Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.ClC1C=CC=C(C(OO)=[O:17])C=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N+:3]=1[O-:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccc(Cl)n1
Solvent: ClCCl
Product: Cc1cccc(Cl)[n+]1[O-]
Reaction time: 8 h

Procedure:
To a cold (0° C.) solution of 2-chloro-6-methylpyridine (24.6 g, 193 mmol) in dichloromethane (100 mL), a solution of m-chloro-per-benzoic acid (46.2 g, 268 mmol; purified) in dichloromethane (480 mL) was added over a period of 30 min. The reaction mixture was stirred at room temp. overnight, and concentrated to about 100 mL. The slurry was filtered, and the solid washed with ice-cold dichloromethane. The combined filtrate was washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under vacuum to provide 2-chloro-6-methylpyridine N-oxide as clear colorless oil.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][CH2:14][C:15]([OH:17])=[O:16]>O.CO.[Ni]>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[CH2:2][NH:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: NCC(=O)O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Ni]
Solvent: CO
Solvent: O
Product: O=C(O)CNCC(O)C(O)C(O)C(O)CO
Yield: 73.2 %

Procedure:
A solution of 39.6 gm of D-glucose in 200 ml of water and 150 ml of methanol was added to a solution of 15 gm (0.2 mol) of glycine in 200 ml of water and 100 ml of methanol in an autoclave. Then, after the addition of 18.0 gm of Raney nickel, a hydrogenation was carried out in the autoclave with stirring at a pressure of 180 to 200 kg/cm2. The autoclave was heated in a progressive manner first for 2 hours to 50° C., subsequently for 2 hours to 70° C. and finally for 2 hours to 90° C. After separation of the catalyst by filtration and evaporation of the reaction solution in vacuum, the highly viscous residue obtained was allowed to stand for a few days. After crystallization had commenced the same was completed by crystallization from 100 ml of boiling methanol. 35 gm (73% of theory) of N-(2,3,4,5,6-pentahydroxy-hexyl)-glycine having a melting point of 172° to 177° C. (decomposition) were obtained. An analytically pure sample recrystallized from water/ 2-propanol melted at 175° to 180° C. with decomposition.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20]Br)C>CCCCCC>[CH:1]1([C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[O:13][CH2:20][CH2:19][CH2:18][C:17]([OH:22])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCCBr
Reactant: Oc1cccc(C2CCCCC2)c1
Solvent: CCCCCC
Product: O=C(O)CCCOc1cccc(C2CCCCC2)c1

Procedure:
Following an analogous procedure to that described in Examples 1 and 2, m-cyclohexylphenol and 4-bromobutyric acid ethyl ester give 4-(m-cyclohexylphenoxy)-butyric acid of melting point 83° -84° C (from hexane).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][OH:8].[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16]Cl.C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH2:7][O:8][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=1
Reactant: OCc1cc(Br)ccc1Cl
Reactant: COCCOCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOCc1cc(Br)ccc1Cl
Yield: 88.1 %

Procedure:
To a solution of 100 g (4.52 mmol) of 5-bromo-2-chlorobenzyl alcohol in dry dichloromethane (20 ml) were added 675 mg (5.42 mmol) of 2-methoxyethoxymethyl chloride and 1.20 ml (6.89 mmol) of N,N-diisopropylethylamine in an atmosphere of argon, and the mixture was allowed to react at room temperature for 18 hours. To the reaction solution at 0° C. was a added saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with dichloromethane-hexane (1:5) yielded 1.23 g (3.98 mmol) of 4-bromo-1-chloro-2-(2-methoxyethoxymethoxymethyl)benzene.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH2:10][C:11](O)([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:6][CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH:10]=[C:11]([C:13]([F:15])([F:14])[F:16])[N:12]=2)=[N:4][CH:3]=1
Reactant: Cc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)nc1

