Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:5]2.[H-].[Na+]>CN(C=O)C>[CH2:15]([O:14][C:12](=[O:13])[CH2:6][C:6]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[C:7]1=[O:11])[CH3:16]
Reactant: CCOC(=O)C1Cc2cc(F)ccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(C(=O)OCC)Cc2cc(F)ccc2C1=O
Temperature: 65 °C
Reaction time: 3 h
Yield: 133.9 %

Procedure:
A mixture of ethyl 5-fluoro-1-oxo-indane-2-carboxylate (1.4 g, 6.3 mmol), sodium hydride (278 mg, 6.9 mmol, 60% in mineral oil) and DMF (dry, 2.5 ml) was heated to 65° C. for one hour. A solution of bromo ethylester (1.15 g, 0.8 ml, 6.9 mmol) in dry DMF (4.0 ml) was added at the same temperature and heating was continued for additional 3 h. After complete the reaction, reaction mass was evaporated to dryness, 5 ml water was added and the suspension was extracted with ethyl acetate (25 ml×3). Combined organic layer was washed with brine, dried over sodium sulphate, evaporated and subjected to column chromatography using ethyl acetate/hexane (15%) to yield a desired product (1.3 g, 72%).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11]C)=[C:9]([F:13])[C:8]([F:14])=[C:4](C(O)=O)[C:3]=1[C:15]([OH:17])=[O:16]>O>[F:1][C:2]1[C:10]([OH:11])=[C:9]([F:13])[C:8]([F:14])=[CH:4][C:3]=1[C:15]([OH:17])=[O:16]
Reactant: COc1c(F)c(F)c(C(=O)O)c(C(=O)O)c1F
Solvent: O
Product: O=C(O)c1cc(F)c(F)c(O)c1F
Temperature: 190 °C
Yield: 74 %

Procedure:
An amount of 0.84 g of to 3,5,6-trifluoro-4-methoxyphthalic acid and 10 ml of water were placed in a sealed tube, replaced with nitrogen and heated at 190° C. for 8 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated, whereby crystals were precipitated. The crystals were filtered, washed (chloroform 5 ml) and then dried. As colorless crystals, 0.48 g of 2,4,5-trifluoro-3-hydroxybenzoic acid was obtained.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[Cl:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:21]1[N:25]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:24]=[C:23]([CH3:34])[CH:22]=1)=[O:4].[OH-].[Li+]>>[Cl:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[S:10]([C@H:8]1[CH2:7][N:6]([C:21]2[N:25]([CH2:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:24]=[C:23]([CH3:34])[CH:22]=2)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]1)(=[O:12])=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1c1cc(C)nn1CCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)O)n(CCc2ccccc2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-1-(3-methyl-1-phenethyl-1H-pyrazol-5-yl)pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow foam which was used in the next step without further purification. MS (ESI): m/z=492.1 [M+H]+.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([O:12][CH2:13][C:14]1[N:15]([CH2:27][C:28]2([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1)[CH3:11]>ClCCl>[CH2:10]([O:12][CH2:13][C:14]1[N:15]([CH2:27][C:28]2([OH:34])[CH2:33][CH2:32][N:31]([C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[CH2:30][CH2:29]2)[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1)[CH3:11]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCNCC1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCN(C(=O)Nc2ccccc2)CC1
Temperature: 25 °C
Yield: 101.3 %

Procedure:
Under a nitrogen atmosphere phenyl isocyanate (1.00 mL, 9.25 mmol) was added dropwise to a chilled mixture of 4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidin-4-ol (3.00 g, 8.81 mmol) and dichloromethane (90 mL). The reaction mixture was allowed to warm to ambient temperature. After 2 hours the reaction mixture was concentrated under reduced pressure to provide an orange oil. This material was triturated with diethyl ether to provide 4.1 g of 4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-4-hydroxy-N-phenylpiperidine-1-carboxamide as a light orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][N:13]3[C:17]4[C:18](=[O:23])[NH:19][N:20]=[C:21]([Cl:22])[C:16]=4[CH:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][N:13]3[C:17]4[C:18](=[O:23])[N:19]([CH3:28])[N:20]=[C:21]([Cl:22])[C:16]=4[CH:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:26][CH:27]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cn2ccc3c(Cl)n[nH]c(=O)c32)cc1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nc(Cl)c2ccn(Cc3ccc(C(=O)c4ccc(Cl)cc4)cc3)c2c1=O
Temperature: 25 °C
Reaction time: 95 h
Yield: 86.4 %

