Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([OH:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=O)=[N:9]2)=[CH:4][CH:3]=1.[C:23]([O:27][C:28]([CH:30]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]3[CH2:30][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1c2ccccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 90.1 %

Procedure:
A mixture of 46.0 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxyisoindolin-1-one, 78 g of t-butyloxycarbonylmethylenetriphenylphosphorane and 800 ml of toluene was refluxed for 5 hours. The mixture was concentrated and the residue was purified by silica gel column chromatography (dichloromethane-ethyl acetate) to give 54.5 g of t-butyl 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxoisoindoline-1-acetate. Recrystallization from toluene-ether gave colorless crystals melting at 210°-211° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([CH2:15]Br)[CH:12]=[CH:11][N:10]=2)[CH:4]=1.C([O:19][P:20]([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])C>C(Cl)(Cl)Cl>[CH3:23][CH2:22][O:21][P:20]([O:24][CH2:25][CH3:26])([CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([CH2:15][P:20]([O:21][CH2:22][CH3:23])([O:24][CH2:25][CH3:26])=[O:19])[CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: BrCc1ccnc(-c2cc(CBr)ccn2)c1
Reactant: CCOP(OCC)OCC
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(Cc1ccnc(-c2cc(CP(=O)(OCC)OCC)ccn2)c1)OCC
Yield: 80 %

Procedure:
A chloroform (10 mL) solution of (3) (1.5 g, 4.4 mmol) and 15 mL of triethylphosphite was refluxed for 3 hours under nitrogen. The excess phosphite was removed under high vacuum, then the crude product was purified by column chromatography on silica gel (eluent ethyl acetate/methanol 80/20) yielding 1.6 g (80%) of (4). 1H NMR (300 MHz, CDCl3) δ ppm: 1.29(12H, t, 3JHH=7 Hz, 4 POCH2CH3), 3.23 (4H, d, 2JPCH=22 Hz, 2CH2P), 4.09 (8H, dq, 3JPOCH=7 Hz, 3JHH=7 Hz, 4 POCH2CH3), 7.35-7.38 (2H, m, aryl H on C5 and C5′), 8.34-8.37 (2H, m, aryl H on C3 and C3′), 8.62 (2H, d, 3JHH=5 Hz, aryl H on C6 and C6′). 31P NMR (CDCl3) δ ppm: 25.37. Elemental analysis C20H30N2O6P2: calcd. C 52.63, H 6.63, N 6.14%, found C 52.83, H 6.59, N 6.01%.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:8][C:7]=2[CH:6]=[CH:5][C:4]=1[C:17]#[N:18].Cl.C1(C)C=CC(S(O[CH:30]([CH3:37])[CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])(=O)=O)=CC=1.C(OCC)(=O)C>CN(C)C=O>[CH2:33]([N:32]([CH2:35][CH3:36])[CH2:31][CH:30]([N:15]1[C:16]2[CH:3]=[C:4]([C:17]#[N:18])[CH:5]=[CH:6][C:7]=2[S:8][C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:37])[CH3:34]
Reactant: N#Cc1ccc2c(c1)Nc1ccccc1S2
Reactant: CCN(CC)CC(C)OS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Temperature: 110 °C
Reaction time: 7 h

