Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[F:20])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[BH4-].[Na+].C(=O)([O-])O.[Na+]>C1COCC1.O>[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][OH:11])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1cccc(Cl)c1F
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CO)c1cccc(Cl)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Of the compound from Example 159A, 2 g (6.59 mmol) were dissolved under argon in 20 ml of THF. The solution was then cooled to 0° C. and 0.918 ml (6.59 mmol) of triethylamine and 0.94 ml (7.24 mmol) of isobutyl chloroformate were added dropwise. The reaction mixture was subsequently stirred at 0° C. for 1 h. Thereafter the suspension was filtered through a Seitz frit into a cooled flask, with washing with a little THF. A second flask was charged with 747 mg (19.76 mmol) of sodium borohydride in 3 ml of water, with ice cooling. With vigorous stirring, the filtrate was slowly added dropwise. After 1 h, the batch was carefully admixed with saturated aqueous sodium hydrogen carbonate solution. It was then extracted with 30 ml of ethyl acetate. The organic phase was washed again once with saturated aqueous sodium hydrogen carbonate solution and once with saturated aqueous sodium chloride solution. It was then dried over sodium sulphate, filtered and freed from the solvent on a rotary evaporator. Drying in an HV gave 1.74 g (75% of theory) of the title compound in approximately 83% purity.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30]Br)=[CH:26][CH:25]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[Na+].[CH3:33][S:34]([O-:36])=[O:35].[Cl-].[NH4+].C(OCC)(=O)C>CN(C)C=O>[CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:26][CH:25]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)c1cn(-c2cccc(-c3ccc(CBr)cc3)c2)c2ncccc2c1=O
Reactant: CS(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1ccc(-c2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-Cyclopropyl-1-[3-(4-bromomethylphenyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Step 1 in N,N-dimethylformamide (20 ml/mmol) was added methanesulfinic acid sodium salt (1.3 eq) and the resulting mixture was stirred at room temperature for 18 hours. To the mixture was added saturated aqueous ammonium chloride solution and ethyl acetate, and the insoluble solid was filtered and washed well with water, hexane, ether and ethyl acetate to afford the title compound as a solid.
Reaction SMILES: P(C#N)(=O)(OCC)OCC.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[CH2:19][CH2:18][C:17]([C:25]([OH:27])=O)=[CH:16]2.[ClH:28].Cl.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:42]=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46])[CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.Cl>C(OCC)(=O)C.O.CN(C)C=O.C(N(CC)CC)C>[ClH:28].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[CH2:19][CH2:18][C:17]([C:25]([N:39]1[CH2:38][CH2:37][N:36]([CH2:35][C:34]3[CH:42]=[C:43]([O:47][CH3:48])[C:44]([O:45][CH3:46])=[C:32]([O:31][CH3:30])[CH:33]=3)[CH2:41][CH2:40]1)=[O:27])=[CH:16]2
Reactant: COc1cc2c(cc1OC)CCC(C(=O)O)=C2
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OC)CCC(C(=O)N1CCN(Cc3cc(OC)c(OC)c(OC)c3)CC1)=C2
Reaction time: 1 h