Procedure:
In DMF (200 ml) was dissolved 1-[4-(4-chlorobenzoyl)benzyl]-4-chloropyrrolo [2,3-d]pyridazin-7(6H)-one (830 mg) followed by addition of potassium carbonate (2.11 g). Then, methyl iodide (0.13 ml) was added and the mixture was stirred at room temperature for 95 hours. This reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (200 ml). The organic layer was washed with water (100 ml) 3 times and further with saturated aqueous NaCl solution (100 ml) and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure and the resulting crystals were rinsed with ethyl acetate to provide 742 mg (yield 84%) of the title compound.
Reaction SMILES: [ClH:1].[CH:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[OH:19][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26]Br)=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+]>>[ClH:1].[CH:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:26][CH2:25][O:24][C:23]2[CH:28]=[CH:29][C:20]([OH:19])=[CH:21][CH:22]=2)[CH2:15][CH2:14]1
Reactant: c1cc2c(cc1CC1CCNCC1)CCCC2
Reactant: Oc1ccc(OCCBr)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1ccc(OCCN2CCC(Cc3ccc4c(c3)CCCC4)CC2)cc1

Procedure:
The title compound was prepared from 4-((5,6,7,8-tetrahydro-2-naphthyl)methyl)piperidine hydrochloride (250 mg, 940 μmol), 2-(4-hydroxyphenoxy)ethyl bromide (204 mg, 940 μmol) and NaHCO3 (162 mg, 1.93 mmol) as a pale beige solid (152 mg): 1H NMR (CD3OD) 1.55-1.65 (m, 2H), 1.70-1.96 (m, 7H), 2.54 (d, J=6.3 Hz, 2H), 2.62-2.78 (m, 4H), 3.05 (t, J=12 Hz, 2H), 3.43-3.68 (m, 4H), 4.25 (t, J=4.8 Hz, 2H), 6.72 (d, J=9.0 Hz, 2H), 6.80-6.90 (m, 4H), 6.95 (d, J=7.5 Hz, 1H); Anal. Calcd for C24H32ClNO2 ·H2O: C, 68.64; H, 8.16; N, 3.33. Found: C, 68.39; H, 7.99; N, 3.36.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11](=[O:16])[NH:12][CH2:13][CH2:14][N:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C=O.O.[C:20]([BH3-])#N.[Na+].[OH-].[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH3:20][N:15]1[CH2:14][CH2:13][NH:12][C:11](=[O:16])[CH:10]1[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: O=C1NCCN=C1c1ccc([N+](=O)[O-])cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCNC(=O)C1c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A 10-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen, charged with 104a (196 mg, 0.89 mmol), 37% solution of formaldehyde in water (35 mg, 1.16 mmol) and anhydrous methanol (3 mL). A solution of sodium cyanoborohydride (169 mg, 2.68 mmol) and anhydrous zinc chloride (183 mg, 1.34 mmol) in anhydrous methanol (3 mL) was added, and the reaction was stirred at room temperature for 1 h. After this time, 1N aqueous sodium hydroxide (2 mL) was added, and the methanol was evaporated under reduced pressure. The remaining aqueous solution was extracted with ethyl acetate (3×25 mL). The organic layers were combined, washed with water (20 mL) and brine (20 mL) and dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate concentrated under reduced pressure to afford 104b in 100% yield (210 mg) as a yellow solid: mp 185-186° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.18 (d, 2H, J=8.1 Hz), 8.05 (d, 1H, J=3.6 Hz), 7.63 (d, 2H, J=7.8 Hz), 3.82 (s, 1H), 3.45 (m, 1H), 3.17 (m, 1H), 2.95 (m, 1H), 2.56 (m, 1H), 2.06 (s, 3H); MS (ESI+) m/z 236 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.O>C(Cl)Cl>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][N:14]1[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc(F)cc1F
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2,4-difluorobenzaldehyde (3.0 g, 21.1 mmol) and t-butyl piperazine-1-carboxylate (4.3 g, 23.1 mmol) in 30 mL of dry DCM is stirred for 2 h at RT, and NaHB(OAc)3 (6.7 g, 31.6 mmol) is added in portions with stirring. After the addition, the reaction mixture is stirred further overnight at RT. Water is added and the resulting mixture is extracted twice with DCM. The organic layer is dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain t-butyl 4-(2,4-difluorobenzyl)piperazine-1-carboxylate as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 1.46 (s, 9H), 2.40 (m, 4H), 3.42 (m, 4H), 3.54 (s, 2H), 6.78 (dt, 1H, J=10.0 Hz and 2.4 Hz), 6.85 (dt, 1H, J=8.4 Hz and 2.4 Hz), 7.33 (dd, 1H, J=15.2 Hz and 8.0 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[Br:27][C:28]1[CH:29]=[C:30]([CH:34]2[CH2:43][CH:42]([OH:44])[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([OH:45])[CH:40]=3)[O:35]2)[CH:31]=[CH:32][CH:33]=1>>[Br:27][C:28]1[CH:29]=[C:30]([CH:34]2[CH2:43][CH:42]([OH:44])[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([O:45][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)[CH:40]=3)[O:35]2)[CH:31]=[CH:32][CH:33]=1
Reactant: Oc1ccc2c(c1)C(O)CC(c1cccc(Br)c1)O2
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)C(O)CC(c2cccc(Br)c2)O3)nc1