Procedure:
Sodium hydride (19.2 g; in 50% strength dispersion in vaseline) is added in the course of 20 minutes to a solution of 2-phenothiazinecarbonitrile (44.86 g) in N,N-dimethylformamide (600 cc). The mixture obtained is then heated to 110° C., after which the solution of 1-diethylamino-2-propyl p-toluenesulphonate hydrochloride prepared above is added in the course of 35 minutes. The reaction mixture is stirred at 110° C. for 7 hours and then diluted, after being cooled, with ethyl acetate (2 liters). The mixture is washed with distilled water (5 ×1 liter). The organic phase is extracted with 4 N hydrochloric acid (240 cc) and the acid aqueous phase is washed with ethyl acetate (750 cc) and then alkalinized medium is then extracted with ethyl acetate (1250 cc). The organic phase is washed with distilled water (3×300 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is stirred in the presence of ethyl ether (100 cc); a precipitate forms and this is filtered off, and the filtrate is purified by chromatography on a column of silica gel (0.2-0.063 mm) (height: 82 cm; diameter: 4.5 cm), eluting with an 80:20 (by volume) mixture (7 liters) of cyclohexane and ethyl acetate and collecting 100-cc fractions. After concentration to dryness under reduced pressure (30 mm Hg., 4 kPa) at 50° C., 10-[(2RS)-1-diethylamino-2-prop-yl]-2-phenothiazinecarbonitrile (6.76 g) is obtained from fractions 4 to 9, and a mixture (8.5 g) of 10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbonitrile and 10-[(lRS)-2-diethylamino-1-propyl]-2-phenothiazinecarbonitrile is obtained from fractions 10 to 22. The mixture is purified by chromatography on a column of silica gel (0.2-0.063 mm) (height: 67 cm; diameter: 3.0 cm), eluting with an 85:15 (by volume) mixture (3 liters) cyclohexane and ethyl acetate and collecting 50-cc fractions. Fractions 22 to 29 are combined and concentrated to dryness at 50° C. under reduced pressure (30 mm Hg; 4 kPa) to give 10-[(2RS)-1-diethylamino2-propyl]-2-phenothiazinecarbonitrile (2.76 g).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:9]1([CH:15]([OH:32])[CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:32]([CH:15]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][CH:21]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=2)[CH2:22][CH2:23]1)[Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc(NC2CCN(CCC(O)C3CCCCC3)CC2)nc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC2CCN(CCC(O[Si](C)(C)C(C)(C)C)C3CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.8 %

Procedure:
After adding tert-butyldimethylsilyl chloride (203 mg, 1.5 mmol) to a solution of 1-(3-cyclohexyl-3-hydroxypropyl)-4-(5-methylpyridin-2-yl)aminopiperidine (405 mg, 1.22 mmol), triethylamine (0.20 mL) and 4-dimethylaminopyridine (30 mg, 0.24 mmol) in methylene chloride (5 mL) while cooling on ice, the mixture was stirred at room temperature for 18 hours. Triethylamine (0.20 mL), 4-dimethylaminopyridine (30 mg, 1.5 mmol) and tert-butyldimethylsilyl chloride (203 mg, 1.5 mmol) were further added to the reaction mixture and stirring was continued at room temperature for 70 hours. NH silica Chromatorex DM1020 was added to the reaction mixture, which was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60 g NH silica Chromatorex DM2035, hexane:ethyl acetate=4:1) to obtain the title compound as a colorless oil (423 mg) (77.7% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24](F)=[CH:23][N:22]=2)=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[CH3:28][S:29](C)=O.C[S-].[Na+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:29][CH3:28])=[CH:23][N:22]=2)=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: CS(C)=O
Reactant: O=C(Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1)c1ccc(F)cn1
Agent: C[S-]
Agent: [Na+]
Solvent: O
Product: CSc1ccc(C(=O)Nc2ccc(F)cc2C(=O)Nc2ccc(Cl)cn2)nc1
Temperature: 50 °C
Yield: 86 %

