Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:31]([Si:33]([CH3:36])([CH3:35])[CH3:34])#[CH:32].CCN(CC)CC>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([C:32]#[C:31][Si:33]([CH3:36])([CH3:35])[CH3:34])=[CH:6][CH:5]=1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Reaction time: 0.33 h
Yield: 54 %

Procedure:
4-Bromobenzoic acid methyl ester (1.124 g, 5.22 mmol), PdCl2(PPh3)2 (192 mg, 27.4 mmol), and PPh3 (37 mg, 14.1 mmol) were suspended in THF (25.0 mL). Ethynyltrimethylsilane (1.14 mL, 8.1 mmol) and Et3N (1.14 mL, 7.8 mmol) were added and the reaction was allowed to stir for 20 min. CuI (14 mg, 0.075 mmol) was added and the reaction color changed from orange to red. Reaction was allowed to proceed overnight. After overnight reaction, the solution was brown in color and TLC analysis indicated the reaction was complete. The reaction mixture was concentrated to a brown residue, redissolved in DCM and filtered through Celite. The filtrate and rinses were evaporated to dryness and purification via Silica in 15:1 cyclohexane: EtOAc afforded 4-(trimethylsilyl)ethynyl-benzoic acid methyl ester (656 mg, 2.82 mmol, 54%) as an orange solid. H-NMR (CD3C1, 500 MHz) δ (ppm): 0.239 (s, 9H); 3.89 (s, 3H); 7.49 (d, J=16.84 Hz, 2H); 7.94 (d, J=16.4 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[CH:4][CH:3]=1.[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([Cl:38])=[C:33]([CH:37]=1)[C:34](O)=[O:35])=[O:26])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl.CCO>[CH3:18][O:17][C:11]1[CH:12]=[CH:13][C:14]([NH:16][C:34](=[O:35])[C:33]2[CH:37]=[C:29]([CH2:28][NH:27][C:25]([O:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:26])[CH:30]=[CH:31][C:32]=2[Cl:38])=[CH:15][C:10]=1[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(C(=O)O)c1
Reactant: COc1ccc(N)cc1C(=O)Nc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(NC(=O)c2cc(CNC(=O)OC(C)(C)C)ccc2Cl)cc1C(=O)Nc1ccc(Br)cc1

Procedure:
Prepared analogously to Example 4c from N-(4-bromophenyl)-2-methoxy-5-amino-benzoic acid amide and 5-(tert.butoxycarbonylamino)methyl-2-chloro benzoic acid with TBTU and TEA. Yield: (85%). MS [m+H]+=588 (Br/Cl-isotope pattern); TLC: Rf=0.60 (silica gel, DCM:EtOH 9:1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([OH:21])=O)[C@H:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([CH2:30][C@H:31]([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:26]=[CH:27][C:28]=1[F:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([NH:22][C:23]1[CH:24]=[C:25]([CH2:30][C@H:31]([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:26]=[CH:27][C:28]=1[F:29])=[O:21])[C@H:13]([C:15]([F:16])([F:17])[F:18])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]([C@H](NC(=O)OCc1ccccc1)C(=O)O)C(F)(F)F
Reactant: CCOC(=O)[C@@H](C)Cc1ccc(F)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)[C@@H](C)Cc1ccc(F)c(NC(=O)[C@@H](NC(=O)OCc2ccccc2)[C@@H](C)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.87 g (2.85 mmol) of (3R)—N-[(benzyloxy)carbonyl]-4,4,4-trifluorovaline (diastereomer mixture) and 0.77 g (3.42 mmol) of (+)-ethyl (2S)-3-(3-amino-4-fluorophenyl)-2-methylpropanoate were dissolved in a mixture of 5 ml of DMF and 2.5 ml of pyridine, and 1.41 g (3.71 mmol) of HATU were added at RT. The reaction mixture was stirred at RT overnight and then diluted with ethyl acetate. The mixture was washed successively with 1 N hydrochloric acid, sat. sodium bicarbonate solution and sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 6:1). This gave 1.27 g of the target product (87.2% of theory, diastereomer ratio about 4.8:1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([NH:29][S:30]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:37]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[S:34][C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([CH3:24])[CH:11]=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=4)[N:13]=3)[CH:3]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1