Procedure:
2-(3-Bromophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 215 mg of 2-(3-bromophenyl)chroman-4,6-diol (Example 15(b)). The product was recrystallised from a mixture of 2-propanol and acetone. 1H NMR (300 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.8 Hz), 8.61 (dd, 1H, J 9.1, 2.8 Hz), 7.69 (m, 1H), 7.58-7.50 (m, 2H), 7.40 (m, 1H), 7.25 (d, 1H, J 2.7 Hz), 7.22 (d, 1H, 9.1 Hz), 7.02 (dd, 1H, J 8.8, 2.7 Hz), 6.91 (d, 1H, J 8.8 Hz), 5.65 (d, 1H, J 6.4 Hz), 5.33 (d, 1H, J 10.8 Hz), 4.97 (m, 1H), 2.36 (m, 1H), 1.94 (m, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][CH:4]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1>CN(C)C=O.O>[CH3:11][O:10][N:8]([CH3:9])[C:6]([CH:4]1[CH2:5][CH:2]([NH:1][C:19]2[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:3]1)=[O:7]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CON(C)C(=O)C1CC(N)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CC(Nc2ncccc2[N+](=O)[O-])C1
Yield: 79.9 %

Procedure:
To a solution of 3-amino-N-methoxy-N-methylcyclobutanecarboxamide (0.606 g, 3.84 mmol) in dry dimethylformamide (15 mL) was added sodium carbonate (1.22 g, 11.5 mmol) and 2-chloro-3-nitropyridine (608 mg, 3.84 mmol). The reaction mixture was stirred and heated at reflux for 14 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with water (30 mL), brine (30 mL) and dried over sodium sulfate. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel (20% to 50% ethyl acetate in petroleum ether) to give N-methoxy-N-methyl-3-((3-nitropyridin-2-yl)amino)cyclobutanecarboxamide (0.86 g, 3.07 mmol, 80% yield) as yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:40])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:23])[F:22])=[N:14]2)([CH3:4])([CH3:3])[CH3:2].[CH:42]1([C:45]2[CH:46]=[N:47][NH:48][CH:49]=2)[CH2:44][CH2:43]1>>[C:1]([O:5][C:6](=[O:41])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:40])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:47]3[CH:46]=[C:45]([CH:42]4[CH2:44][CH2:43]4)[CH:49]=[N:48]3)=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:22])[F:23])=[N:14]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12
Reactant: c1n[nH]cc1C1CC1
Product: Cc1c(Cc2ccc(-n3cc(C4CC4)cn3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12

Procedure:
The title compounds was prepared by the method of Preparation 18a using {8-chloro-2-difluoromethoxy-4-methyl-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]quinolin-5-yloxy}acetic acid tert-butyl ester and 4-cyclopropyl-1H-pyrazole.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=1[NH2:11].Cl>N1C=CC=CC=1>[Cl:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=1[NH:11][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: CCCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC(=O)Nc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C