Procedure:
A mixture of the 4,5-dihydro-imidazole of step 2 (10 mmol) and p-toluenesulfonic acid monohydrate (2 mmol) in toluene (200 ml) is heated to reflux for 24 hours. The reaction mixture is cooled and the solvent removed under reduced pressure. The crude mixture is chromatographed on silica gel using mixtures of ethyl acetate and acetone as eluants to give the desired product.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH3:34][N:35]1[C:39]([CH3:40])=[CH:38][C:37]([C:41](Cl)=[O:42])=[N:36]1>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:41]([C:37]3[CH:38]=[C:39]([CH3:40])[N:35]([CH3:34])[N:36]=3)=[O:42])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1cc(C(=O)Cl)nn1C
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(C(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)nn1C
Reaction time: 0.17 h
Yield: 36.6 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (1.0 g, 6.6 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol) in acetonitrile (40 mL). After stirring for 10 minutes, 1,5-dimethyl-1H-pyrazole-3-carbonyl chloride (0.4 g, 2.6 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was dissolved in CH2Cl2 (80 mL). The CH2Cl2 solution was washed with water (2×30 mL) and brine (30 mL), and dried (MgSO4). Solvent was removed, and the residue was purified by chromatography (SiO2, CH2Cl2: CH3OH 97.5:2.5) to give 1,5-dimethyl-1H-pyrazole-3-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (0.3 g, 38%) as a white solid: mp 213-215° C.; 1H NMR (DMSO-d6) δ 2.05-2.09 (m, 1H), 2.28 (s, 3H), 2.50-2.64 (m, 2H), 2.84-2.97 (m, 1H), 3.79 (s, 3H), 4.86 (d, J=5.9 Hz, 2H), 5.13-5.20 (dd, J=5.1 and 12.4 Hz, 1H), 6.44 (s, 1H), 7.65-7.79 (m, 3H), 8.69 (t. J=5.9 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 10.66, 21.97, 30.93, 36.39, 37.80, 48.86, 105.53, 121.71, 127.01, 131.51, 132.78, 134.70, 139.60, 140.35, 144.26, 161.91, 167.00, 167.56, 169.83, 172.75; Anal. calcd. for C20H19N5O5+0.4H2O: C, 57.66; H, 4.79; N, 16.81. Found: C, 57.85; H, 4.80; N, 16.64.
Reaction SMILES: [CH3:1]S(O)(=O)=O.C(OC([N:13]1[CH2:21][CH2:20][CH2:19][C@H:15]([C:16]([OH:18])=[O:17])[CH2:14]1)=O)(C)(C)C>CO>[NH:13]1[CH2:21][CH2:20][CH2:19][C@H:15]([C:16]([O:18][CH3:1])=[O:17])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1
Reactant: CS(=O)(=O)O
Solvent: CO
Product: COC(=O)[C@H]1CCCNC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonic acid (576 mg, 6 mmol) was added to a solution of (S)—N-(tert-butoxycarbonyl)nipecotic acid (1145 mg, 5 mmol) and methanol (5 mL). When the mixture was stirred at 25° C. for 16 hours, (S)-methyl nipecotate was produced, and the object (S)-nipecotic acid was not produced.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.C1C=C(Cl)C=C(C(OO)=[O:22])C=1.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N+:4]([O-:22])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2cc(Br)cnc2c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2cc(Br)c[n+]([O-])c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-7-methoxyquinoline (2.0 g, 8.40 mmol) in DCM (42 mL) at RT, mCPBA (2.9 g, 16.8 mmol) was added, and the reaction mixture was stirred at RT for 1 hour. A second portion of mCPBA (2.9 g, 16.8 mmol) was then added, and the reaction mixture was stirred at RT for 18 hours. The reaction mixture was poured onto 10% aqueous Na2SO3 and DCM, and the layers were separated. The organic layer was washed with NaHCO3, dried over MgSO4, filtered and concentrated. The resulting product was used with no further purification. LRMS (M+H)+=254.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([F:20])[CH:14]=3)=[CH:11][C:10]([C:21](O)=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:57]3[CH2:61][C:60](=[O:62])[NH:59][CH2:58]3)=O)=N2)C=CC=1>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([F:20])[CH:14]=3)=[CH:11][C:10]([C:21]([N:57]3[CH2:61][C:60](=[O:62])[NH:59][CH2:58]3)=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Reactant: Cc1cc(F)cc(-c2cc(C(=O)O)nn2-c2cccc(Cl)c2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=CO
Product: Cc1cc(F)cc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 107A using 3.2 equivalents of N,N-diisopropylethylamine and with the addition of 0.1% formic acid in the preparative HPLC in analogy to the synthesis of the compound of Example 23. 24 mg (19% of theory) of the title compound are obtained.
Reaction SMILES: O[CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1.[ClH:16]>>[Cl:16][CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1
Reactant: Cl
Reactant: COC(=O)C(C)Oc1ccc(CO)cc1
Product: COC(=O)C(C)Oc1ccc(CCl)cc1
Temperature: 25 °C
Yield: 67.3 %

