Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:15](=[O:16])[C:14]2[N:13]=[C:12]([CH:17]=O)[CH:11]=[CH:10][C:9]=2[C:8](=[O:19])[CH:7]=1)=[O:4].[CH2:20]([O:25][C:26](=[O:39])[C@H:27]([CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)[NH2:28])[CH2:21][CH:22]([CH3:24])[CH3:23].[K+].[Br-].COC(=O)[C@H](C(C)C1C2C(=CC=CC=2)NC=1)N>>[CH3:24][CH:22]([CH2:21][CH2:20][O:25][C:26]([C:27]1[CH:29]=[C:30]2[C:31](=[C:17]([C:12]3[CH:11]=[CH:10][C:9]4[C:8](=[O:19])[CH:7]=[C:6]([NH:5][C:3]([CH2:2][Cl:1])=[O:4])[C:15](=[O:16])[C:14]=4[N:13]=3)[N:28]=1)[NH:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:38]2=1)=[O:39])[CH3:23]
Reactant: CC(C)CCOC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=Cc1ccc2c(n1)C(=O)C(NC(=O)CCl)=CC2=O
Agent: COC(=O)[C@@H](N)C(C)c1c[nH]c2ccccc12
Agent: [Br-]
Agent: [K+]
Product: CC(C)CCOC(=O)c1cc2c([nH]c3ccccc32)c(-c2ccc3c(n2)C(=O)C(NC(=O)CCl)=CC3=O)n1
Temperature: 76 °C
Yield: 27 %

Procedure:
In a 100 ml. three-necked, round-bottomed flask equipped with a reflux condenser, flowing argon and a magnetic bar, 7-chloro-acetamido-2-formylquinoline-5,8-dione (24) (prepared as described in Example 24) (0.0500 g., 0.18 mmol), L-tryptophan isoamyl ester (37) (prepared as described in Example 37) (0.0490 g., 0.18 mmol), and 75 ml. of dried and distilled xylene were slowly heated to 76° C. over a five-hour period. Upon the first detection of the formation of a light-colored precipitate, the mixture was filtered hot. The filtrate was concentrated under reduced pressure to about 10 ml. The filtrate was stored in a refrigerator overnight during which a considerable amount of a dark orange-brown solid formed. This was filtered and washed with cold ethyl acetate giving 25.5 mg. of the crude product (a yield of 27%). The filtrate was further concentrated which, upon cooling, yielded an additional 15 mg. of the product (16% yield, total yield 43%): mp. 280-284° C.; 1H NMR (CDCl3) δ 1.05 (6H, d, J=6.3 Hz., (CH3)2), 1.76-1.95 (3H, m, COOCH2CH2CH), 4.29 (2H, s, C-7NHCOCH2Cl), 4.52 (2H, t, J=6.8 Hz., COOCH2), 7.39 (1H, dd, J=8.0 Hz., J=8.0 Hz., C-11'H), 7.66 (1H, dd, J=8.0 Hz., J=8.0 Hz., C-10'H), 7.78 (1H, d, J=8.0 Hz., C-9'H), 7.95 (1H, s, C-6H), 8.23 (1H, d, J=8.0 Hz., C-12'H), 8.54 (1H, d, J=8.3 Hz., C-3H), 8.93 (1H, s, C-3'H), 9.18 (1H, d, J=8.3 Hz., C-4H), 9.56 (1H, br s, C-7NH), 11.76 (1H, br s, NH); IR (KBr) vmax 3336, 2957, 2929, 2908, 2871, 1713, 1680, 1651, 1588, 1520, 1337, 1308, 1265, 1219, 1119, 738 cm1 ; EIMS, m/e (relative intensity) 530/532 (M+, 2.4/1, 45), 496 (58), 480 (6), 454 (39), 416 (83), 382 (95), 366 (15), 340 (base); HRMS, m/e for C28 H23ClN4O5 calculated 530.135698, found 530.135781.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH:6]=[CH:5]2.[P:14]([O:21]CC)([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>[Ni](Cl)Cl>[CH2:16]([O:15][P:14]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH:6]=[CH:5]2)([O:18][CH2:19][CH3:20])=[O:21])[CH3:17]
Reactant: CC1(C)C=Cc2cc(Br)ccc2O1
Reactant: CCOP(OCC)OCC
Agent: Cl[Ni]Cl
Product: CCOP(=O)(OCC)c1ccc2c(c1)C=CC(C)(C)O2
Temperature: 180 °C