Procedure:
Diethyl phosphorocyanidate (1 ml) is added dropwise, under ice-cooling, to a mixture of 1,2-dihydro-6,7-dimethoxy-3-naphthoic acid (0.8 g), 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (1 g), triethylamine (0.35 g) and N,N-dimethylformamide (30 ml). The whole mixture is stirred for one hour under ice-cooling and allowed to stand at room temperature for one hour. Water (100 ml) is added to the reaction mixture and the mixture is extracted with ethyl acetate (100 ml). The organic layer is washed with water, dried and concentrated under reduced pressure. The residue is purified silica gel column chromatography (hexane:acetone=1:1-1:2). The oily product thus obtained is treated with hydrogen chloride is ethyl acetate to afford 1-(6,7-dimethoxy-1,2-dihydro-3-naphthoyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride, which is identical with the product obtained in Example 5. The yield is 0.85 g.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH2:6][C:7]1[O:15][C:10]2[CH2:11][NH:12][CH2:13][CH2:14][C:9]=2[CH:8]=1)[CH3:5].[C:16]([C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[CH3:5][N:4]([CH2:6][C:7]1[O:15][C:10]2[CH2:11][N:12]([C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[C:16](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:14][C:9]=2[CH:8]=1)[CH3:3]
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: CN(C)Cc1cc2c(o1)CNCC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)Cc1cc2c(o1)CN(C(=O)c1ccccc1C(=O)c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.228 g (0.900 mmol) of the above N,N-dimethyl-(4,5,6,7-tetrahydrofuro[2,3-c]pyridin-2-ylmethyl)amine dihydrochloride, 0.24 g (1.1 mmol) of 2-benzoylbenzoic acid and 0.50 ml (3.6 mmol) of triethylamine in 30 ml of dichloromethane, 0.22 g (1.35 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel chromatography (chloroform to chloroform/methanol=25/1) to yield the desired product.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([O:11]C)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.Cl>C(Cl)Cl>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](=[O:19])[C:8]2[CH:7]=[CH:6][C:5]([OH:11])=[CH:10][CH:9]=2)=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
510 g of aluminium chloride (3.82 M), then 3.5 l of dry methylene chloride, and, slowly, 430 g (4 M) of anisole are added to a 5-liter flask; the flask is cooled to maintain the temperature at about 25° C, and 600 g (3.44 M) of 4-chlorobenzoyl chloride is then added dropwise; the reaction mixture is next heated 6 hours under reflux, is left to cool to about 25° C, and the reaction mixture is poured onto 5 kg of ice and 0.5 l of concentrated HCl; the mixture is stirred well during this hydrolysis; the methylene chloride phase is decanted, washed once with water, and transferred to another 5-liter vessel. The methylene chloride is removed by evaporation and replaced in the flask by 2 l of chlorobenzene; a Dean-Stark apparatus is connected and the reaction mixture is refluxed to dehydrate the medium; when this operation is complete the mixture is cooled to approximately 50° C and 800 g (6 M) of aluminium chloride is added; the reaction mixture is heated 1 hour 30 minutes under reflux (very gentle reflux), and demethylation proceeds rapidly; the reaction mixture is cooled and poured onto 6 kg of ice and 0.5 l of concentrated HCl; the mixture is stirred for 1 hour 30 minutes and the precipitate is dried; the latter is washed with water, with methylene chloride, and then dried:
Reaction SMILES: [CH2:1]([N:8]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[C:9]1[C:10](=[O:26])[N:11]([C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=2[CH3:25])[C:18]([O:20]C)=O)[CH:12]=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]1([NH2:35])[CH2:34][CH2:33]1>O>[CH:32]1([NH:35][C:18](=[O:20])[C:17]2[CH:22]=[CH:23][C:24]([CH3:25])=[C:15]([N:11]3[CH:12]=[CH:13][N:14]=[C:9]([N:8]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:10]3=[O:26])[CH:16]=2)[CH2:34][CH2:33]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(C)c(-n2ccnc(N(CCN(C)C)Cc3ccccc3)c2=O)c1
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(N(CCN(C)C)Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 240 h

Procedure:
A mixture of 3-{3-[benzyl-(2-dimethylamino-ethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-4-methylbenzoic acid, methyl ester (Example 121a, 50 mg), cyclopropylamine (1 mL) and water (0.5 mL) was stirred at room temperature for 10 days. Purification by preparative HPLC (Gemini column, 0.1% ammonia: acetonitrile eluent) afforded the title compound as a solid (10 mg).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16](O)=[O:17])=[N:4][NH:3]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[F:47][C:48]([F:59])([F:58])[C:49]1[N:53]2[CH2:54][CH2:55][NH:56][CH2:57][C:52]2=[N:51][N:50]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[F:59][C:48]([F:58])([F:47])[C:49]1[N:53]2[CH2:54][CH2:55][N:56]([C:16]([C:15]3[CH:14]=[C:13]([CH2:12][C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2](=[O:1])[NH:3][N:4]=4)[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:57][C:52]2=[N:51][N:50]=1
Reactant: FC(F)(F)c1nnc2n1CCNC2
Reactant: O=C(O)c1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccc(Cc2n[nH]c(=O)c3ccccc23)c1)N1CCn2c(nnc2C(F)(F)F)C1
Reaction time: 12 h
Yield: 20.6 %