Procedure:
A mixture of 5-fluoro-2-[(5-fluoropyridin-2-yl)-carbonylamino]-N-(5-chloropyridin-2-yl)benzamide (502 mg, 1.29 mmol), DMSO (4 mL) and sodium thiomethoxide (95 mg, 1.36 mmoL) was heated to 50° C. for 18 h. The reaction was cooled, added water, filtered, and dried. The solid was triturated with CH2Cl2 and filtered to give the title compound as a white solid (461 mg, 86%).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19]>C([O-])(O)=O.[Na+].C(OCC)C>[OH:5][C:4]1[CH:3]=[C:2]([O:10][S:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])(=[O:20])=[O:19])[CH:9]=[C:7]([CH3:8])[CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
Orcinol monohydrate (1.42 g, 10 mmol) and 2-chlorobenzenesulfonyl chloride (2.43 g, 11 mmol) were mixed in saturated NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at room temperature for 2 days. The reaction mixture was quenched with 50 mL of water and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (2% ethyl acetate in methylene chloride) to give the title compound as a pale-yellow liquid (2.15 g, 71%). 1H-NMR (300 MHz, CDCl3) δ 2.22 (s, 3 H), 5.24 (s, 1 H), 6.43 (s, 1 H), 6.52 (s, 2H), 7.38 (m, 1 H), 7.60 (m, 2 H), and 7.96 (dd, 1 H, J=0.6, 3.9 Hz).
Reaction SMILES: CNCCN.C(OC([S:13][C:14]1[N:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=1)=O)(C)(C)C>O1CCOCC1>[CH3:21][C:16]1[CH:17]=[C:18]([CH3:20])[N:19]=[C:14]([SH:13])[N:15]=1
Reactant: Cc1cc(C)nc(SC(=O)OC(C)(C)C)n1
Agent: CNCCN
Solvent: C1COCCO1
Product: Cc1cc(C)nc(S)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of N-methyl-ethylenediamine (0.10 mol. 8.8 cm3) in dioxane (50 cm3), at room temperature and under a nitrogen atmosphere, was added a solution of S-tert-butyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine (0.05 mol, 12 g) in dioxane (50 cm3), dropwise, over 3 h. After the addition was complete, the solution was stirred at room temperature for a further 15 h. The precipitate which formed (4,6dimethyl-2-mercaptopyrimidine) was removed from the solution, and the filtrate conc. in vacuo to half its original volume (50 cm3). To this residue, was added water (80 cm3) and the solution then left to stand at room temperature for 15 min. The bis-(t-BOC)-diamine precipitate was then removed, and the filtrate conc. in vacuo. To the residue was added water (80 cm3), and the solution subsequently saturated with sodium chloride. This saturated solution was extracted with ethyl acetate (4×40 cm3), and the organic extracts combined, dried (MgSO4), filtered, and conc. in vacuo to give an oil. This oil was dissolved in water (50 cm3) and acidified to pH 3 with 1M hydrochloric acid. The solution was then extracted with ethyl acetate (3×100 cm3). The aqueous layer was then collected, decolourized with activated charcoal and filtered over Celite. The filtrate was then conc. in vacuo. If necessary, fractional recystallization from room temperature methanol was used to separate the required product from any diamine dihydrochloride by-product. The filtrate was then conc. in vacuo. The product was isolated by trituration from hexane, to give a fine off-white solid which consisted of a mixture of N-t-BOC, N-methylethylenediamine monohydrochloride and N-t-BOC, N′-methyl ethylenediamine monohydrochloride in a 4:1 ratio (4.8 g, 45%), m.p. 104-105° C. δH (400 MHZ; methanol-d4) 3.52-3.37 (2H, t, J 4.8 Hz), CH2NH; 3.31 (2H, t, J 4.8 Hz), CH2NH(CH3); 2.81 (3H, s), NCH3; 1.43 (9H, s) C(CH3)3. δC (75.4 MHz: methanol-d4) 157.88, C═O; 81.60 C(CH3)3; 47.47, CH2NH(CH3); 39.09, CH2NH; 28.65, C(CH3)3. Found: M+. 210.72.
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH:16]=O.C([O-])(=O)C.[Na+].Cl.[NH2:24][OH:25]>O>[CH3:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH:16]=[N:24][OH:25]
Reactant: NO
Reactant: COc1ccc2ccccc2c1C=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc2ccccc2c1C=NO
Yield: 97.7 %