Procedure:
16 g of 6-bromo-2,2-dimethyl-2H-chromene are dissolved in 100 ml of triethyl phosphite. 2 g of nickel chloride are added and the mixture is refluxed at 180° C. for 24 hours in an autoclave. After the remaining triethyl phosphite has been concentrated, the expected product distills at 130°-140° C. under 0.1 mm Hg. 11.5 g are collected.
Reaction SMILES: [CH:1]1([N:4]([CH2:15][CH3:16])[CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][C:7]=2[CH3:14])[CH2:3][CH2:2]1.[CH3:17][O:18][C:19](=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1>C(N(CC)CC)C.[Cu]I.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>[CH:1]1([N:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:24]3[CH:25]=[CH:26][C:21]([CH2:20][C:19]([O:18][CH3:17])=[O:28])=[CH:22][CH:23]=3)=[CH:8][C:7]=2[CH3:14])[CH2:15][CH3:16])[CH2:3][CH2:2]1
Reactant: C#Cc1ccc(CN(CC)C2CC2)c(C)c1
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCN(Cc1ccc(C=Cc2ccc(CC(=O)OC)cc2)cc1C)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
Using General Procedure F; cyclopropyl-ethyl-(4-ethynyl-2-methyl-benzyl)-amine (Intermediate 161, 300.0 mg, 1.41 mmols) and methyl-(4-iodophenyl)-acetate (Reagent B, 388.0 mg, 1.41 mmols) in triethylamine (8 mL) was treated with copper(I)iodide (67.0 mg, 0.35 mmol) and sparged with argon for 15 minutes. Dichlorobis(triphenylphosphine)palladium(II) (246 mg, 0.35 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (5-7% EtOAc-hexanes) afforded 270.0 mg (53%) of the title compound as a pale-yellow oil.
Reaction SMILES: CN(C)C=O.[C:6](Cl)(=O)[C:7]([Cl:9])=[O:8].[Cl:12][C:13]1[C:18]([Cl:19])=[C:17]([O:20][CH3:21])[CH:16]=[CH:15][C:14]=1CC(O)=O>ClCCl>[Cl:12][C:13]1[C:18]([Cl:19])=[C:17]([O:20][CH3:21])[CH:16]=[CH:15][C:14]=1[CH2:6][C:7]([Cl:9])=[O:8]
Reactant: COc1ccc(CC(=O)O)c(Cl)c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CC(=O)Cl)c(Cl)c1Cl

Procedure:
0.5 ml of dimethylformamide and 60.9 g (0.48 mol) of oxalyl chloride were added to a solution of 37.3 g (0.16 mol) of 2,3-dichloro-4-methoxyphenylacetic acid in 0.5 l of dichloromethane. After evolution of gas had ceased (about 2 hours), the mixture was concentrated. The crude product was reacted further in the next step without any purification. Yield: quantitative.
Reaction SMILES: C([O:4][C:5]1[C:10]([C:11](=[O:13])[NH2:12])=[C:9]([NH:14][C:15]2[CH:16]=[N:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:8]=[C:7]([S:25][CH3:26])[N:6]=1)(=O)C.C(O)C.[OH-].[Na+].Cl>C1COCC1>[CH3:26][S:25][C:7]1[NH:6][C:5](=[O:4])[C:10]([C:11]([NH2:12])=[O:13])=[C:9]([NH:14][C:15]2[CH:16]=[N:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:8]=1
Reactant: CSc1nc(Nc2cnc3ccccc3c2)c(C(N)=O)c(OC(C)=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CSc1nc(Nc2cnc3ccccc3c2)c(C(N)=O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To 5-carbamoyl-2-(methylsulfanyl)-6-(quinolin-3-ylamino)pyrimidin-4-yl acetate (Preparation Example 346) (0.71 g), ethanol (14 mL) and THF (14 mL) were added, and 1M aqueous sodium hydroxide (6 mL) was added and stirred at room temperature for 1 hour. Then, 1M hydrochloric acid (6 mL) was added, and the precipitated solid was collected by filtration and dried to give 2-(methylsulfanyl)-6-oxo-4-(quinolin-3-ylamino)-1,6-dihydropyrimidine-5-carboxamide (0.63 g).
Reaction SMILES: F[C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:10][NH2:11]>O>[NH:10]1[C:2]2[C:3](=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:8]=[N:11]1
Reactant: NN
Reactant: O=Cc1ncccc1F
Solvent: O
Product: c1cnc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 60.3 %