Procedure:
3-[(4-Oxo-3H-phthalazin-1-yl)methyl]benzoic acid 15a (300 mg, 1.07 mmol, prepared according to a known method disclosed by “patent application WO2004080976”) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (730 mg, 1.93 mmol), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride 1b (269 mg, 1.40 mmol) and N,N-diisopropylethylamine (0.9 mL, 5.30 mmol). After stirring for 12 hours, the reaction mixture was added with 15 mL of H2O, extracted with ethyl acetate (20 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[3-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 15 (100 mg, yield 20.6%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([NH:9][N:10]=[C:11]([C:15](=[O:17])[CH3:16])[C:12](=[O:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.[CH3:20]OC(OC)N(C)C>CN(C=O)C.Cl>[C:15]([C:11]1[C:12](=[O:14])[CH:13]=[CH:20][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:18])([F:19])[F:1])[CH:4]=2)[N:10]=1)(=[O:17])[CH3:16]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)C(=NNc1cccc(C(F)(F)F)c1)C(C)=O
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 80 °C
Yield: 65.1 %

Procedure:
A mixture of 3-{[3-(trifluoromethyl)phenyl]hydrazono}pentane-2,4-dione (5.00 g, 18.4 mmol) and N,N-dimethylformamide dimethyl acetal (2.44 mL, 18.4 mmol) in DMF (100 mL) was heated to 80° C. for 4 h. The mixture was diluted with 1 M HCl aqueous solution, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100 and EtOAc/MeOH=100/0 to 80/20) and triturated with EtOAc/hexane to yield the title compound (3.38 g, 65% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 2.55 (3H, s), 6.75 (1H, d, J=8.0 Hz), 7.78-7.88 (2H, m), 8.06-8.16 (2H, m), 8.96 (1H, d, J=8.2 Hz).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2([CH3:13])O.[N-:14]=[N+:15]=[N-:16].[Na+].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl.O>[N:14]([C:5]1([CH3:13])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[O:8][CH2:7][CH2:6]1)=[N+:15]=[N-:16]
Reactant: CC1(O)CCOc2ccc(I)cc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC1(N=[N+]=[N-])CCOc2ccc(I)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 6-iodo-4-methylchroman-4-ol (1.0 g, 3.4 mmol) and NaN3 (0.7 g, 10.3 mmol) in CHCl3 (15 ml), at 0° C., was added TFA (1.3 ml, 17.2 mmol) as a solution in 10 ml of CHCl3 dropwise via addition funnel. The addition was carried out over 2 h and stirring continued for an additional 2 h at 0° C. The mixture was warmed to r.t. and stirred over night. The mixture was diluted with 30 ml of water and extracted with CH2Cl2. The organic layer was dried over Na2SO4 and concentrated in vacuo to yield 4-azido-6-iodo-4-methylchroman as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J=2.07 Hz, 1 H), 7.50 (dd, J=8.71, 2.07 Hz, 1 H), 6.66 (d, J=8.71 Hz, 1 H), 4.27 (m, 2 H), 2.06 (m, 2 H), 1.68 (s, 3 H). MS (ESI+) for C10H10IN3O m/z 273.0 (M+H)+ loss of azide. The crude azide was dissolved in THF (15 ml) followed by the addition of trimethylphosphine (4 ml, 1.0 M in THF) at r.t. After 15 min. 3 ml of water was added and stirring continued at r.t. for 2 h until complete as indicated by LC/MS. The solvent was removed in vacuo and the residue diluted with water (75 ml) and extracted with CH2Cl2 (3×50 ml). The organic layer was dried over Na2SO4 and concentrated in vacou to yield 6-iodo-4-methylchroman-4-amine (0.900 g, 91%) as a yellow oil. This material was used in the next step without purification. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J=2.07 Hz, 1 H), 7.40 (dd, J=8.60, 2.18 Hz, 1 H), 6.59 (d, J=8.50 Hz, 1 H), 4.25 (m, 2 H), 2.01 (m, 2 H), 1.53 (s, 3 H). MS (ESI+) for C10H12INO m/z 273.2 (M+H)+ loss of NH3.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[H][H].C(OCC)(=O)C.CCCCCC>C(O)C.[OH-].[NH4+].[Ni]>[NH2:5][CH2:4][C:3]1[CH:6]=[C:7]([C:10]([F:12])([F:13])[F:11])[CH:8]=[CH:9][C:2]=1[NH2:1]
Reactant: N#Cc1cc(C(F)(F)F)ccc1N
Reactant: [H][H]
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: NCc1cc(C(F)(F)F)ccc1N

