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Reactant: CCn1c(=O)n(C2CCNCC2)c2ccccc21
Solvent: O
Solvent: CCOCC
Product: CCn1c(=O)n(C2CCN(CCCCN3C(=O)c4ccccc4S3(=O)=O)CC2)c2ccccc21

Procedure:
From 4-(3-ethyl-2-oxo-1-benzimidazolinyl)piperidine and 1,1-dioxido-2-(4-bromobutyl)-1,2-benzisothiazol-3(2H)-one (prepared as shown in Example 21) using the procedures described in Example 1 there was obtained a white solid as the freebase (from diethyl ether), melting point 124-25° C. Analysis calculated for C25H30N4O4S.0.4 H2O: C, 61.30; H, 6.34; N, 11.44; found: C, 61.34; H, 6.18; N, 11.47. The NMR was consistent with the structure.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:25])[C:12]([C:20]([O:22]CC)=[O:21])=[CH:13][N:14]3[CH:17]3[CH2:19][CH2:18]3)=[C:9]([CH3:26])[C:8]=2[F:27])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH-].[Na+].C(O)C>O>[N:1]1([C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:25])[C:12]([C:20]([OH:22])=[O:21])=[CH:13][N:14]3[CH:17]3[CH2:18][CH2:19]3)=[C:9]([CH3:26])[C:8]=2[F:27])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)c(C)c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(F)c(N2CCNCC2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 56.4 %

Procedure:
To ethyl 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (23 mg) are added 10% aqueous solution of sodium hydroxide (3 ml) and ethanol (3 ml), and the mixture is refluxed for 1 hour. After cooling, the reaction mixture is diluted with water and washed with dichloromethane. After the aqueous layer is made acidic with acetic acid and then made weak alkaline with an aqueous sodium hydrogen carbonate. The resultant is extracted with dichloromethane and the extract is dried. The solvent is distilled off under reduced pressure and to the residue is added ethanol. The precipitated crystals are filtered and recrystallized from dimethylformamide to give 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (12 mg), as white powder, m.p. 231°-233° C.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:8]([N:10]1[CH2:21][CH2:20][CH2:19][C@H:11]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:9])[CH3:7])=[O:4].[H][H]>CO.[Pd]>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:8]([N:10]1[CH2:21][CH2:20][CH2:19][C@H:11]1[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[O:9])[CH3:7])=[O:4]
Reactant: C[C@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H](NC(=O)CN)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C

Procedure:
2.06 g of Z-Gly-Ala-Pro-OtBu are hydrogenated in 30 ml of methanol in the presence of 300 mg of Pd on charcoal (10%) at room temperature. The hydrogen uptake has ended after 90 minutes. The catalyst is filtered off and the filtrate is concentrated to about 5 ml. 10 ml of ether are added. The product crystallises out overnight. Melting point 132°-134° C.; Rf = 0.3 in the system chloroform-methanol (1:1) on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:23])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.[CH2:24]=[O:25]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:23])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH2:24][OH:25]
Reactant: O=C(c1ccccc1Cl)c1cc([N+](=O)[O-])ccc1-n1ccnc1
Reactant: C=O
Solvent: Cc1ccccc1C
Product: O=C(c1ccccc1Cl)c1cc([N+](=O)[O-])ccc1-n1ccnc1CO

Procedure:
In the manner given in Example 1, 2'-chloro-5-nitro-2-(imidazol-1-yl)benzophenone is heated in a bomb with paraformaldehyde in xylene to 140° C. to give 2'-chloro-5-nitro-2-[2-(hydroxymethyl)imidazol-1-yl]-benzophenone.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[S:12][C:13]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[NH2:10][C:11]1[S:12][C:13]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17]
Reactant: [H][H]
Reactant: NC(=O)c1cc(-c2ccc(F)cc2F)sc1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: NC(=O)c1cc(-c2ccc(F)cc2F)sc1N
Temperature: 25 °C

Procedure:
A suspension of benzyl[3-(aminocarbonyl)-5-(2,4-difluorophenyl)-2-thienyl]carbamate (240 mg, 0.618 mmol) and 10% palladium on carbon (326 mg, 0.306 mmol) in ethanol (130 mL) was placed under a hydrogen atmosphere by performing 5×15 second vacuum/hydrogen purge (supplied by balloon) fill cycles while vigorously stirring the mixture. The reaction was heated to reflux for 18 hours and then allowed to cool to ambient temperature. The suspension was filtered; the filtrate was collected and concentrated to yield the title compound as a light yellow solid.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[F:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:26][C:27]1[C:32]([C:2]2[N:6]([S:7]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=2)=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: OB(O)c1cccnc1F
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 105 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
A suspension of tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), (2-fluoropyridin-3-yl)boronic acid (221 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (173 mg) in 1,2-dimethoxyethane (10 mL) and water (5 mL) was stirred at 105° C. for 1 hr. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→1:1) to give the title compound as a pale-yellow oil (yield 310 mg, 69%).
Reaction SMILES: [CH3:1][C:2](=[CH:5][C:6]#[C:7][C:8]([CH3:12])=[CH:9][CH2:10][OH:11])[CH:3]=[O:4].[H][H].N1C2C(=CC=CC=2)C=CC=1>C(=O)([O-])[O-].[Ca+2].[Pd+2].C(=O)([O-])[O-].C1(C)C=CC=CC=1>[CH3:1][C:2](=[CH:5][CH:6]=[CH:7][C:8]([CH3:12])=[CH:9][CH2:10][OH:11])[CH:3]=[O:4]
Reactant: CC(C#CC=C(C)C=O)=CCO
Reactant: [H][H]
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: Cc1ccccc1
Solvent: c1ccc2ncccc2c1
Product: CC(C=O)=CC=CC(C)=CCO

