Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([C:19]([O:21]CC)=[O:20])=[CH:6][N:7]2[C@@H:15]1[CH2:17][C@H:16]1[F:18].O.S(=O)(=O)(O)O>C(O)(=O)C>[F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[C@@H:15]1[CH2:17][C@@H:16]1[F:18]
Reactant: CCOC(=O)c1cn([C@@H]2C[C@H]2F)c2c(F)c(F)c(F)c(F)c2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2c(F)c(F)c(F)c(F)c2c1=O
Temperature: 0 °C

Procedure:
1.35 g (3.9 mmol) of ethyl 5,6,7,8-tetrafluoro-1-(trans-2-fluoro-cyclopropyl)-1,4-dihydro-4-oxo-3quinolinecarboxylate are heated under reflux for 2 hours in a mixture of 6.3 ml of acetic acid, 4.2 ml of water and 0.64 ml of concentrated sulphuric acid. After having been cooled down, this mixture is introduced into 40 ml of ice water and the undissolved precipitate is filtered off, washed with water and dried at 110° C. under high vacuum. Yield: 0.9 g (72% of theory) of 5,6,7,8-tetrafluoro-1-(trans-2-fluoro-cyclopropyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point: 184°-186° C. (with decomposition). 5,6,7,8-Tetrafluoro-1-(cis-2-fluoro-cyclopropyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is prepared in an analogous manner.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[NH2:16])=[CH:4][CH2:3]1.Cl.Cl[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]Cl>ClC1C=CC=CC=1Cl>[CH3:1][C:2]1([CH3:17])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[N:16]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:4][CH2:3]1
Reactant: ClCCNCCCl
Reactant: COc1ccc(C2=CCC(C)(C)CC2)c(N)c1
Agent: Cl
Solvent: Clc1ccccc1Cl
Product: COc1ccc(C2=CCC(C)(C)CC2)c(N2CCNCC2)c1
Temperature: 25 °C
Yield: 48.2 %

Procedure:
A solution of 2-(4,4-dimethylcyclohex-1-enyl)-5-methoxyphenylamine (3.35 g, 14.5 mmol) prepared in Example (1d) and bis(2-chloroethyl)amine hydrochloride (3.1 g, 17.4 mmol) in 1,2-dichlorobenzene (10 mL) was stirred at 210° C. for 30 minutes. Nitrogen gas was blown into the reactor several times during the reaction to remove the excess hydrogen chloride gas in the reactor. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 2.1 g of the title compound as a yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([CH2:23][O:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[CH2:31][CH:30]([CH2:35][N:36]([CH3:38])[CH3:37])[CH2:29][CH2:28]3)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH3:38][N:36]([CH2:35][CH:30]1[CH2:29][CH2:28][C:27]2[C:32](=[CH:33][CH:34]=[C:25]([O:24][CH2:23][C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:1](=[O:10])[C:2]4[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=4)=[CH:40][CH:39]=3)[CH:26]=2)[CH2:31]1)[CH3:37]
Reactant: CN(C)CC1CCc2cc(OCc3ccc(N)cc3)ccc2C1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccc(COc3ccc4c(c3)CCC(CN(C)C)C4)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
p-Anisoyl chloride (0.20 ml) was added dropwise to pyridine solution (6 ml) of 6-[(4-aminobenzyl)oxy]-2-[(N,N-dimethylamino)methyl]tetralin (300 mg) under ice-cooling, which was stirred at room temperature for 30 minutes. 10% aqueous potassium carbonate solution was added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using alumina column chromatography (development solvent: ethyl acetate), and recrystallized (THF-IPE) to give the titled compound (300 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][C@H:14]2[C@@H:18]3[O:19][C:20]([CH3:23])([CH3:22])[O:21][C@@H:17]3[C@@H:16]([O:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:15]2)=[N:4][C:5]([S:9][CH2:10][CH2:11][CH3:12])=[N:6][C:7]=1[Cl:8].C(O[N:35]=O)CC(C)C>C(#N)C>[Cl:8][C:7]1[C:2]2[N:1]=[N:35][N:13]([C@H:14]3[C@@H:18]4[O:19][C:20]([CH3:22])([CH3:23])[O:21][C@@H:17]4[C@@H:16]([O:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:15]3)[C:3]=2[N:4]=[C:5]([S:9][CH2:10][CH2:11][CH3:12])[N:6]=1
Reactant: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCC(=O)O)[C@H]3OC(C)(C)O[C@H]32)n1
Reactant: CC(C)CCON=O
Solvent: CC#N
Product: CCCSc1nc(Cl)c2nnn([C@@H]3C[C@H](OCC(=O)O)[C@H]4OC(C)(C)O[C@H]43)c2n1
Temperature: 27.5 °C
Reaction time: 0.75 h
Yield: 113.8 %