Procedure:
To 400 ml of ethanol and 180 ml of water were added 80 g (0.43 mole) of 2-methoxy-1-naphthaldehyde, 66 g (0.81 mole) of sodium acetate and 35.5 g (0.51 mole) of hydroxylamine hydrochloride, and the mixture was refluxed by heating for 2 hours. After the reaction, the reaction mixture was added to 1 liter of water. The precipitated crystals were collected by filtration to obtain 85 g (0.42 mole) of 2-methoxy-1-naphthaldoxime.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][O:8][C:4]=2[CH:3]=1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2ccoc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc2c(c1)OCC2

Procedure:
6-Methylbenzofuran (15 g) was dissolved in methanol (200 ml) containing 0.5 g of 10% palladium on carbon. This solution was shaken on a Paar hydrogenator under hydrogen at 40 psi. When hydrogen uptake was complete, the solution was filtered through Celite and the ethanol evaporated to yield 6-methyl-2,3-dihydrobenzofuran.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20]CC)=O)[CH2:14][CH2:13]1)=[CH:5][NH:6]2.[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=1.[Mg]>C(OCC)C.CCCCCC>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][N:12]1[CH2:13][CH2:14][CH:15]([C:18]([C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]([F:23])([F:33])[F:34])=[CH:31][CH:30]=3)([C:29]3[CH:30]=[CH:31][C:26]([O:25][C:24]([F:34])([F:33])[F:23])=[CH:27][CH:28]=3)[OH:20])[CH2:16][CH2:17]1)=[CH:5][NH:6]2
Reactant: CCOC(=O)C1CCN(Cc2c[nH]c3cccc(F)c23)CC1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: [Mg]
Solvent: CCCCCC
Solvent: CCOCC
Product: OC(c1ccc(OC(F)(F)F)cc1)(c1ccc(OC(F)(F)F)cc1)C1CCN(Cc2c[nH]c3cccc(F)c23)CC1
Yield: 9.7 %

Procedure:
This compound was prepared in a manner analogous to that of Step B of Example 3, with 0.5 gram (0.0016 mole) of ethyl N-(4-fluoroindol-3-ylmethyl)piperidin-4-ylcarboxylate, 2.0 grams (0.0082 mole) of 4-trifluoromethoxyphenyl bromide, and 0.2 gram (0.0086 gram-atom) of magnesium turnings in about 10 mL of diethyl ether as reagents. The crude reaction product was taken up in hexane. The hexane-insoluble material was collected by filtration and purified by preparative thin layer chromatography with 1:3 ethyl acetate:hexane as an eluant, yielding about 0.09 gram of N-(4-fluoroindol-3-ylmethyl)-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine, mp 76°-88° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=1)[C:2]([NH2:4])=[NH:3].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][O:11][S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(CO)cs1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCc2csc(NC(=N)N)n2)cc1
Yield: 45.9 %

Procedure:
To a solution of 2-guanidino-4-hydroxymethylthiazole (0.69 g) in pyridine (5 ml) is gradually added 4-toluenesulfonyl chloride (0.763 g), and the resultant mixture is stirred at room temperature for 4 hours. The resultant mixture is concentrated in vacuum, and the residue is chromatographed on a column of silica gel, which is eluted with methanol. The eluate is concentrated in vacuum to give 2-guanidino-4-(4-toluenesulfonyloxymethyl)thiazole (0.6 g) as an oil. The yield is 45.8%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.CC[O:14]C(C)=O>>[CH3:10][C:9]([N:8]=[C:5]1[N:6]([OH:14])[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4]1)=[O:11]
Reactant: CC(=O)Nc1ccc(Br)cn1
Reactant: CCOC(C)=O
Product: CC(=O)N=c1ccc(Br)cn1O

Procedure:
Prepared according to the procedure described in EXAMPLE 9, Step 4, but using N-(5-bromo-pyridin-2-yl)-acetamide from Step 1 as starting material. Flash chromatography (EtOAc) afforded the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:20][CH3:21])=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]3[CH2:16][CH2:17][CH2:18][C:11]=3[C:10]=2[CH:19]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(O)C.C([O-])(=O)/C=C/C([O-])=O>O>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[C:7]([O:20][CH3:21])=[CH:8][C:9]3[O:14][C:13](=[O:15])[C:12]4[CH2:16][CH2:17][CH2:18][C:11]=4[C:10]=3[CH:19]=2)[CH2:31][CH2:30]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCl)CCC3
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: O
Solvent: CCO
Product: COc1cc2oc(=O)c3c(c2cc1OCCCN1CCN(c2ccccc2F)CC1)CCC3
Yield: 59 %