Procedure:
N-tert-Butyl-5-{3-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyrimidine (example E.47) (0.39 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.41 g, 1.2 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.16 g), which was subsequently deprotected.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].S(Cl)(Cl)=O.[CH2:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[N:1]1[CH:6]=[C:5]([C:7]([O:9][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([O:12][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:11]
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccc(C(=O)O)nc1
Solvent: O=S(Cl)Cl
Product: O=C(OCc1ccccc1)c1ccc(C(=O)OCc2ccccc2)nc1

Procedure:
Analogously to Example 1, 20 g of pyridine-2,5-dicarboxylic acid are converted into the acid chloride with 160 m of thionyl chloride and this is reacted with 25.9 g of benzyl alcohol. The product is recrystallized from ethyl acetate, with the addition of active charcoal.
Reaction SMILES: O[CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[C:13](O)(=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[Na+].[Na+].[PH2]([O-])=O.[Na+]>>[CH3:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]/[CH:22]=[CH:21]\[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]([O:12][CH2:11][CH:9]([OH:10])[C@H:7]1[O:8][CH2:2][C@H:3]([OH:4])[C@H:5]1[OH:6])=[O:31]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: O=[PH2][O-]
Agent: [Na+]
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
After 497 g of a 70% by weight sorbitol aqueous solution (aldehyde value of sorbitol: 5.0 ppm), 863 g of oleic acid, 3.0 g of sodium carbonate, and 1.7 g of sodium hypophosphite were charged into a 2000 mL four-neck flask fitted with a stirring apparatus, a thermometer, and a nitrogen gas inlet, replacement with nitrogen was performed at room temperature for 30 minutes. Thereafter, the temperature was raised stepwise to 110° C., 140° C., and 170° C. After the temperature reached 170° C. as a reaction temperature, the pressure was reduced to 6.5 kPa and the reaction was carried out under a nitrogen stream. At the time point when the spot of oleic acid as a raw material disappeared on thin-layer chromatography, it was judged that the reaction was completed. The reaction time was 20 hours and, after the completion of the reaction was confirmed, the product was filtrated at 80° C. to obtain sorbitan monooleate.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([O:12][C:13](=[O:25])[CH2:14][C@@:15]1([CH2:21][C:22]([OH:24])=[O:23])[CH2:19][CH2:18][C@@H:17]([CH3:20])[CH2:16]1)([CH3:11])([CH3:10])[CH3:9]>C1(C)C=CC=CC=1.CO>[C:8]([O:12][C:13](=[O:25])[CH2:14][C@@:15]1([CH2:21][C:22]([O:24][CH3:1])=[O:23])[CH2:19][CH2:18][C@@H:17]([CH3:20])[CH2:16]1)([CH3:9])([CH3:10])[CH3:11]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C[C@@H]1CC[C@](CC(=O)O)(CC(=O)OC(C)(C)C)C1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C[C@]1(CC(=O)OC(C)(C)C)CC[C@@H](C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
Trimethylsilyldiazomethane (14 mL of a 2 M solution in hexanes, 26.9 mmol) was added dropwise to a stirring solution of [(1S,3R)-1-carboxymethyl-3-methyl-cyclopentyl]-acetic acid tert-butyl ester (6.9 g, 26.9 mmol) in toluene (60 mL) and methanol (15 mL) at 10° C. under argon, and the mixture was allowed to warm to room temperature. The mixture was stirred for 2 hours, and then the solvent was evaporated under reduced pressure. The residue was taken up in ethyl acetate (200 mL), washed with saturated sodium hydrogen carbonate solution, dilute hydrochloric acid, dried (MgSO4), and the solvent removed in vacuo. The residue was purified by chromatography (silica gel, eluting with a gradient of heptane to 95:5 heptane:ethyl acetate) to give 6.73 g (92.4%) of [(1S,3R)-1-methoxycarbonylmethyl-3-methyl-cyclopentyl]-acetic acid tert-butyl ester;
Reaction SMILES: [Cl:1][C:2]1[N+:7]([O-:8])=[N:6][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2SC)=[CH:4][CH:3]=1.Cl[C:19]1C=CC=C(C(OO)=O)C=1.[S:29]([O-:32])([O-])=[O:30].[Na+].[Na+]>ClCCCl>[Cl:1][C:2]1[N+:7]([O-:8])=[N:6][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:29]([CH3:19])(=[O:32])=[O:30])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])[O-]
Reactant: CSc1ccccc1Oc1ccc(Cl)[n+]([O-])n1
Agent: [Na+]
Solvent: ClCCCl
Product: CS(=O)(=O)c1ccccc1Oc1ccc(Cl)[n+]([O-])n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.7 %