Procedure:
Valeryl chloride (12.06 g., 0.10 mole) is added dropwise to a cooled stirred solution of 2-chloro-4-nitroaniline (17.26 g., 0.10 mole) in pyridine (100 ml.). The mixture is warmed to ambient temperature, then heated (80°-100° C.) for 24 hours. The cooled solution is poured into cold 1 N hydrochloric acid (500 ml.) with stirring. The precipitated solid is collected, washed well with water and dried, 25.1 g., m.p. 80°-95° C. Recrystallization from cyclohexane yeilds mater al (19.75 g.) of m.p. 95°-97° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:45])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([N:42]([CH3:44])[CH3:43])[N:39]=[CH:38][N:37]=2)[CH:31]=1)=O)(C)(C)C>>[CH3:44][N:42]([CH3:43])[C:40]1[N:39]=[CH:38][N:37]=[C:36]([C:32]2[CH:31]=[C:30]([C:28]3[CH2:27][C:26](=[O:45])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[CH:41]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CN(C)c1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ncn1
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(N(C)C)ncn3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (116 mg, 0.4 mmol) and 3-[3-(6-dimethylamino-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K55) (150 mg, 0.44 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (143 mg).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:14]=[C:13]([Cl:15])[C:12]2[C:7](=[CH:8][C:9]([C:16]3[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][N:11]=2)[N:6]=1.O>C1COCC1>[Cl:15][C:13]1[C:12]2[C:7](=[CH:8][C:9]([C:16]3[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][N:11]=2)[N:6]=[C:5]([O:2][CH3:1])[CH:14]=1
Reactant: FC(F)(F)c1cccnc1-c1cnc2c(Cl)cc(Cl)nc2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)c2ncc(-c3ncccc3C(F)(F)F)cc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add sodium methoxide (4M, 0.45 mL, 1.8 mmol) to a solution of 2,4-dichloro-7-[3-(trifluoromethyl)pyrdin-2yl]-1,5-naphthyridine (575 mg, 1.6 mmol) in THF (10 mL). Stir at room temperature for 1 hour, add water (15 mL) and extract with ethyl acetate. Wash the combined organic extracts with brine, dry (MgSO4) and evaporate. Purify the residue by flash chromatography (elute with 1:2 hexane:ether) to give the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[C:11]([CH:20]=O)=[CH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[CH:9]=1)([CH3:3])[CH3:2].[F:24][C:25]([F:39])([F:38])[C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:29][NH2:30].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[F:24][C:25]([F:38])([F:39])[C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:33]=1)[CH2:29][NH:30][CH2:20][C:11]1[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=1[C:8]1[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[O:22][CH3:23]
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
5′-Isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde (5.0 g) is dissolved in 1,2-dichloroethane (20 ml) and thereto are added 3,5-bis-(trifluoromethyl)benzylamine (3.8 g), acetic acid (1.1 ml) and triacetoxy-sodium borohydride (4.0 g), and the mixture is stirred at room temperature overnight. To the reaction mixture is added a saturated aqueous sodium bicarbonate solution and the mixture is extracted with chloroform. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=10:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine (7.2 g). MS (m/z): 550 [M+H]+
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]([NH:13][C:14]([C:16]1[N:17]=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[C:16]([C:14]([NH:13][C@@H:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:32]3[CH:33]=[CH:34][C:29]([C:28]([F:39])([F:38])[F:27])=[CH:30][CH:31]=3)=[CH:8][CH:7]=2)[C:3]([OH:2])=[O:26])=[O:15])[N:17]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc2ccccc2cn1
Product: O=C(N[C@@H](Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)C(=O)O)c1cc2ccccc2cn1
Yield: 71.8 %

Procedure:
The resulting amide (100 mg, 0.24 mmol) was reacted with 4-trifluoromethylphenyl boronic acid (95 mg, 0.5 mmol) as described in general procedure D yielding the title compound (80 mg, 80%) as a white solid.
Reaction SMILES: [Br-].[C:2]1([CH2:8][C:9]([NH:11][C@@H:12]2[C:47](=[O:48])[N:14]3[C:15]([C:39]([O:41][CH2:42][C:43]([Cl:46])([Cl:45])[Cl:44])=[O:40])=[C:16]([CH2:19][P+](C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:49]=O.P([O-])([O-])(O)=O.[Na+].[Na+]>CN(C)C=O.O>[C:2]1([CH2:8][C:9]([NH:11][C@@H:12]2[C:47](=[O:48])[N:14]3[C:15]([C:39]([O:41][CH2:42][C:43]([Cl:44])([Cl:46])[Cl:45])=[O:40])=[C:16]([CH:19]=[CH2:49])[CH2:17][S:18][C@H:13]23)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=O
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Agent: O=P([O-])([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1

