Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:9]([O:15][CH3:16])(=[O:14])[CH2:10][CH2:11][C:12]#[CH:13].C(N(CC)CC)C.[Cl-].[NH4+]>CN(C)C=O.[Cu](I)I.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:8][C:5]1[N:4]=[CH:3][C:2]([C:13]#[C:12][CH2:11][CH2:10][C:9]([O:15][CH3:16])=[O:14])=[CH:7][N:6]=1
Reactant: C#CCCC(=O)OC
Reactant: Clc1ncc(Br)cn1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCC#Cc1cnc(Cl)nc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
To a solution of 500 mg (2.58 mmol) of 5-bromo-2-chloropyrimidine in 10 ml of N,N-dimethylformamide, 397 mg (3.54 mmol) of methyl 4-pentinoate, which was synthesized by the method described in W. D. Wulff et al., Journal of the American Chemical Society, 1988, Vol. 110, pp. 7419-7434, 49 mg (0.26 mmol) of copper iodide, 149 mg (0.129 mmol) of tetrakis(triphenylphosphine)palladium (0) and 5.0 ml of triethylamine were added, and the reaction solution was stirred at 80° C. for 4 hours. After completion of the reaction, saturated ammonium chloride aqueous solution was added to the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=93/7-75/25 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 347 mg (yield: 60%) of methyl 5-(2-chloropyrimidin-5-yl)-4-pentinoate.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)(=[O:5])=[O:4]>CO.[Pd]>[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)CCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CNS(=O)(=O)CCc1ccc(N)cc1
Yield: 89.9 %

Procedure:
A solution of 402 mg (1.65 mmol) of 2-(4-nitro-phenyl)-ethanesulfonic acid methylamide (as prepared in the previous step) in MeOH (30 mL) was hydrogenated over 10% Pd/C (Degussa type E101-NE/W, Aldrich, 50% by weight water) at 20 psi of H2 for 19 h. The reaction mixture was filtered through Celite, and the filter cake was washed with MeOH. Solvents were evaporated in vacuo. Silica gel chromatography of the residue on a 25-g Varian MegaBond Elut SPE column with 50% EtOAc-hexane afforded 318 mg (90%) of the title compound as a white solid: 1H-NMR (CD3CN; 400 MHz): δ 7.01 (d, 2H, J=8.4 Hz), 6.61 (d, 2H, J=8.4 Hz), 5.00-4.92 (br s, 1H), 4.12-4.02 (br s, 2H), 3.24-3.17 (m, 2H), 2.92-2.86 (m, 2H), 2.67 (s, 3H, J=5.2 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:13][C:12]3=[O:25])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:26][NH:27][CH2:28][CH2:29][C:3]1=2.[C:30]1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:42].Cl>>[ClH:42].[ClH:42].[CH3:30][N:27]1[CH2:28][CH2:29][C:3]2[N:2]([CH3:1])[C:10]3[CH:9]=[C:8]([N:11]4[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=5)=[CH:13][C:12]4=[O:25])[CH:7]=[CH:6][C:5]=3[C:4]=2[CH2:26]1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccn5)cc4=O)cc31)CNCC2
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Product: CN1CCc2c(c3ccc(-n4ccc(OCc5ccccn5)cc4=O)cc3n2C)C1
Yield: 98 %