Procedure:
In 1,2-dichloroethane (5 mL) was dissolved 208 mg (0.774 mmol) of 6-chloro-3-[2-(methylsulfanyl)phenoxy]pyridazine 1-oxide obtained in Example 11 (1), 829 mg (3.84 mmol) of 80% m-chloroperbenzoic acid was added to the solution and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into 10% aqueous sodium sulfite solution, and extracted with ethyl acetate. The organic layers were combined, washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from Merck Co., 1.05744, developed by hexane:ethyl acetate=1:1) to obtain 132 mg (0.439 mmol, Yield: 56.7%) of 6-chloro-3-[2-(methylsulfonyl)phenoxy]pyridazine 1-oxide.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:12][C:13](O)([CH3:15])[CH3:14].CCN=C=NCCCN(C)C.O>CC(N(C)C)=O.CN(C1C=CN=CC=1)C>[C:1]([C:4]1[S:8][C:7]([C:9]([O:11][C:13]([CH3:15])([CH3:14])[CH3:12])=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)s1
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)c1ccc(C(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.2 %

Procedure:
A solution of 5-acetylthiophene-2-carboxylic acid (7 g, 41 mmol) in DMA (100 mL) was treated with 2-methyl-2-propanol (54 mL, 576 mmol), DMAP (3 g, 25 mmol), and EDCI (9.9 g, 51.5 mmol). The resulting mixture was stirred at 25° C. for 16 h. Water (200 mL) was added and the mixture was extracted with ethyl ether (350 mL). The organic phase was washed with 1 N HCl (100 mL), water (3×100 mL), saturated aqueous NaHCO3 (100 mL), and brine (100 mL); dried (Na2SO4); filtered; and evaporated to afford 6.7 g (72%) of the title compound as a tan solid. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.53 (s, 9H) 2.58 (s, 3H) 7.75 (d, J=3.68 Hz, 1H) 7.92 (d, J=3.68 Hz, 1H); MS (DCI) 227 m/z (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6](Br)[CH:5]=1.B(O)(O)[C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:10][C:8]1[CH:9]=[C:4]([C:3]([O:2][CH3:1])=[O:12])[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:7]=1
Reactant: COC(=O)c1cc(O)cc(Br)c1
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc(O)cc(-c2ccc(C)cc2)c1

Procedure:
To a stirred solution of 3-bromo-5-hydroxy-benzoic acid methyl ester (4.09 g, 17.7 mmol) and p-tolylboronic acid (2.86 g, 21 mmol) in toluene (36 mL) was added cesium carbonate (7.14 g, 22 mmol) in water (3.6 mL) at room temperature. The mixture was purged with nitrogen, and tetrakis(triphenylphosphine)palladium(0) (1.05 g, 0.906 mmol) was added. The reaction mixture was subjected to microwave irradiation at 110° C. for 1 hour. After cooling, the mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by flash chromatography to afford the title compound.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH3:7])(=[O:4])=[O:3].[Li+].CCC[CH2-].[P:13](Cl)(=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>O1CCCC1>[CH2:15]([O:14][P:13]([CH2:1][S:2]([O:5][CH2:6][CH3:7])(=[O:4])=[O:3])([O:17][CH2:18][CH3:19])=[O:20])[CH3:16]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CCOS(C)(=O)=O
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(CS(=O)(=O)OCC)OCC
Reaction time: 0.25 h
Yield: 117.1 %