Procedure:
To a solution of compound 8a (18 g) in acetonitrile (150 mL) was added isoamylnitrite (7.45 g) at 30° C. The reaction mixture was stirred at 25-30° C. for 45 minutes. The reaction was monitored by TLC. After completion, the reaction was quenched with 10% NaHSO3 solution in water (10 ml) and concentrated under reduced pressure. The obtained residue was extracted with ethyl acetate (10 vol). The extract was washed with water and then concentrated at reduced pressure to provide the product (21 g, 92.68%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15].Cl.O>N1C=CC=CC=1.C1(C)C(C)=CC=CC=1>[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CS(=O)(=O)Nc1ccc(Cl)c([N+](=O)[O-])c1
Yield: 78.1 %

Procedure:
Methanesulphonyl chloride (58.3 g, 0.509 mole) was added in one portion to a stirred solution of 97% 4-chloro-3-nitroaniline (86 g, 0.485 mole) in pyridine (80 ml) and xylene (500 ml). The temperature rose to 50° and the mixture was allowed to stand for a further 2 hr before addition of a mixture of 10M-hydrochloric acid (100 ml) and water (100 ml). The brown solid which was collected and washed successively with xylene (50 ml) and water (3×50 ml). The damp material was crystallized from methanol (800 ml) to give a solid which was collected, washed with methanol (2×50 ml) and dried to give the product 95 g (78%) m.p. 163°.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][C:5](F)=[CH:4][C:3]=1[F:10].O.FC1C=C(F)C=C(F)C=1.[NH3:21]>[Cu].CO>[F:10][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([F:8])[CH:2]=1)[NH2:21]
Reactant: Fc1cc(F)c(Cl)c(F)c1
Reactant: N
Agent: [Cu]
Agent: Fc1cc(F)cc(F)c1
Solvent: O
Solvent: CO
Product: Nc1cc(F)cc(F)c1

Procedure:
EP 460 639 describes a three-stage preparation of 3,5-difluoroaniline. Starting from 5-chloro-2,4,6-trifluoroisophthalic acid, this is decarboxylated to give 2-chloro-1,3,5-trifluorobenzene. By reaction of the 2-chloro-1,3,5-trifluorobenzene with copper and water at 300° C., 1,3,5-trifluorobenzene can be prepared. According to Example 6 of EP 460 639, 1,3,5-tri-fluorobenzene is reacted with methanol saturated with ammonia at 200° C. for 60 hours and 3,5-difluoroaniline is obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11](Cl)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([OH:20])[CH2:17][CH2:18][OH:19].[OH-].[K+].CN(C)C=O>O>[CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([O:19][CH2:18][CH2:17][CH2:16][OH:20])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(Cl)cnn1Cc1ccccc1
Reactant: OCCCO
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(OCCCO)cnn1Cc1ccccc1
Yield: 79.7 %