Procedure:
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(pyridin-2-ylmethoxy)pyridin-2(1H)-one (45 mg, 0.116 mmol) was reacted according to the procedure of Example 47 to provide the free-base. Conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound (54 mg, 98%) as a white solid: mp 260-265° C.; 1H NMR (500 MHz, CD3OD) δ 8.87 (d, J=5.7 Hz, 1H), 8.58 (overlapping dd, J=8.2 Hz, 1H), 8.14 (d, J=7.9 Hz, 1H), 8.00 (overlapping dd, J=6.6 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.49 (s, 1H), 7.07 (dd, J=8.3, 1.7 Hz, 1H), 6.44 (dd, J=7.5, 2.6 Hz, 1H), 6.20 (d, J=2.0 Hz, 1H), 5.56 (s, 2H), 4.76 (d, J=14.2 Hz, 1H), 4.40 (d, J=14.2 Hz, 1H), 3.91 (m, 1H), 3.74 (s, 3H), 3.61 (m, 1H), 3.29-3.17 (m overlapping with solvent, 2H), 3.13 (s, 3H); ESI MS m/z 401 [M+H]+; HPLC (Method B)>99% (AUC), tR=9.2 min.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][O:4][CH2:5][C:6]1[N:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[O:9][C:10]=1[C:11](O)=[O:12].C(OCC)(=O)C>O1CCCC1>[F:25][C:2]([F:1])([F:24])[CH2:3][O:4][CH2:5][C:6]1[N:7]=[C:8]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[O:9][C:10]=1[CH2:11][OH:12]
Reactant: O=C(O)c1oc(-c2ccc(C(F)(F)F)cc2)nc1COCC(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1oc(-c2ccc(C(F)(F)F)cc2)nc1COCC(F)(F)F
Temperature: 60 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
1.0 g 4-(2,2,2-Trifluoro-ethoxymethyl)-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylic acid were dissolved in 30 ml tetrahydrofuran. At 0-5° C. 6.6 ml of a one molar solution of borane tetrahydrofuran complex were added. The reaction mixture was stirred at room temperature for three hours and at 60° C. for one hour. The cooled reaction mixture was diluted by addition of 100 ml ethyl acetate and washed with 50 ml water. The organic phase was dried over MgSO4 then the solvent was removed in vacuo. The residue was purified by RP-HPLC to obtain 422 mg [4-(2,2,2-trifluoro-ethoxymethyl)-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([Cl:25])[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[NH:39][CH:38]=[CH:37]3)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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:25][C:4]1[CH:3]=[C:2]([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[NH:39][CH:38]=[CH:37]3)[CH:7]=[CH:6][C:5]=1[N:8]1[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C:19]([CH:21]3[CH2:23][CH2:22]3)=[O:20])[CH2:15]2)=[N:11][NH:10][C:9]1=[O:24]
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2Cl)C1
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4[nH]ccc4c3)cc2Cl)C1
Temperature: 120 °C
Yield: 48 %

Procedure:
A mixture of 4-(4-bromo-2-chlorophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (140 mg, 0.329 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (80 mg, 0.329 mmol), potassium carbonate (182 mg, 1.315 mmol), and tetrakis(triphenylphosphine)palladium(0) (19.0 mg, 0.016 mmol) in 1,4-dioxane (5 mL) and water (2 mL) was heated at 120° C. for 3.5 hr. The reaction mixture was cooled and loaded onto a silica gel pre-column and purified by flash chromatography (dichloromethane to 6% methanol in dichloromethane) to afford the title product (73 mg, 0.158 mmol, 48% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.96-8.78 (m, 1H), 8.37 (br. s, 1H), 7.92-7.82 (m, 2H), 7.76-7.64 (m, 1H), 7.56-7.47 (m, 1H), 7.47-7.39 (m, 2H), 7.36-7.30 (m, 1H), 6.76-6.61 (m, 1H), 4.04-3.02 (m, 4H), 2.80-2.39 (m, 3H), 2.34-2.03 (m, 1H), 1.84-1.60 (m, 1H), 1.07-0.94 (m, 2H), 0.76 (dd, J=3.3, 7.8 Hz, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1.Cl>C(Cl)(Cl)Cl>[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH2:13][NH:12][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:17][CH2:18]1
Reactant: CN1CCN(CCCN)CC1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN1CCN(CCCNc2ccc(Cl)cc2[N+](=O)[O-])CC1
Temperature: 130 °C
Yield: 85 %