Procedure:
A mixture of 2.19 g (0.0104 mole) of methyl 2-(4-hydroxymethylphenoxy)propionate and 3.00 g (0.0823 mole) of 36% hydrochloric acid was stirred for fifteen minutes at room temperature. The reaction mixture was then poured into ice-water, and the resulting mixture was extracted with diethyl ether. The extracts were combined and washed in succession with water and a saturated aqueous solution of sodium bicarbonate. The extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated from the filtrate under reduced pressure, leaving a colorless liquid. This liquid was placed on a column of silica gel and eluted with methylene chloride. After the product-containing fractions were combined and the solvent evaporated under reduced pressure, 1.6 g of methyl 2-(4-chloromethylphenoxy)propionate was isolated as a colorless liquid. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [CH:1]1([N:6]([C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[C:7]2[CH:14]=[CH:13][C:10]([O:11][CH3:12])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].Cl.CO>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:7]2[CH:14]=[CH:13][C:10]([O:11][CH3:12])=[CH:9][CH:8]=2)=[O:25])=[CH:17][CH:18]=1
Reactant: COc1ccc(N(C(=O)c2ccc([N+](=O)[O-])cc2)C2CCCC2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc(N(C(=O)c2ccc(N)cc2)C2CCCC2)cc1
Reaction time: 4 h
Yield: 95.4 %

Procedure:
A solution of N-cyclopentyl-N-(4-nitrobenzoyl)-p-anisidine (1.0 g), 10% palladium on carbon (100 mg) and 2 drops of conc. hydrochloric acid in methanol (10 ml) was stirred under 3 atmospheric pressure of hydrogen at ambient temperature. After 4 hours, the reaction mixture was filtered through a bed of Celite, and concentrated to give N-(4-aminobenzoyl)-N-cyclopentyl-p-anisidine (870 mg), which was used directly for the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH2:27][NH:28][CH3:29])=[C:19]([CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2].CCN(CC)CC.[CH3:42][O:43][CH2:44][C:45](Cl)=[O:46]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]([C:3]1[C:4]([NH:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH2:27][N:28]([CH3:29])[C:45](=[O:46])[CH2:44][O:43][CH3:42])=[C:19]([CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: COCC(=O)Cl
Reactant: CNCc1cc2c(nc1C(OC)OC)N(C(=O)Nc1cc(NCCOC)c(C#N)cn1)CCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CN(C)C(=O)COC)c(C(OC)OC)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-((methylamino)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 188, 230 mg, 0.490 mmol) in DCM (4 ml) at 0° C. was added NEt3 (0.100 ml, 0.721 mmol) and 2-methoxyacetyl chloride (50 μl, 0.548 mmol) and the reaction mixture was allowed to warm to room temperature and stirred for approximately 2 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and DCM. Phases were separated and the water phase was extracted with DCM (2×), organic phases were combined and dried using Na2SO4, filtered and concentrated. The crude product was purified using silica gel column chromatography eluting with a gradient of MeOH (2-5%) in DCM. Fractions containing the product were combined and evaporated to yield the title compound as a colorless resin. (UPLC-MS 3) tR 0.91 min, ESI-MS 542.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[NH:13][C@@H:12]([C@@H:14]([O:16]C(=O)C3C=CC([N+]([O-])=O)=CC=3)[CH3:15])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[NH:13][C@@H:12]([C@@H:14]([OH:16])[CH3:15])[CH2:11][O:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C[C@H](OC(=O)c1ccc([N+](=O)[O-])cc1)[C@H]1COC[C@@H](c2ccc(Cl)cc2)N1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](O)[C@H]1COC[C@@H](c2ccc(Cl)cc2)N1
Yield: 92.2 %