Procedure:
A solution of ethyl methanesulfonate (4.14 mL, 40.2 mmol) in anhydrous tetrahydrofuran (100 ml) was cooled to −78° C. under a nitrogen atmosphere. N-Butyllithium (20 ml, 50.0 mmol) was added slowly in 7 minutes after which stirring was continued for 15 minutes. Diethyl phosphorochloridate (4.36 mL, 30.2 mmol) was added, the reaction mixture was stirred for 2.5 h, the cooling bath was removed and the mixture was allowed to reach room temperature. The reaction mixture was quenched with aqueous saturated ammonium chloride (150 ml) and the resulting mixture was extracted with EtOAc (2×100 ml). The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to yield 9.20 g of a yellow oil. The oil was purified over silicagel (600 g) using a gradient of ethyl acetate (0-100%) in heptane to yield 1.75 g of the product (6.7 mol, 17%).
Reaction SMILES: CO[C:3](=[O:16])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14]Br)=[N:5]/[O:6][CH3:7].[Cl:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][NH2:32].Cl>CN(C=O)C.CO>[CH3:31][NH:32][C:3](=[O:16])[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=1)=[N:5][O:6][CH3:7]
Reactant: CN
Reactant: Oc1cccc(Cl)c1
Reactant: CO/N=C(/C(=O)OC)c1ccccc1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CNC(=O)C(=NOC)c1ccccc1COc1cccc(Cl)c1
Reaction time: 10 h

Procedure:
Methyl-(E)-2 -(bromomethylphenyl)-2-methoxyiminoacetate as obtained in Example 27 (1) (250 mg), 3-chlorophenol (225 mg) and potassium carbonate (482 mg) were dissolved in DMF, and the resultant mixture was stirred at room temperature for 10 hours. A solution (677 mg) of methylamine in 30% methanol was added thereto, and stirring was continued for 10 hours. The reaction mixture was neutralized with dilute hydrochloric acid, extracted with diethyl ether. The solvent was dried and evaporated, and the residue was purified by silica gel column chromatography to give 265 mg of the objective compound.
Reaction SMILES: N[C@@H:2]1[C@@H:5]([CH2:6][CH:7]=[CH2:8])[N:4]([C:9](=[C:14]([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])[C:3]1=[O:17].C(ON=O)CC(C)C.[ClH:26].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)C.C(OCC)(=O)C>[CH2:6]([C@H:5]1[N:4]([C:9](=[C:14]([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])[C:3](=[O:17])[CH:2]1[Cl:26])[CH:7]=[CH2:8]
Reactant: C=CC[C@@H]1[C@@H](N)C(=O)N1C(C(=O)OC)=C(C)C
Reactant: Cl
Agent: CC(C)CCON=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: C=CC[C@@H]1C(Cl)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
A solution of methyl 2-[(3R,4R)-3-amino-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (1.0 g) in methylene chloride (10 ml) was cooled to -65° C., and isopentylnitrite (1.01 ml) and a solution of hydrogen chloride (524 mg) in ethyl ether (8 ml) were added. The mixture was allowed to warm to 0° C. during a period of 45 minutes and stirred for one hour and half at 0° C. The reaction mixture was poured into a mixture of ethyl acetate (40 ml) and dilute aqueous sodium bicarbonate. The organic layer was separated and washed with brine, dried over magnesium sulfate and evaporated to leave an oil, which was chromatographed on silica gel (15 g) eluting with a mixture of methylene chloride and acetone (100:2-100:5) to give methyl 2-[(4R)-4-allyl-3-chloro-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (658 mg) as an oil.
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:11]([C:14]([OH:16])=[O:15])[CH2:12][CH2:13][CH:7]2[CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)(O)[O-].[Na+].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O.C(Cl)Cl.CCOCC>[C:22]([NH:1][C@@H:2]1[C:9](=[O:10])[N:8]2[C@H:11]([C:14]([OH:16])=[O:15])[CH2:12][CH2:13][C@@H:7]2[CH2:6][CH2:5][CH2:4][CH2:3]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC1CCCCC2CCC(C(=O)O)N2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(N[C@H]1CCCC[C@H]2CC[C@@H](C(=O)O)N2C1=O)c1ccccc1
Reaction time: 18 h