Procedure:
A mixture of 2,5-dichloronitrobenzene (95.5 g., 0.497 mole) and 1-(3-aminopropyl)-4-methylpiperazine (82.2 g., 0.522 mole) was heated in a nitrogen atmosphere at 130° C. for 5 hours and cooled to room temperature. The mixture was poured into a separatory funnel containing 1500 ml. of 3N HCl and 500 ml. chloroform. After shaking and separation of layers, the chloroform was withdrawn and the aqueous layer extracted with fresh CHCl3. The aqueous layer was made alkaline with 20% NaOH and the resulting oil extracted with 3 × 600 ml. CHCl3. The combined extracts were dried over Na2SO4 and the solvent evaporated at reduced pressure to give 131.5 g. (85% yield) of 2-[3-(4-methyl-1-piperazinyl)propylamino]-5-chloronitrobenzene as a dark orange oil.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[S:10][C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15]>CN(C)C=O.O>[C:18]1([C:11]2[S:10][CH:9]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1cc(-c2ccccc2)sc1N
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1csc(-c2ccccc2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of tert-butyl nitrite (428 μL, 3.6 mmol) in N,N-dimethylformamide (5 mL) at 60° C. was dropwise added a solution of methyl 2-amino-5-phenylthiophene-3-carboxylate (11a) (420 mg, 1.8 mmol) in N,N-dimethylformamide (2.5 mL). The mixture was stirred at 60° C. for 1 hour, poured in water (15 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was washed with brine (2×10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in toluene (5 mL) and concentrated in vacuo to provide the desired product (11b) (390 mg, 1.8 mmol, 99%) which was used without further purification.
Reaction SMILES: [CH:1](=[C:8]1[CH2:13][CH:12]([CH3:14])[CH2:11][CH2:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)/C=C\C(OCC)=O>[C].[Pd].C1(C)C=CC=CC=1>[CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CCC(=O)C(=Cc2ccccc2)C1
Agent: [Pd]
Agent: CCOC(=O)/C=C\C(=O)OCC
Solvent: Cc1ccccc1
Product: Cc1ccc(O)c(Cc2ccccc2)c1
Temperature: 200 °C
Reaction time: 2 h
Yield: 49.4 %

Procedure:
In a 100-ml, four-necked flask equipped with a magnetic stirrer, a reflux condenser and a thermometer were placed 20.0 g (0.1 mole) of the 2-benzylidene-4-methylcyclohexanone produced in Example 10 and 51.7 g (0.3 mole) of diethyl maleate in this order. The flask inside was purged with nitrogen. Thereto was added 1.0 g (5 wt. %, 0.47 mmole as palladium) of 5% palladium carbon (a product of Wako Pure Chemical Industries, Ltd.). The system was made vacuum using an aspirator and then returned to ordinary pressure using nitrogen; this operation was repeated three times. Then, the system was stirred at 180° C. for 2 hours and at 200° C. for 2 hours, and then cooled to room temperature. 100 ml of toluene was added to the system. Filtration was conducted to remove the palladium carbon. The filtrate was subjected to vacuum distillation to remove the solvent including toluene and diethyl maleate. To the residue was added 100 ml of toluene, followed by extraction with 100 ml of a 10% aqueous sodium hydroxide solution; and this operation was repeated twice. To the aqueous layer was added 35% hydrochloric acid until the aqueous layer became acidic, after which the aqueous layer was extracted with 100 ml of ethyl acetate. The ethyl acetate layer was washed with water and a saturated aqueous sodium chloride solution in this order. The ethyl acetate layer was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove ethyl acetate, to obtain 9.8 g of a brown oil. Yield: 50% The purity of the intended product in the oil was 91% as measured by gas chromatography.
Reaction SMILES: BrCCCCCCCC(NC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br-].C(CCCCCCCCC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(O)=O.C([O:71][C:72]1[CH:89]=[CH:88][C:87]2[C@@H:86]3[C@H:77]([C@H:78]4[C@@:82]([CH2:84][CH2:85]3)([CH3:83])[C@@H:81]([OH:90])[CH2:80][CH2:79]4)[C@H:76]([CH:91]=[CH:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][C:99]([NH:101][CH3:102])=[O:100])[CH2:75][C:74]=2[CH:73]=1)C1C=CC=CC=1>>[OH:71][C:72]1[CH:89]=[CH:88][C:87]2[C@@H:86]3[C@H:77]([C@H:78]4[C@@:82]([CH2:84][CH2:85]3)([CH3:83])[C@@H:81]([OH:90])[CH2:80][CH2:79]4)[C@H:76]([CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][C:99]([NH:101][CH3:102])=[O:100])[CH2:75][C:74]=2[CH:73]=1
Reactant: CNC(=O)CCCCCCC=C[C@@H]1Cc2cc(OCc3ccccc3)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Agent: CNC(=O)CCCCCCCBr
Agent: O=C(O)CCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CNC(=O)CCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12