Procedure:
The mixture of 10 g of 2-benzyl-5-chloro-3(2H)-pyridazinone, 50 g of 1,3-propanediol, 3.0 g of 85 % potassium hydroxide and 50 ml of N,N-dimethylformamide was reacted for 24 hours at room temperature, then to the reaction solution was added water and extracted with ethyl acetate, dried and freed of solvent to obtain 9.4 g of the intended compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][O:24][CH2:25][CH3:26])=[CH:17][CH:16]=2)=[CH:13][C:12]([C:27](OC)=[O:28])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][O:24][CH2:25][CH3:26])=[CH:19][CH:20]=2)=[CH:13][C:12]([CH2:27][OH:28])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCCOc1ccc(-c2cc(C(=O)OC)ccc2OCc2ccccc2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCOCCOc1ccc(-c2cc(CO)ccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
To a solution (40 mL) of methyl 6-(benzyloxy)-4′-(2-ethoxyethoxy)biphenyl-3-carboxylate (2.0 g, 4.92 mmol) in anhydrous tetrahydrofuran was added lithium aluminum hydride (0.19 g, 5.01 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The reaction solution was ice-cooled, and sodium sulfate decahydrate (3.0 g, 5.74 mmol) was added. The mixture was stirred at room temperature for 1 hr. The precipitated insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:2-1:1), and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (1.7 g, yield 91%) as colorless needle crystals.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[C:9]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=2[Cl:27])=[C:10]([Cl:18])[C:11]2[N:12]([C:14]([CH3:17])=[N:15][N:16]=2)[CH:13]=1)=[O:7])C.C1COCC1.Cl>[Cl-].[Na+].O.O>[Br:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:9]2[C:8]([C:6]([OH:7])=[O:5])=[CH:13][N:12]3[C:14]([CH3:17])=[N:15][N:16]=[C:11]3[C:10]=2[Cl:18])=[C:21]([Cl:27])[CH:22]=1
Reactant: CCOC(=O)c1cn2c(C)nnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nnc2c(Cl)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cn12
Reaction time: 16 h

Procedure:
Sodium hydroxide (715 μL of a 1 M solution) was added to a solution of 7-(4-bromo-2-chlorophenylamino)-8-chloro-3-methyl-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid ethyl ester (51a) (79 mg, 179 mmol) in 3:1 THF:water (4.5 mL). After 16 hours, the reaction mixture was poured into a separatory funnel, diluted with brine and acidified with 1 N HCl to about pH 2. The aqueous layer was extracted with 1:1 EtOAc:THF. The combined organic extracts were dried (Na2SO4) and concentrated and the residue (52a) was carried forward without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[CH:6][N:7]=1.O.[NH2:16][NH2:17]>N1C=CC=CC=1>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[N:4]=[N:3][C:2]([NH:16][NH2:17])=[N:7][CH:6]=1
Reactant: Fc1ccccc1-c1cnc(Cl)nn1
Reactant: NN
Solvent: c1ccncc1
Solvent: O
Product: NNc1ncc(-c2ccccc2F)nn1
Temperature: 60 °C

Procedure:
A 17.9 g. portion of 3-chloro-6-(o-fluorophenyl)-1,2,4-triazine is dissolved in 120 ml. of pyridine and cooled in an ice bath. An 8.5 g. portion of hydrazine hydrate is added and the mixture is heated at 60° C. for one hour and then cooled, poured into ice water and filtered giving 6-(o-fluorophenyl)-3-hydrazino-1,2,4-triazine as yellow plates.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:17]([N:24]1[C@@H:29]([CH3:30])[CH2:28][C:27](=O)[CH2:26][C@H:25]1[CH3:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl>[CH2:17]([N:24]1[C@@H:29]([CH3:30])[CH2:28][CH:27]([NH:1][C:2]2[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:26][C@H:25]1[CH3:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@@H]1CC(=O)C[C@H](C)N1Cc1ccccc1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(C(F)(F)F)cc(NC2C[C@@H](C)N(Cc3ccccc3)[C@@H](C)C2)c1C
Temperature: 25 °C
Reaction time: 7 h
Yield: 34.2 %