Procedure:
A mixture of 3-fluoro-2-pyridinecarboxaldehyde (4 g, 32 mmol) and hydrazine (20.5 g) was kept at 115° C. for 7 hr, then cooled to rt. The reaction mixture was diluted with water and extracted with EtOAc. The organic phases were combined, washed with brine, and dried. Concentration followed by flash chromatography afforded 1H-pyrazolo[4,3-b]pyridine (2.3 g, 60.4%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:14]2[CH:10]([CH2:11][N:12]([CH2:15][C:16]#[N:17])[CH2:13]2)[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2>CO.N.[Rh]>[CH3:1][O:2][CH:3]1[CH:14]2[CH:10]([CH2:11][N:12]([CH2:15][CH2:16][NH2:17])[CH2:13]2)[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: COC1c2ccccc2C2CN(CC#N)CC21
Agent: [Rh]
Agent: N
Solvent: CO
Product: COC1c2ccccc2C2CN(CCN)CC21
Reaction time: 4 h
Yield: 95.3 %

Procedure:
The product from Example 16 (1.00 g) was dissolved in 90 ml methanol and 10 ml anhydrous ammonia. 0.100 g 5% Rh/Al2O3 was added and the reaction was hydrogenated at 4 atm for 4 h. The reaction was filtered and the solvent removed to yield 0.97 g of the desired product as a colorless oil. NMR (CDCl3) δ2.20-2.61 (m, 3H), 2.66-3.45 (m, 8H), 3.82 (s, 3H), 3.89 (m, 1H), 6.67 (d, 1H), 6.78 (d, 1H), 7.14 (t, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([C:25]([CH3:35])([CH3:34])[CH2:26][C:27](=[O:33])[N:28]5[CH2:31][OH:32])=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.S1C=CC2C(N3CCN(CCCCOC4C=C5C(C(C)(C)CC(=O)N5)=CC=4)CC3)=CC=CC1=2.N1C=CC=CC=1.Cl[C:76]([O:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])=[O:77]>C(Cl)Cl.O>[CH2:79]([O:78][C:76](=[O:77])[O:32][CH2:31][N:28]1[C:29]2[C:24](=[CH:23][CH:22]=[C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][N:13]3[CH2:14][CH2:15][N:10]([C:6]4[C:3]5[CH:4]=[CH:5][S:1][C:2]=5[CH:9]=[CH:8][CH:7]=4)[CH2:11][CH2:12]3)[CH:30]=2)[C:25]([CH3:35])([CH3:34])[CH2:26][C:27]1=[O:33])[CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88]
Reactant: CC1(C)CC(=O)N(CO)c2cc(OCCCCN3CCN(c4cccc5sccc45)CC3)ccc21
Reactant: CCCCCCCCCCOC(=O)Cl
Agent: CC1(C)CC(=O)Nc2cc(OCCCCN3CCN(c4cccc5sccc45)CC3)ccc21
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCOC(=O)OCN1C(=O)CC(C)(C)c2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21
Yield: 34.1 %

Procedure:
7-[4-(4-Benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (460 mg), which is a mixture with 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one obtained in Example 155, was suspended in methylene chloride (10 ml), pyridine (0.06 ml) and decyl chloroformate (103 mg) were added, and the mixture was stirred under ice-cooling for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:1) to give carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)-butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester decyl ester (108 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5](I)=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24][CH3:25])O1>C1COCC1.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>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24][CH3:25])=[CH:4][N:3]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: CSc1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccccc1-c1cnc(Cl)nc1Cl
Temperature: 70 °C
Yield: 71.9 %