Procedure:
Method B (50 h at 60° C.); starting materials: 8-(3-chloropropoxy)-2,3-dihydro-7-methoxy-cyclopenta[c][1]benzopyran-4(1H)-one (example 83) and 1-(2-fluorophenyl)piperazine; yield 59%; fusion point 148°-150° C. (from ethanol). Fumarate (×H2O): method E; yield 78%; the fusion point being 205°-210° C. (from water).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:3]=1[NH2:4].[CH3:11][S:12][CH3:13].ClN1C(=O)CCC1=O.[OH-].[Na+]>ClCCl.C(N(CC)CC)C>[Br:1][C:2]1[C:3]([NH2:4])=[C:5]([CH2:11][S:12][CH3:13])[C:6]([F:10])=[C:7]([F:9])[CH:8]=1
Reactant: Nc1cc(F)c(F)cc1Br
Reactant: CSC
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSCc1c(N)c(Br)cc(F)c1F

Procedure:
To a solution of 2-bromo-4,5-difluoroaniline (100 g) and dimethyl sulfide (49 ml) in anhydrous dichloromethane (1.2 liter) is added gradually N-chlorosuccinimide (90 g) at below 15° C., and thereafter is further added in portions triethylamine (93 ml) at 15° C. After the addition, the mixture is refluxed for 7 hours. After cooling, 10% aqueous sodium hydroxide (one liter) is added to the reaction mixture, and the mixture is extracted with dichloromethane. The extract is dried over magnesium sulfate and concentrated, and the resulting residue is purified by silica gel column chromatography (solvent, dichloromethane:n-hexane=1:2). The product is recrystallized from n-hexane to give 6-bromo-3,4-difluoro-2-methylthiomethylaniline (52 g) as a white crystal, m.p. 60°-61° C.
Reaction SMILES: [CH3:1][C:2](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:3].[NH2:25][C:26]1[CH:27]=[C:28]([S:32]([NH:35][C:36]2[C:37](=[O:62])[N:38]([CH2:48][C:49]([NH:51][CH:52]([CH:59]([CH3:61])[CH3:60])[C:53](=[O:58])[C:54]([F:57])([F:56])[F:55])=[O:50])[C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:40][CH:41]=2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[C:2]([NH:25][C:26]1[CH:27]=[C:28]([S:32]([NH:35][C:36]2[C:37](=[O:62])[N:38]([CH2:48][C:49]([NH:51][CH:52]([CH:59]([CH3:60])[CH3:61])[C:53](=[O:58])[C:54]([F:56])([F:57])[F:55])=[O:50])[C:39]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[CH:40][CH:41]=2)(=[O:33])=[O:34])[CH:29]=[CH:30][CH:31]=1)(=[O:3])[CH3:1]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NS(=O)(=O)c2cccc(N)c2)c1=O)C(=O)C(F)(F)F
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Product: CC(=O)Nc1cccc(S(=O)(=O)Nc2ccc(-c3ccccc3)n(CC(=O)NC(C(=O)C(F)(F)F)C(C)C)c2=O)c1