Procedure:
In a rocker shaker was charged 37 g (0.2 mol) of 2-amino-5-(trifluoromethyl)benzonitrile in 500 mL of ethanol and 76 mL of ammonium hydroxide. The contents were degassed/blanketed with nitrogen, 25 g of Raney nickel were added, then the shaker was pressurized with 40 psi hydrogen gas. At 15 hours TLC analysis (20/80 ethyl acetate/hexane) revealed no starting material. The contents were filtered through Celite and washed with ether and concentrated to 37 g black oil. The oil was chromatographed on a Biotage 75L cartridge with methanol/methylene chloride and ammonium hydroxide/methanol/methylene chloride to give [2-(aminomethyl)-4-(trifluoromethyl)phenyl]amine as a green oil.
Reaction SMILES: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(O)=O.C[C@H]1[C@@H](CC2OC3C=CC(NC)=C(C(O)=O)C=3N=2)O[C@]2(O[C@H]([C@@H](C(C3NC=CC=3)=O)C)[C@H](C)C[C@H]2C)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CC(C(CC1C=CC(O)=C(O)C=1)C)CC1C=CC(O)=C(O)C=1.[CH3:96][CH2:97][CH2:98][CH2:99][CH2:100][CH:101]=[CH:102][CH2:103][CH:104]=[CH:105][CH2:106][CH:107]=[CH:108][CH:109]=[CH:110][CH:111]([OH:118])[CH2:112][CH2:113][CH2:114][C:115]([OH:117])=[O:116]>>[CH3:96][CH2:97][CH2:98][CH2:99][CH2:100]/[CH:101]=[CH:102]\[CH2:103]/[CH:104]=[CH:105]\[CH2:106]/[CH:107]=[CH:108]\[CH:109]=[CH:110]\[C@@H:111]([OH:118])[CH2:112][CH2:113][CH2:114][C:115]([OH:117])=[O:116]
Reactant: CCCCCC=CCC=CCC=CC=CC(O)CCCC(=O)O
Agent: CC(Cc1ccc(O)c(O)c1)C(C)Cc1ccc(O)c(O)c1
Agent: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Agent: CNc1ccc2oc(C[C@H]3O[C@@]4(CC[C@H]3C)O[C@H]([C@H](C)C(=O)c3ccc[nH]3)[C@H](C)C[C@H]4C)nc2c1C(=O)O
Product: CCCCC/C=C\C/C=C\C/C=C\C=C\[C@@H](O)CCCC(=O)O

Procedure:
A suspension of human neutrophils in buffer is incubated for 3 min at 30° C. with (14C)-arachidonic acid (AA) and calcium ionophore A23187. Citric Acid (2M) /NDGA* (10 mM) is used to quench the reaction. Following the addition of a trace amount of (3H)-5-HETE together with an excess of unlabeled 5-HETE to each tube, the mixture is extracted with chloroform/methanol. The organic layer is washed with dilute hydrochloric acid and the total volume is transferred to glass tubes and dried in vacuo. The residue is dissolved in a small volume of chloroform and is spotted on silica gel TLC sheets which are developed with an ethyl acetate/isooctane/water/acetic acid solvent system
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].CCN=C=NCCCN(C)C.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.N1C=CC=CC=1>O>[OH:13][C:3]1[CH:4]=[CH:5][C:6]([S:8][C:9]([F:12])([F:10])[F:11])=[CH:7][C:2]=1[NH:1][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1cc(SC(F)(F)F)ccc1O
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc(SC(F)(F)F)ccc1O)c1ccncc1
Temperature: 80 °C
Yield: 40.1 %

Procedure:
A mixture of 0.70 g of 2-amino-4-(trifluoromethylthio)phenol, 0.83 g of WSC, 0.41 g of isonicotinic acid and 7 ml of pyridine was stirred while heating at 80° C. for three hours. The reaction mixture was cooled to room temperature, and then water was poured into the reaction mixture, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.42 g of N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:40]=[CH:39][C:29]([CH2:30][N:31]2[C:35](=[O:36])[CH:34]([CH3:37])[NH:33][C:32]2=[O:38])=[CH:28][CH:27]=1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:33]4[CH:34]([CH3:37])[C:35](=[O:36])[N:31]([CH2:30][C:29]5[CH:39]=[CH:40][C:26]([O:25][CH3:24])=[CH:27][CH:28]=5)[C:32]4=[O:38])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: COc1ccc(CN2C(=O)NC(C)C2=O)cc1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Product: COc1ccc(CN2C(=O)C(C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)cc3)C2=O)cc1
Yield: 86.5 %