Procedure:
The residue obtained (240 g.) is dissolved in 1800 ml. of acetone, treated with 300 ml. of N-sulfuric acid and allowed to stand at room temperature in a nitrogen atmosphere for 1 hour. Then the reaction mixture, after dilution with 4000 ml. of water, is taken up in ether. The ether extract is washed with sodium bicarbonate solution and water, dried over sodium sulfate, filtered, and evaporated. 170 g. of crude 2,6-dimethyl-8-hydroxy-2,6-octadien-4-in-1-al is obtained which can be purified through adsorption on aluminum oxide (activity II deactivated by the addition of 7 per cent water). A small portion is removed by washing with petroleum ether/ether mixture (4:1). By elution with a petroleum ether/ether mixture (3:2) there is obtained pure 2,6-dimethyl-8-hydroxy-2,6-octadien-4-in-1-al (Abs. Max. 312 mμ; E11 = 1200) (in 96 per cent ethyl alcohol). 125 g. of 2,6-dimethyl-8-hydroxy-2,6-octadien-4-in-1-al are dissolved in 600 ml. of toluene and hydrogenated until the cessation of hydrogen takeup after the addition of 15 g. of a lead/palladium-calcium carbonate catalyst and 2 ml. of quinoline in the usual manner. After filtration and evaporation of the solution, there is obtained 2,6-dimethyl-8-hydroxy-2,4,6-octatrien-1-al.
Reaction SMILES: [CH3:1][N:2](C(OC(C)(C)C)=O)[CH:3]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[CH3:4].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[CH3:1][NH:2][CH:3]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[CH3:4]
Reactant: CC(C/C=C/c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CNC(C)C/C=C/c1ccc(Cl)c(Cl)c1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 98.1 %

Procedure:
Under a nitrogen atmosphere, a cold (0-5° C.), stirring solution of (4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(3,4-dichlorophenyl)-4-penten-2-amine (1.38 g, 4.01 mmol) in anisole (20 mL) was treated drop-wise over 45 min with trifluoroacetic acid (20.72 g, 181.7 mmol). The resulting solution was stirred for 1.5 h at 0-5° C. The solution was then concentrated by rotary evaporation followed by further drying under high vacuum. The resulting residue was cooled (0-5° C.), basified with 10% NaOH solution (15 mL), treated with saturated NaCl solution (10 mL) and extracted with CHCl3 (6×20 mL). The combined CHCl3 extracts were washed with saturated NaCl solution (25 mL), dried (Na2SO4), filtered, concentrated by rotary evaporation, followed by further drying under high vacuum to produce a light-brown oil (0.96 g). The crude product was purified by column chromatography on silica gel (50 g), eluting with CH3OH—Et3N (98:2, v/v). Selected fractions containing the product (Rf 0.44) were combined and concentrated on a rotary evaporator. The residue was dissolved in CHCl3. The CHCl3 solution was dried (Na2SO4), filtered, concentrated by rotary evaporation and dried under high vacuum to give 467 mg (47.7%) of a light-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:23]2([O:29][CH3:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:5]=[C:6]([S:8][C:9]2[CH:22]=[CH:21][C:12]([C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=O)=[CH:11][CH:10]=2)[CH:7]=1.Cl.[NH2:32][OH:33]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:23]2([O:29][CH3:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:5]=[C:6]([S:8][C:9]2[CH:22]=[CH:21][C:12]([C:13](=[N:32][OH:33])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH:7]=1
Reactant: NO
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(=O)c4ccccc4)cc3)c2)CCOCC1
Agent: Cl
Solvent: c1ccncc1
Product: COC1(c2cc(F)cc(Sc3ccc(C(=NO)c4ccccc4)cc3)c2)CCOCC1
Temperature: 25 °C
Yield: 52.7 %

Procedure:
A mixture of 4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]benzophenone (0.22 g), hydroxylamine hydrochloride (0.042 g) and pyridine (4 ml) was stirred and heated to reflux for 3 hours. The mixture was cooled to ambient temperature and partitioned between diethyl ether and water. The organic phase was washed with brine. dried (MgSO4) and evaporated. There was thus obtained, as a mixture of (E)- and (Z)-isomers, 4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]benzophenone oxime as a foam (0.12 g, 53%);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH2:25])[CH2:11][CH2:10]1.N[C:28](N)=[O:29].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:18](=[O:26])[C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:25][C:28]2=[O:29])[CH2:11][CH2:10]1
Reactant: NC(N)=O
Reactant: COc1ccccc1N1CCN(CCNC(=O)c2ccccc2N)CC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3ccccc3c2=O)CC1
Yield: 92.1 %

Procedure:
1-(2-Methoxyphenyl)-4-[2-(2-aminobenzoyl)aminoethyl]piperazine (3.54 g) and urea (1.2 g) were dissolved in dimethylformamide (20 ml) and the resulting solution was heated at an external temperature of 140° to 180° C. for 5 to 8 hours. After completion of the reaction, water (200 ml) was added to the reaction mixture and the resulting crystal was filtered off. Upon recrystallization from dioxane, 3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]2,4-(1H,3H)-quinazolinedione (3.5 g) was obtained as needles. Its physicochemical data was the same as that of the product obtained in (a).