Procedure:
To a stirred mixture of MS3A (1.0 g), methyl 3-amino-2-methyl-5-(trifluoromethyl)benzoate (350 mg, 1.50 mmol) and (2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-one (359 mg, 1.65 mmol) in chloroform (10 mL) was added acetic acid (500 uL) at 0° C. and stirred at r.t. for 7 hours. To the reaction mixture was added sodium triacetoxyborohydride (670 mg, 3.00 mmol) at 0° C. The reaction mixture was stirred at 23° C. for 1.5 hours. Then the reaction mixture was quenched with aq. NaHCO3 until pH8-9. The MS 3 Å was removed by Celite filtration and the content was extracted with ethylacetate, dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (heptane/ethylacetate=5/1 to 3/1). Target fractions were collected and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH—SiO2; heptane/ethylacetate=5/1) to give the titled compound as a light yellow oil (223 mg, 62% yield.). For major isomer; 1H-NMR (400 MHz, CDCl3) δppm; 7.40-7.21 (m, 6H), 6.85 (s, 1H), 4.00-3.95 (m, 1H), 3.91 (s, 3H), 3.88 (d, 2H), 3.84-3.76 (m, 1H), 2.83-2.73 (m, 2H), 2.25 (s, 3H), 1.83-1.69 (m, 4H), 1.13 (d, J=6.4 Hz, 6H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][OH:7].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([O:7][CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccco1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccco1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To the solution of furan-2-ylmethanol (500 mg, 5.1 mmol) in CH2Cl2 (10 mL) and triethylamine (1.54 g, 15.3 mmol) at 0° C. was added dropwise methanesulfonyl chloride (695 mg, 6.1 mmol). The mixture was stirred at 0° C. for 15 min and was quenched with 10 mL of water. The layers were separated and the aqueous layer was extracted with CH2Cl2 (1×10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: F[C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:43]([O:50][C:51](=[O:57])[NH:52][CH2:53][C:54](=[NH:56])[NH2:55])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C.ClCCl>[CH2:43]([O:50][C:51](=[O:57])[NH:52][CH2:53][C:54]1[NH:56][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([F:11])[CH:9]=[N:10][C:2]=2[N:55]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: O=C(O)c1cc(F)cnc1F
Reactant: N=C(N)CNC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCc1nc2ncc(F)cc2c(=O)[nH]1)OCc1ccccc1
Temperature: 90 °C
Reaction time: 30 h
Yield: 22 %

Procedure:
2,5-Difluoronicotinic acid (547 mg, 3.44 mmol), TBTU (1.33 g, 4.14 mmol) and DIPEA (3.40 ml, 19.85 mmol) were added to a solution of carbamimidoylmethyl-carbamic acid benzyl ester [77390-81-9] (725 mg, 3.51 mmol) in DMF (20 ml). The solution was stirred for 5 hours at ambient temperature and 30 hours at 90° C. The brown suspension was poured onto ice cold aqueous buffer solution pH5/dichloromethane 1/1. The layers were separated, the aqueous layer was extracted twice with dichloromethane, the combined extracts were washed with brine and dried over magnesium sulfate. Removal of the solvent under reduced pressure and crystallization (EtOAc/TBME) yielded (6-fluoro-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-carbamic acid benzyl ester (250 mg, 0.757 mmol; 22%) as white solid. MS: m/e=327.1 [M−H−].
Reaction SMILES: [OH:1][N:2]=C(OCC)C.C(N(CC)CC)C.[C:15]1([CH3:27])[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23](Cl)(=[O:25])=[O:24].Cl(O)(=O)(=O)=O>CN(C=O)C.O>[C:15]1([CH3:27])[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23]([O:1][NH2:2])(=[O:25])=[O:24]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CCOC(C)=NO
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a suspension of ethyl N-hydroxyacetimidate (4.72 g, 45.7 mmol) in DMF (453 ml) was added triethylamine (9.53 ml, 68.6 mmol) followed by portionwise addition of mesitylenesulfonyl chloride (1, 10 g, 45.7 mmol). The reaction mixture was stirred for 2 hours at room temperature then poured into ice water (150 mL). The resulting precipitate was collected by vacuum filtration. The collected solids were treated with neat perchloric acid (32.8 ml, 229 mmol) and stirred until homogeneous. Distilled water (30 mL) was used to titurate white crystals of O-mesitylenesulfonylhydroxylamine (2, 8.31 g, 38.6 mmol, 84% yield). MS APCI: [M+H]+ m/z 216.3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][S:21](=[O:23])[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15].[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=C1>O.CN(C=O)C>[CH2:35]([NH:42][C:30](=[O:32])[CH2:29][O:28][C:27]1[CH:33]=[CH:34][C:24]([C:3]2[C:2]([Cl:1])=[C:7]([CH2:8][N:9]3[C:10](=[O:15])[CH2:11][CH2:12][C:13]3=[O:14])[N:6]=[C:5]3[S:16][C:17]4[CH2:22][S:21](=[O:23])[CH2:20][CH2:19][C:18]=4[C:4]=23)=[CH:25][CH:26]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(O)COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCS(=O)C4)cc1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1cnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCS(=O)C4)cc1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of the compound obtained in Example 115 (104 mg), benzylamine (24 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC, 42 mg), 1-hydroxy-1H-benzimidazole monohydrate (HOBt, 34 mg) and DMF (3 ml) was stirred at room temperature for 10 hours. The reaction mixture was poured into water. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4) and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to obtain N-benzyl-2-(4-{3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)methyl]-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-4-yl}phenoxy)acetamide from the fraction eluted with ethyl acetate-methanol (6:1) (70 mg, 57%). It was recrystallized from THF-hexane. Colorless prisms. Melting point 220–221° C.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].C(OCC)(=O)C.O1CCCC1.CCCCCC>C(O)C.O.C(OCC)C.[Fe]>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)N1CCOCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCOCC3)c2)cc1
Temperature: 25 °C
Yield: 39.2 %