Procedure:
The procedure described in the last paragraph of Example 6 was repeated except that (7-N-methylcarbamoylheptyl)triphenylphosphonium bromide (prepared from 8-bromo-N-methyloctanamide and triphenylphosphine by a similar process to that described in the last part of Example 22) was used in place of (9-carboxynonyl)triphenylphosphonium bromide. The hydrogenation process described in the second paragraph of Example 6 was then repeated using the 9-(3-benzyloxy-17β-hydroxyoestra-1,3,5(10)trien-7α-yl)-N-methylnon-8-enamide thus obtained as starting material, and there was thus obtained as an oil 9-(3,17β-dihydroxyoestra-1,3,5(10)-trien-7α-yl)-N-methyl-nonanamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.O[CH2:13][CH:14]=[C:15]([CH2:17][CH2:18][CH:19]=[C:20]([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH3:21])[CH3:16].[Na+].[Cl-]>C(Cl)Cl.ClCl>[CH2:13]([Cl:1])[CH:14]=[C:15]([CH2:17][CH2:18][CH:19]=[C:20]([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH3:21])[CH3:16]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Agent: ClCl
Agent: [Cl-]
Agent: [Na+]
Solvent: CSC
Solvent: ClCCl
Product: CC(C)=CCCC(C)=CCCC(C)=CCCl
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
N-Chlorosuccinimide (0.66 g, 4.95 mmol) was dissolved in 20 ml of dry CH2Cl2 under a nitrogen atmosphere. The solution was cooled to -30° C. and 0.37 ml dimethyl sulphide (5 mmol) was added. The mixture was allowed to warm to 0° C. before it was cooled to -40° C. Then farnesol (1 g, 4.5 mmol) dissolved in 2.5 ml CH2 Cl2 was added dropwise to the mixture over a period of 3 minutes. The reaction mixture was warmed to 0.C in 1 h, at which temperature it was maintained for another hour. After 15 minutes of stirring at room temperature the reaction mixture was poured into a separatory funnel which contained 12.5 ml of cold saturated NaCl. The aqueous layer was extracted with two 10 ml portions of pentane. The organic layers were combined with an additional 10 ml of pentane and washed with two 5 ml portions of cold saturated NaCl. The organic layer was dried over MgSO4 and concentrated to dryness in vacuo. Compound (b) was thus obtained in a yield of 89%.
Reaction SMILES: C(Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](=O)([O:13][CH3:14])[O:11]C>S1(CCCC1)(=O)=O.[Cl-].[Li+]>[C:10]([O:13][CH3:14])(=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)OC
Agent: [Cl-]
Agent: [Li+]
Solvent: O=S1(=O)CCCC1
Product: COC(=O)c1ccccc1
Temperature: 150 °C
Yield: 70.1 %