Procedure:
Using a procedure similar to that described in Example 197.1., except replacing trifluoroacetic anhydride with acetic anydride, 2-[3-(3-aminophenylsulfonylamino)-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide was converted into the title compound. Chromatography solvent: dichloromethane:methanol (35:1); TLC: Rf =0.24, dichloromethane:methanol (20:1); NMR (DMSO/D2O): 8.22 (s,1) 7.73 (d,1), 7.60 (d,1), 7.5 (br m, 7), 6.16 (d,1), 4.40 (m,2), 4.02 (d,1), 2.12 (m,1), 2.09 (s,3), 0.80 (d,2); MS: m/z=593(M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][NH:11][C:12]([CH:14]2[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15]2)=O)[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C([O-])=O.[NH4+:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:35]=[C:12]([CH:14]3[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:15]3)[NH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(=O)CNC(=O)C2CN(Cc3ccccc3)CCO2)c1
Reactant: [NH4+]
Agent: O=C([O-])C(F)(F)F
Product: COc1cccc(-c2c[nH]c(C3CN(Cc4ccccc4)CCO3)n2)c1
Temperature: 150 °C
Reaction time: 0.75 h
Yield: 102.9 %

Procedure:
A mixture of N-{2-[3-(methyloxy)phenyl]-2-oxoethyl}-4-(phenylmethyl)-2-morpholinecarboxamide (1.6 g, 4.34 mmol) and ammonium trifluoroacetate (2.85 g, 21.71 mmol) was stirred for 0.75 hours at 150° C. The LCMS indicated that the starting material was consumed. The desired product was contained in the residue. Water (50 mL) was added to the residue, and the resulting mixture was extracted with EtOAc (3×50 mL). The organics were dried (Na2SO4), filtered, and concentrated to afford the title compound (1.56 g) as a brown oil. LC-MS (ES) m/z=350 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:6][CH:5]=1.[C:23]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)#[CH:24]>CCCCCCC>[F:22][C:2]([F:1])([F:21])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:24]#[C:23][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(OC(F)(F)F)cc2)cc1
Reactant: C#Cc1ccc(N)cc1
Solvent: CCCCCCC
Product: Nc1ccc(C#Cc2ccc(OC(F)(F)F)cc2)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-trifluoromethoxy-phenyl ester and 4-ethynyl-phenylamine. Chromatography eluent: heptane; yield (111 mg, 80%); 1H NMR δ (CDCl3): 7.5 (d, J=8.42 Hz, 2H), 7.33 (d, J=8.60 Hz, 2H), 7.18 (d, J=8.41 Hz, 2H), 6.62 (d, J=8.62 Hz, 2H), 3.82 (s, 2H); LCMS m/z 277.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.CN(C=O)C.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:36](=[O:37])[C:35]3[C:26](=[C:27]([O:38][CH2:39][CH2:40][CH3:41])[CH:28]=[C:29]4[C:34]=3[O:33][CH2:32][CH2:31][CH2:30]4)[N:25]([CH2:42][C:43](O)=[O:44])[CH:24]=2)=[CH:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(N(CC)CC)C>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:36](=[O:37])[C:35]3[C:26](=[C:27]([O:38][CH2:39][CH2:40][CH3:41])[CH:28]=[C:29]4[C:34]=3[O:33][CH2:32][CH2:31][CH2:30]4)[N:25]([CH2:42][C:43]([NH:1][CH2:2][CH2:3][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)=[O:44])[CH:24]=2)=[CH:21][CH:22]=1
Reactant: NCCN1CCOCC1
Reactant: CCCOc1cc2c(c3c(=O)c(-c4ccc(OC)cc4)cn(CC(=O)O)c13)OCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCOc1cc2c(c3c(=O)c(-c4ccc(OC)cc4)cn(CC(=O)NCCN4CCOCC4)c13)OCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
4-(2-Aminoethyl)morpholine (217 mg, 1.7 mmol) was added to a DMF solution (10 ml) of [3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-oxa-1-aza-phenanthren-1-yl]acetic acid (580 mg, 1.39 mmol), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU, 790 mg, 2.1 mmol) and triethylamine (5 ml). The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. Water and ethyl acetate were added to the residue, followed by separation. The thus-obtained organic layer was washed with water and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=10:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate, giving a pale brown powder of 2-[3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-oxa-1-aza-phenanthren-1-yl]-N-(2-morpholin-4-ylethyl)acetamide (115 mg, yield: 16%).