Procedure:
To a solution of 4-nitrobenzoic acid (S)-1-[(3R,5R)-5-(4-chlorophenyl)morpholine-3-yl]ethyl ester (1.46 g mg) in methanol (40 mL) was added sodium methoxide (1.9 mL, 28% methanol solution), and the resultant solution was stirred at room temperature for 1 hour. Solvent was removed by distillation under reduced pressure, and the resultant product was diluted with ethyl acetate and water. The organic layer was partitioned and washed with brine. The organic layer was then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (heptane/ethyl acetate 9/1→1/3), to thereby obtain the titled compound (833 mg). The physical properties of the compound were as follows.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C@H:7]([CH2:12][OH:13])[CH2:8][CH:9]([CH3:11])[CH3:10].C([O-])(=O)C.[Na+]>CC(C)=O.O>[Cl:1][CH2:2][C:3]([NH:6][C@H:7]([CH2:12][OH:13])[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CC(C)C[C@H](N)CO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)C[C@@H](CO)NC(=O)CCl
Reaction time: 2 h

Procedure:
A solution of chloroacetyl chloride, 25.64 g (0.227 mol), in 57 ml of acetone is added dropwise with stirring to a solution of L-leucinol, 26.63 g (0.227 mol), and sodium acetate, 37.24 g (0.454 mol), in a mixture of 340 ml of acetone and 170 ml of water at 0°-5° C. The mixture is stirred and allowed to reach room temperature over two hours, the solvent is evaporated in vacuo and the residue is suspended in 250 ml of chloroform and washed with water, 2×300 ml. The chloroform layer is separated, dried over sodium sulfate, evaporated in vacuo and the residue is purified by chromatography using silica gel and eluting with dichloromethane-methanol (95:5) to give (S)-2-chloro-N-[1-(hydroxymethyl)-3-methylbutyl]acetamide, 28 g; [α]D25 -32.6° (c 0.52, methanol).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].O[CH:10]([N:12]1[C:17]([CH3:19])([CH3:18])[CH2:16][CH:15]([OH:20])[CH2:14][C:13]1([CH3:22])[CH3:21])[CH3:11]>>[CH3:22][C:13]1([CH3:21])[N:12]([CH2:10][CH2:11][O:5][C:4]([CH2:3][CH2:2][C:1]([OH:8])=[O:7])=[O:6])[C:17]([CH3:19])([CH3:18])[CH2:16][CH:15]([OH:20])[CH2:14]1
Reactant: O=C(O)CCC(=O)O
Reactant: CC(O)N1C(C)(C)CC(O)CC1(C)C
Product: CC1(C)CC(O)CC(C)(C)N1CCOC(=O)CCC(=O)O

Procedure:
This is an oligo ester of succinic acid and 1-hydroxyethyl-4-hydroxy-2,2,6,6-tetramethylpiperidine of Ciba-Geigy, Basel.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)=[CH:5][CH:4]=1.[I:15](O)(=O)=O.II>C(O)(=O)C.O.S(=O)(=O)(O)O>[I:15][C:4]1[CH:5]=[C:6]([CH:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C2CNC(=O)C2)cc1
Reactant: [O-][I+2]([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C2CNC(=O)C2)cc1I
Temperature: 80 °C
Reaction time: 10 h
Yield: 414.5 %

Procedure:
A solution of 19.1 g of 4-(4-methoxyphenyl)-pyrrolidin-2-one (100 mmol) in 200 ml of glacial acetic acid, 4.8 ml of water and 1.2 ml of concentrated sulfuric acid is combined with 3.44 g (19.55 mmol) of iodic acid and 8.64 g (70 mmol) of iodine and stirred at a bath temperature of 80° C. for 10 hours. Subsequently, the mixture is concentrated on a rotary evaporator up to onset of crystallization, cooled, the crystalline precipitate is suctioned off and recrystallized from ethyl acetate, thus obtaining 25.7 g (81% of theory) of 4-(3-iodo-4-methoxyphenyl)pyrrolidin-2-one, mp 158° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:10]([C:13]1[CH:17]=[C:16]([Cl:18])[S:15][C:14]=1Cl)(=[O:12])[CH3:11].O>CN(C=O)C.[Cu]I>[C:10]([C:13]1[CH:17]=[C:16]([Cl:18])[S:15][C:14]=1[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:12])[CH3:11]
Reactant: Oc1ccccc1
Reactant: CC(=O)c1cc(Cl)sc1Cl
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cc(Cl)sc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 66.9 %