Procedure:
Morpholine-4-carboxylic acid [4-(4-nitrophenoxy)pyridin-2-yl]amide (227 mg) was dissolved in ethanol (10 ml)-water (2 ml), and then electrolytic iron powder (150 mg) and ammonium chloride (300 mg) were added thereto, followed by heating under reflux for 1 hr. The reaction mixture was cooled down to room temperature, and then ethyl acetate-tetrahydrofuran (1:1) was added, followed by stirring. The mixture was filtered through celite to remove an insoluble portion, which was washed with ethyl acetate and water. The organic layer of the filtrate was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:5, then ethyl acetate). Fractions containing the target compound were concentrated under a reduced pressure to give a residue, which was then suspended in diethyl ether (6 ml)-hexane (12 ml). The solid was filtered, and dried under aeration to provide the titled compound (81.3 mg, 59.3%) as a pale yellow solid.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])=[N:7]2.[OH:22][CH2:23][CH2:24][S:25][CH3:26].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Cu]I.O>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[O:22][CH2:23][CH2:24][S:25][CH3:26])[N:7]=1
Reactant: CSCCO
Reactant: COc1ccccc1CNc1ccc2c(I)cccc2n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccccc1CNc1ccc2c(OCCSC)cccc2n1
Temperature: 100 °C
Yield: 21.2 %

Procedure:
(5-Iodo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (0.3 g, 1.0 mmol) was dissolved in toluene (2 mL). After addition of 2-hydroxyethyl-methylsulfid (130 μL, 2.0 mmol), CuI (15 mg, 0.1 mmol), phenantroline (28 mg, 0.2 mmol) and caesium carbonate (0.5 g, 2.0 mmol) the reaction mixture was heated to 100° C. for 72 h. Then water was added and the mixture twice extracted with toluene. The combined organic phases were dried on sodium sulfate and evaporated. The residue was subjected to column chromatography (silica gel; heptane, ethyl acetate 10:0->3:2) to yield the title compound (75 mg, 26%) as a brown oil; MS: m/e=355.6 (M+H+).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:4](=[O:23])[C:3]=1[C:24](=O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33].O.[NH2:36][NH2:37].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][C:24]1[C:3]2[C:4](=[O:23])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:20])([F:22])[F:21])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:37][N:36]=1
Reactant: NN
Reactant: COc1ccccc1CC(=O)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1Cc1n[nH]c2c1c(=O)n(-c1cccc(OC(F)(F)F)c1)c1ncccc21
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-3-(2-methoxyphenylacetyl)-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one (840 mg, 1.8 mmol) produced in Synthesis Example 27 in DMF (7 mL) was added hydrazine monohydrate (purity of 80%, 285 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(2-methoxybenzyl)-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (770 mg, yield 92%).