Procedure:
Using (4-bromophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 165 and 3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione (141 mg) described in Preparation Example 51 and by the reaction and treatment in the same manner as in Example 1, the title compound (183 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[CH3:22].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:22][C:13]1[CH:14]=[C:15]([S:18](=[O:20])(=[O:19])[NH2:21])[CH:16]=[CH:17][C:12]=1[NH:11][C:8]([C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][N:5]=1)=[O:9]
Reactant: Cc1cc(S(N)(=O)=O)ccc1N
Reactant: O=C(Cl)c1cc(Cl)ncn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(S(N)(=O)=O)ccc1NC(=O)c1cc(Cl)ncn1

Procedure:
A cooled (0° C.) solution of 6-chloropyrimidine-4-carbonyl chloride (4.56 g; 25.8 mmol) in DCM (80 ml) was treated dropwise over 30 minutes with a solution of 4-amino-3-methyl-benzenesulfonamide (4.00 g; 21.5 mmol) and DIEA (7.40 ml; 43.0 mmol) in anhydrous DMF (10 mL). At the end of addition the reaction mixture was concentrated under vacuum and the residue was taken up in EtOAc (200 mL). The organic phase was washed with water/brine (80 mL). A precipitate was formed, which was filtered and dried under vacuum to afford the crude product which was recrystallized from EtOH. The title product was obtained as a white solid.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(O)(=O)/C=C/C(O)=O.O[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]([CH3:41])[CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:28][CH2:27]2)=[CH:22][CH:21]=1)[CH3:19].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[OH-].[Na+]>O>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH2:18]([C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:27][CH2:28][CH:29]([N:32]([CH3:41])[CH2:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:30][CH2:31]2)=[CH:24][CH:25]=1)[CH3:19]
Reactant: CC(O)c1ccc(N2CCC(N(C)CCc3ccccc3)CC2)cc1
Agent: CC[SiH](CC)CC
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCc1ccc(N2CCC(N(C)CCc3ccccc3)CC2)cc1
Temperature: 60 °C
Yield: 22.8 %

Procedure:
A mixture of 5.1 g (15 mmol) of the product from Example 13, 2.6 g (22.5 mmol) of triethylsilane and 17.1 g (15 mmol) of trifluoroacetic acid was heated at 60° C. for 2 hours. The mixture was then poured into water, made alkaline with 4M sodium hydroxide solution and extracted with methylene chloride. The organic phase was separated off, dried and evaporated in a rotary evaporator. The resulting residue was purifed by chromatography on silica gel (eluent: toluene/acetone=2/1). The oily product crystallized as the fumarate. 1.5 g of 1-(4-ethylphenyl)-4-(N-methyl-N-(2-phenylethyl)amino)piperidine fumarate were obtained. Melting point 163°-165° C.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[OH:20].C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:31][CH3:32])(=O)=O>CS(C)=O>[CH2:31]([O:20][C:3]1[C:4]2=[C:13]3[N:8]([CH:7]([CH3:19])[CH2:6][CH2:5]2)[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11](=[O:15])[C:12]3=[CH:14][C:2]=1[F:1])[CH3:32]
Reactant: CCOS(=O)(=O)OCC
Reactant: CC1CCc2c(O)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOc1c(F)cc2c(=O)c(C(=O)O)cn3c2c1CCC3C

Procedure:
A solution of 1.0 g of 6,7-dihydro-9-fluoro-8-hydroxy-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 1.4 g of potassium carbonate and 2.0 ml of diethyl sulfate in 15 ml of dimethyl sulfoxide was heated at its reflux temperature for sixteen hours. The solution was then evaporated to dryness by heating on a steam bath under a stream of nitrogen. Fifty ml of 1% aqueous sodium hydroxide solution was added to the resulting residue. The mixture was heated on a steam bath for one hour, acidified with concentrated hydrocloric acid and cooled. The solid was separated by filtration and recrystallized from aqueous ethanol to provide 6,7-dihydro-8-ethoxy-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. 208°-210° C. (dec.). Analysis: Calculated for C16H16FNO4 : %C, 63.0; %H, 5.3; %N, 4.6; Found: %C, 62.9; %H, 5.3; %N, 4.6.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.[CH3:15][S:16]([C:19]1[CH:20]=[C:21]([C:31](O)=[O:32])[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)(=[O:18])=[O:17]>>[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:21]([C:31]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=3)[CH2:9]2)=[O:32])[CH:20]=1)(=[O:17])=[O:18]
Reactant: FC(F)(F)c1ccc2c(c1)CCNC2
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)N2CCc3cc(C(F)(F)F)ccc3C2)c1

Procedure:
Prepared in analogy to example 1.1 from 6-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline and 4-methanesulfonyl-biphenyl-2-carboxylic acid (example 2.5).