Procedure:
A solution of 2,4-dichloro-5-iodopyrimidine (50.15 g, 182 mmol), 4,4,5,5-tetramethyl-2-(2-(methylthio)phenyl)-1,3,2-dioxaborolane (47.9 g, 192 mmol) in THF (1368 ml) and water (456 ml) was degassed with nitrogen. Pd(PPh3)4 (10.54 g, 9.12 mmol) was added and degassing continued for several minutes. The mixture was then heated to reflux at 70° C. overnight. After 24 hrs the reaction was cooled to room temperature, the aqueous layer was removed, and the organic layer was washed with brine. The aqueous layer was extracted once with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography in 10-15% DCM 1-2% EtOAc/heptanes (v/v/v). The product was further purified by dissolving in EtOH and precipitating with heptanes, yielding 35.5 g (72% yield) of 2,4-dichloro-5-(2-(methylthio)phenyl)pyrimidine as white solids.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[C:11](=O)[CH2:12]Cl.O1CCOCC1.[BH4-].[Na+].Cl>C(Cl)Cl.O>[CH3:10][O:9][C:5]1[CH:4]=[C:3]2[C:2](=[C:7]([CH3:8])[CH:6]=1)[NH:1][CH:12]=[CH:11]2
Reactant: COc1cc(C)c(N)c(C(=O)CCl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(C)c2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a solution of 4-methoxy-2-methylanaline (0.36 mole, 50.0 g) in methylene chloride (450 mL) cooled to 10° C. (acetone/ice) was added a solution of 1.0 M boron trichloride in methylene chloride (0.50 mole, 500 mL) while maintaining the reaction temperature below −10° C. Chloroacetonitrile (1.82 mole, 137.6 g) was added to the reaction while maintaining the internal temperature below 0° C. This was followed by the addition of diethylaluminum chloride (0.40 mole, 48.34 g, 50 mL) while maintaining the reaction temperature below 0° C. The solution was then refluxed for 5.25 hours. The reaction was cooled to room temperature and carefully treated with 5N hydrochloric acid (0.450 L) and water (1 L). The suspension was heated to reflux and cooled to room temperature. The phases were separated and the aqueous phase was extracted with methylene chloride (3×500 mL). The combined organic phases were filtered through a pad of silica (height of silica=8 cm) in a scintered glass funnel (inner diameter of funnel=12 cm). Material eluted from silica pad with methylene chloride (3×500 mL) to afford 1-(2-amino-5-methoxy-3-methylphenyl)-2-chloroethanone plus chloroacetonitrile. The mixture was concentrated in vacuo to afford 40.1 g (51%) 1-(2-amino-5-methoxy-3-methylphenyl)-2-chloroethanone that slowly crystallized. A solution of 1-(2-amino-5-methoxy-3-methylphenyl)-2-chloroethanone (0.19 mole, 40.1 g) in 9:1 dioxane:water (935 mL) was added sodium borohydride (0.19 mole, 7.1 g). The reaction was stirred one hour at room temperature refluxed for 4.5 hours. The reaction was cooled to room temperature and treated with 1N hydrochloric acid (310 mL). This mixture was heated to 80° C. and cooled to room temperature. The reaction was treated with water (500 mL), extracted with ethyl acetate (3×500 mL) and the organic phases were combined, concentrated in vacuo to afford an oil. The oil was dissolved in methylene chloride and filtered through a pad of silica (height of silica=10 cm) in a scinter glass funnel (inner diameter of funnel=14.5 cm). Material eluted with methylene chloride. Fractions containing the title compound were combined, concentrated in vacuo to afford 23.32 g (77%) of the title compound as an oil: mass spectrum (ion spray): m/z=161 (M); 1H NMR (DMSOd6): 7.25 (t, J=2.93 Hz, 1H), 6.84 (d, J=2.20 Hz, 1H), 6.53 (d, J=1.46 Hz, 1H), 6.32 (dd, J=2.93, 1.83 Hz, 1H), 3.71 (s, 3H), 2.41 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:3]=1.[NH2:24][CH2:25][C:26]([N:28]([CH:30]1[CH2:32][CH2:31]1)[CH3:29])=[O:27].C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[CH:30]1([N:28]([CH3:29])[C:26](=[O:27])[CH2:25][NH:24][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=[C:4]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:3]=2)[CH2:32][CH2:31]1
Reactant: FC(F)(F)c1ccc(-c2nc(Cl)cc(-c3ccccc3)n2)cc1
Reactant: CN(C(=O)CN)C1CC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C(=O)CNc1cc(-c2ccccc2)nc(-c2ccc(C(F)(F)F)cc2)n1)C1CC1
Temperature: 150 °C
Yield: 89 %

Procedure:
A mixture of 4-chloro-6-phenyl-2-(4-trifluoromethylphenyl)-pyrimidine (15 g), 2-amino-N-cyclopropyl-N-methylacetamide (10 g) and triethylamine (5.4 g) is heated at 150° C. under reflux for 2 hours. To the reaction mixture are added water and chloroform, and the chloroform layer is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform), and recrystallized from ethanol to give the desired compound (17 g).
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: CCOC(=O)[C@@H](C)Cc1ccc(F)c(N)c1
Reactant: C[C@H]([C@H](NC(=O)OCc1ccccc1)C(=O)O)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)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: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:12]([SH:15])[NH:13][N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30]Br>CN(C=O)C.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:12]3[S:15][CH2:29][CH2:30][N:13]3[N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: BrCCBr
Reactant: O=[N+]([O-])c1cccc(-c2n[nH]c(S)c2-c2ccncc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(-c2nn3c(c2-c2ccncc2)SCC3)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
5-(3-Nitro-phenyl)-4-pyridin-4-yl-2H-pyrazole-3-thiol (298 mg, 1.0 mmol) was dissolved in dry DMF (12.5 mL) under nitrogen atmosphere. Solid potassium carbonate (690 mg, 5 mmol, 5 eq) was added followed by 1,2-dibromoethane (0.086 mL, 1 mmol, 1 eq) and the suspension was stirred at room temperature for 3 hours. The reaction mixture was then diluted with ethyl acetate (60 mL) and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. 280 mg of 6-(3-nitro-phenyl)-7-pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazole were obtained as an off-white solid (87%).
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([OH:15])[CH:8]=1)C.[OH-].[Na+]>C(O)C.O>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:16])=[O:3])=[CH:8][C:9]=1[OH:15])#[N:14]
Reactant: CCOC(=O)CCc1ccc(C#N)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(CCC(=O)O)cc1O
Yield: 9.8 %