Procedure:
[7β-Phenylacetamido-4-(2,2,2-trichloroethoxycarbonyl)ceph-3-em-3-ylmethyl]-triphenylphosphonium bromide (403 mg, 0.5 mmole) was dissolved in N,N-dimethylformamide (10 ml.) and 40% -formaldehyde solution (3 ml.) was added. The solution was stirred vigorously while a solution of disodium hydrogen phosphate (400 mg.) in water (5 ml.) was added dropwise. A white crystalline solid, subsequently identified as the title ester, separated before the addition was complete. The reaction mixture was diluted with chloroform (25 ml.) and water (10 ml.), whereupon the solid dissolved. The aqueous phase was re-extracted with chloroform (25 ml.), and the combined organic phases were washed with 2N-hydrochloric acid (50 ml.) and water (4 × 25 ml.), dried (MgSO4), and evaporated to give the title ester as a pale-yellow solid (128 mg., 54%), λmax. (EtOH) 297 nm (ε13,700). Crystallisation by trituration with ethanol (2 ml.) gave a white solid (75 mg., 31.5%, m.p. 163 to 165°, [α]D 23 - 54° (C 1.15; Me2SO), λmax. (EtOH) 297 nm (ε13,550), νmax. (CHBr3) 3410 (NH), 1772 (azetidin-2-one), 1730 (CO2R), 1674 and 1500 (CONH) and 912 cm-1 (=CH2), τ(CDCl3) 2.68 (5H, s; C6H5), 2.84 (1H, dd, J 11 and 18 Hz; CH=CH2), 3.61 (1H, d, J 8 Hz; NH), 4.13 (1H, dd, J 8 and 5 Hz; C7 --H), 4.48 (1H, d, J 18 Hz) and 4.60 (1H, d, J 11 Hz) (CH=CH2), 4.98 (1H, d, J 5 Hz; C6 --H), 4.99 and 5.25 (2H, AB-q, J 12 Hz; CH2CCl3), 6.30 and 6.53 (2H, AB,-q J 18 Hz; C2 --H2), 6.37 (2H, s; C6H5CH2) (Found: C, 46.8, 47.1; H, 3.6; Cl, 21.8; N, 5.5, 5.5; S, 6.5. C19H17Cl3N2O4S (475.8) requires C, 48.0; H, 3.6; Cl, 22.4; N, 5.9; S, 6.7%).
Reaction SMILES: [O:1]1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][CH2:11][NH:10][C:9]3=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][C:20]([CH:23]([OH:28])[C:24]([F:27])([F:26])[CH3:25])=[CH:19][CH:18]=1>>[F:26][C:24]([F:27])([CH3:25])[CH:23]([C:20]1[CH:19]=[CH:18][C:17]([N:10]2[CH2:11][CH2:12][C:8]3([CH2:14][CH2:15][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)[C:9]2=[O:13])=[CH:22][CH:21]=1)[OH:28]
Reactant: O=C1NCCC12CCC1(CC2)OCCO1
Reactant: CC(F)(F)C(O)c1ccc(Br)cc1
Product: CC(F)(F)C(O)c1ccc(N2CCC3(CCC4(CC3)OCCO4)C2=O)cc1

Procedure:
The title compound was prepared in analogy to example 133, step 4 from 1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (0.8 g) (described in example 133 step 3) and 1-(4-bromo-phenyl)-2,2-difluoro-propan-1-ol (1.14 g) (synthesis: R. Mogi, et al, Journal of Fluorine Chemistry; 10; 2007; p 1098) and the crude product was directly used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[C:6](=[O:26])[N:7]=[C:8]([C:10]3[CH:15]=[C:14]([CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[CH:13]=[C:12]([CH3:25])[N:11]=3)[S:9][C:4]=2[CH:3]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[C:6](=[O:26])[N:7]=[C:8]([C:10]3[CH:15]=[C:14]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:13]=[C:12]([CH3:25])[N:11]=3)[S:9][C:4]=2[CH:3]=1
Reactant: Cc1cc(CCC(=O)OC(C)(C)C)cc(-c2nc(=O)c3ccc(Cl)cc3s2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CCC(=O)O)cc(-c2nc(=O)c3ccc(Cl)cc3s2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
tert-Butyl 3-[2-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-6-methyl-4-pyridyl]propanoate (0.90 g, 2.5 mmol) was dissolved in trifluoroacetic acid (8 ml), and the mixture was stirred at 0° C. for 2 hrs. The solvent was evaporated, and the residue was recrystallized from diisopropyl ether-ethanol to give the titled compound (0.74 g, 82%) as pale yellow crystals.