Procedure:
A solution of 6-amino-5-oxo-decahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid, 19, (181 mg, 0.8 mmol) in H2O/CH2Cl2 (7 mL) is treated with sodium bicarbonate (0.50 g, 6 mmol) and benzoyl chloride (140 mg, 1.0 mmol). The reaction is stirred for 18 hours then diluted with ether (100 mL). The organic layer is washed twice with 1 N HCl, once with water, and dried over MgSO4, filtered, and concentrated under in vacuo to afford a residue which is purified over silica to afford the desired compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[CH3:14][NH:15][CH2:16][CH2:17][CH2:18][CH3:19].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:16]([N:15]([CH3:14])[C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:12])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCNC
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN(C)C(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
2-Naphthoyl chloride (3.81 g 0.020 moles) dissolved in dichloromethane (10 ml) was added dropwise to an ice cold solution of N-methylbutylamine (1.74 g, 0.020 moles) and diisopropylethylamine (4.5 ml, 0.025 moles) in dichloromethane (40 ml). The mixture was stirred at room temperature for 18 hours and evaporated in vacuo. The residue was taken into dichloromethane (50 ml), washed with 2M HCl (2×25 ml), dried (MgSO4) then evaporated in vacuo to give N-butyl-N-methyl-naphthalene-2-carboxamide (4.6 g, 0.019 moles) as a yellow oil.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16](SC)=[N:15][C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:29][NH:30][C:31]1[N:36]=[CH:35][C:34]([Sn](CCCC)(CCCC)CCCC)=[CH:33][N:32]=1>COCCOC.C(OCC)(=O)C.CSC.[Cu]Br.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][NH:30][C:31]1[N:36]=[CH:35][C:34]([C:16]2[N:17]=[C:18]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[C:19]3[S:20][C:12]([CH2:11][N:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]4)=[CH:13][C:14]=3[N:15]=2)=[CH:33][N:32]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(NC)nc1
Reactant: CSc1nc(N2CCOCC2)c2sc(CN3CCN(S(C)(=O)=O)CC3)cc2n1
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CSC
Product: CNc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (80 mg) in 1,2-dimethoxyethane (10 mL) was added methyl-(5-tributylstannyl-pyrimidin-2-yl)-amine (143 mg) and copper(I)bromide-dimethyl sulfide (74 mg) and the reaction mixture was stirred at room temperature for 10 minutes. Tetrakis(triphenylphosphine)palladium (0) (10 mg) was then added and the reaction mixture was heated at reflux for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (20 mL) and washed with water (2×20 mL) and brine (2×20 mL). The organic phase was dried (MgSO4), reduced in vacuo and purified by column chromatography to give 417. NMR: (CDCl3): 2.59-2.61 (4H, m), 2.73 (3H, s, Me), 3.01 (3H, d, J 5.1, Me), 3.21-3.24 (4H, m), 3.78-3.81 (6H, m), 3.93-3.96 (4H, m), 7.22 (1H, s, Ar) and 9.21 (2H, s, Ar) MS: (ESI+): MH+=505.20
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[C:13](=[O:18])[NH:14][CH:15]=[CH:16][CH:17]=1.[CH3:19]I>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[C:13](=[O:18])[N:14]([CH3:19])[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-c1ccc[nH]c1=O
Reactant: CI
Product: COc1cc([N+](=O)[O-])ccc1-c1cccn(C)c1=O

Procedure:
350 mg (1.42 mmol) of the product from example 55A are alkylated analogously to example 56A with 242 mg (1.71 mmol) of methyl iodide. This affords 347 mg (88% of theory) of the title compound.
Reaction SMILES: COC1C=C2C(C(OCC(O)C)=CC=N2)=CC=1.[CH3:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([O:30][CH:31]([CH3:34])[CH2:32]O)=[CH:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1.P(Br)(Br)[Br:36]>C(Cl)Cl>[Br:36][CH2:32][CH:31]([O:30][C:24]1[C:23]2[C:28](=[CH:29][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[N:27]=[CH:26][CH:25]=1)[CH3:34]
Reactant: COc1ccc2c(OC(C)CO)ccnc2c1
Reactant: BrP(Br)Br
Agent: COc1ccc2c(OCC(C)O)ccnc2c1
Solvent: ClCCl
Product: COc1ccc2c(OC(C)CBr)ccnc2c1

Procedure:
To a stirred solution of 1-(7-methoxyquinolin-4-yloxy)propan-2-ol (235 mg, 1007 μmol) and 2-(7-methoxyquinolin-4-yloxy)propan-1-ol (235 mg, 1007 μmol) (mixture of isomers) in CH2Cl2 (3 mL) was added phosphorus tribromide (94.7 μl, 1007 μmol). The mixture was heated to reflux for 18 h. The mixture was quenched with 5% NaHCO3, and was extracted with CH2Cl2 (3×5 mL). The combined organics were dried over MgSO4 and concentrated to a white solid (150 mg) under reduced pressure. MS (ESI pos. ion) m/z (MH+): 296/298. Calc'd exact mass for C13H14BrNO2: 295.