Procedure:
A solution of 3-(4-Cyano-3-hydroxy-phenyl)-propionic acid ethyl ester (2.2 g, 10 mmol) in ethanol (10 mL) and water (40 mL) was treated with aqueous sodium hydroxide solution (2.5 M, 44 mL) at room temperature overnight. The solvent was removed under vacuum and the residue was dissolved in water (150 mL). The pH of the aqueous solution was adjusted to 2–4 by the addition of 3N HCl (aqueous) and the precipitate was then filtered and washed with water to give the title compound as white solid (1.88 g, 0.98 mmol, 98.4% yield). ESMS m/z: 192 [M+H]+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C[N+](C)=CCl.[Cl-].[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH:26]2[CH2:30][CH2:29][CH:28]=[CH:27]2)[C:21]([OH:23])=O)[N:19]=1)=[O:13].[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[NH2:38][C@@H:39]1[C:56](=[O:57])[N:41]2[C:42]([C:53]([O-:55])=[O:54])=[C:43]([CH2:46][N+:47]3[N:48]([CH3:52])[CH:49]=[CH:50][CH:51]=3)[CH2:44][S:45][C@H:40]12.C(OC(C)C)(C)C>C(OCC)(=O)C>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH:26]2[CH2:30][CH2:29][CH:28]=[CH:27]2)[C:21]([NH:38][C@@H:39]2[C:56](=[O:57])[N:41]3[C:42]([C:53]([O-:55])=[O:54])=[C:43]([CH2:46][N+:47]4[N:48]([CH3:52])[CH:49]=[CH:50][CH:51]=4)[CH2:44][S:45][C@H:40]23)=[O:23])[N:19]=1)=[O:13]
Reactant: Cn1ccc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=CNc1nc(C(=NOC2C=CCC2)C(=O)O)cs1
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NOC3C=CCC3)c3csc(NC=O)n3)[C@H]2SC1

Procedure:
N,N-Dimethylformamido (0.75 g) and phosphoryl chloride (1.57 ml) were mixed to prepare Vilsmeier reagent in a usual manner, and the resultant Vilsmeier reagent was suspended in dry ethyl acetate (22 ml). To the suspension was added 2-(2-formamidothiazol-4-yl)-2-(2-cyclopenten-1-yloxyimino) acetic acid (A isomer) (syn isomer) (2.3 g) under ice-cooling with stirring, and then the mixture was stirred for an hour to prepare an activated acid solution. To a solution of bis(trifluoroacetic acid )salts of 7β-amino-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (4.7 g) and N-mono(trimethylsilyl)acetamido (11.8 g) in ethyl acetate (50 ml) was added the activated acid solution prepared above at 3° C. After stirring at the same temperature for an hour, the mixture was poured into diisopropyl ether (500 ml). The precipitates were collected by filtration and successively washed with diisopropyl ether to give trifluoroacetic acid salt of 7β-[2-(2-formamidothiazol-4-yl)-2-(2-cyclopenten-1-yloxyimino)acetamido]-3-(2-methyl-1-pyrazolio)methyl- 3-cephem-4-carboxylate (A isomer) (syn isomer) (6.02 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O.O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:17])[CH:23]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(O)c2)cc1
Temperature: 25 °C
Reaction time: 3.83 h

Procedure:
A mixture of (4-bromo-benzyl)-carbamic acid tert-butyl ester (600 mg), 3-hydroxybenzeneboronic acid (373 mg), sodium carbonate (333 mg), palladium (II) acetate (10 mg) and tricyclohexylphosphine (13 mg) in water (3.5 ml) and dioxane (14 ml) is kept at 90° C. under micro wave conditions for 230 min. The mixture is cooled down to rt and is filtered through an EXTUBE extraction column with EtOAc (200 ml). The filtrate is evaporated and the resulting crude product is purified on silica (90 g) with cyclohexane/EtOAc 95:5 to 70:30 to afford pure (3′-hydroxy-biphenyl-4-ylmethyl)-carbamic acid tert-butyl ester.