Procedure:
A mixture of phenol (1.22 g, 13 mM) and NaH (60% oil dispersion, 0.52 g, 13 mM) in DMF (25 mL) was stirred for 40 minutes at room temperature. 3-Acetyl-2,5-dichlorothiophene (1.95 g, 10 mM) and copper (I) iodide (50 mg) was added to the above mixture, and the resulting mixture was heated at 130° C. for 1.5 hours. After cooling, the mixture was poured into water. The whole was extracted with ethyl acetate-hexane (1:1, 200 mL×1, 100 mL×1), and the combined organic layers washed with water, brine, dried over MgSO4, and concentrated in vacuo. Chromatographic purification eluting with ethyl acetate-hexane (1:20) provided the subtitle compound (1.69 g. 67% yield) as a brown oil.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[F:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([C:19](O)=[O:20])[CH:18]=1)[NH:15][CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=1)[CH2:13][C:12]2([CH3:35])[CH3:34].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[F:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([C:19]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:20])[CH:18]=1)[NH:15][CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=1)[CH2:13][C:12]2([CH3:35])[CH3:34]
Reactant: CS(N)(=O)=O
Reactant: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2c(C(=O)O)cc(F)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2c(C(=O)NS(C)(=O)=O)cc(F)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a suspension of 60% sodium hydride (360 mg, 9 mmol) in N,N-dimethylformamide (5 mL) was added methanesulfonamide (865 mg, 9.1 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A56. A solution of 6-fluoro-4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (500 mg, 1.3 mmol) and 1,1′-carbonyldiimidazole (422 mg, 2.6 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B56. Solution B56 was added to Solution A56 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[6-fluoro-4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carbonyl]-methanesulfonamide (270 mg, 45%) as a white solid: MS (ESI) M+1=462.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:14])[C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:14])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C:25]([F:26])([F:28])[F:27])=[N:23][N:24]=3)[N:21]=2)[CH2:10][CH2:9]1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: Clc1cncc(Cl)c1N1CCNCC1
Product: FC(F)(F)c1nnc2ccc(N3CCN(c4c(Cl)cncc4Cl)CC3)nn12

Procedure:
A mixture of 1-(3,5-dichloropyridin-4-yl)piperazine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(3,5-dichloropyridin-4-yl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH:1]1([C:6]2[CH:15]=[C:14]3[C:9]([C:10](=[O:18])[CH2:11][C:12]([CH3:17])([CH3:16])[O:13]3)=[C:8]([O:19][CH3:20])[C:7]=2[CH:21]=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[Mg][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH:1]1([C:6]2[CH:15]=[C:14]3[C:9]([C:10](=[O:18])[CH2:11][C:12]([CH3:17])([CH3:16])[O:13]3)=[C:8]([O:19][CH3:20])[C:7]=2[CH:21]([OH:22])[C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1c(C=O)c(C2CCCC2)cc2c1C(=O)CC(C)(C)O2
Reactant: FC(F)(F)c1ccc([Mg]Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1c2c(cc(C3CCCC3)c1C(O)c1ccc(C(F)(F)F)cc1)OC(C)(C)CC2=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under argon, 3.7 g (12.24 mmol) of 7-cyclopentyl-5-methoxy-2,2-dimethyl-4-oxochroman-6-carbaldehyde (Example 6A) are suspended in 150 ml of tetrahydrofuran and cooled to −78° C. 29.4 ml (14.68 mmol) of a freshly prepared 0.5 M solution of bromo[4-(trifluoro-methyl)phenyl]magnesium in tetrahydrofuran are added slowly. The mixture is then warmed to −20° C. and stirred at this temperature for 30 min. At −20° C., another 12.3 ml (6.15 mmol) of the above Grignard solution are added, and the mixture is stirred for a further 45 min. The mixture is then hydrolyzed using 5% strength sodium bicarbonate solution and then extracted repeatedly with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is chromatographed on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1→2:1). This gives 2.35 g (43% of theory) of the title compound.