Procedure:
The following example illustrates the use of alkali halide catalysts. A mixture of benzoyl chloride (7.03 g, 0.05 mole), dimethyl carbonate (4.5 g, 0.05 mole) and lithium chloride (0.106 g, 0.0025 mole) in 25 ml of sulfolane was heated to 150° C. for 22 hours. Distillation of the reaction mixture gave 4.77 g (70 percent yield) methyl benzoate.
Reaction SMILES: [BH4-].[Na+].[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:34])[CH:14]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:33])([F:32])[CH:29]([F:31])[F:30])[CH:22]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1)(=[O:6])=[O:5].Cl>C(OCC)C>[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([OH:34])[CH:14]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:32])([F:33])[CH:29]([F:30])[F:31])[CH:22]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1)(=[O:5])=[O:6]
Reactant: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(S(C)(=O)=O)cc1
Reaction time: 1 h

Procedure:
To a suspension of zinc chloride anhydride (1.72 g, 12.6 mmol) in diethyl ether (20 ml) was added sodium borohydride (0.95 g, 25.2 mmol) by small portions, and the mixture was stirred for 1 hr. Insoluble material was removed by filtration, and washed with diethyl ether. The filtrate was ice-cooled, and a solution of ethyl 3-[4-(methylsulfonyl)phenyl]-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate (3.0 g, 6.30 mmol) in diethyl ether (10 ml) was added. The mixture was stirred at room temperature for 1 hr. After ice-cooling again, 1N hydrochloric acid was added to terminate the reaction. The obtained mixture was extracted with ethyl acetate (100 ml), washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1-1:1) to give the objective substance (2.60 g, 86%) as a colorless oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][CH2:13][O:14][C:15]=3[N:16]=2)[CH2:3][CH2:2]1.[ClH:24].C(OCC)(=O)C>>[ClH:24].[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[CH2:10][NH:11][CH2:12][CH2:13][O:14][C:15]=3[N:16]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(OCC3CC3)ccc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1cc2c(nc1OCC1CC1)OCCNC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A mixture of the compound obtained in step 1 (0.33 g) and 4N hydrogen chloride/ethyl acetate (3 mL) was stirred at room temperature for 3 hr. The precipitate was collected by filtration, and the aqueous layer was basified and extracted with ethyl acetate and aqueous sodium hydroxide solution. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and 4N hydrogen chloride/ethyl acetate was added. The precipitate was collected by filtration and recrystallized from methanol-ethanol-diisopropyl ether to give the title compound (0.14 g, 55%) as a white powder.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:24]1[O:25][CH:26]=[CH:27][CH:28]=1)[C:4]([NH:6][CH:7]1[C:22](=[O:23])[N:9]2[C:10]([C:19]([OH:21])=[O:20])=[C:11]([CH2:14]OC(=O)C)[CH2:12][S:13][C@H:8]12)=[O:5].[SH:29][C:30]1[S:31][C:32]([CH3:35])=[N:33][N:34]=1.C(=O)(O)[O-].[Na+].O>P([O-])([O-])([O-])=O>[CH3:1][S:2][CH:3]([C:24]1[O:25][CH:26]=[CH:27][CH:28]=1)[C:4]([NH:6][CH:7]1[C:22](=[O:23])[N:9]2[C:10]([C:19]([OH:21])=[O:20])=[C:11]([CH2:14][S:29][C:30]3[S:31][C:32]([CH3:35])=[N:33][N:34]=3)[CH2:12][S:13][C@H:8]12)=[O:5]
Reactant: Cc1nnc(S)s1
Reactant: CSC(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1ccco1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CSC(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12)c1ccco1
Temperature: 60 °C
Reaction time: 7 h

Procedure:
7-[α-Methylthio(2-furyl)acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid (341 mg), 128 mg of 2-mercapto-5-methyl-1,3,4-thiadiazole and 68 mg of sodium bicarbonate were dissolved in 10 ml of a 0.1M phosphate buffer (pH 6.4), and the solution was stirred at 60° C. for 7 hours, and then at room temperature for 14 hours. Then, 10 ml of water was added, and the mixture was washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid to a pH of 2, and extracted three times with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then concentrated under reduced pressure. Petroleum ether was added to the residue, and it was powderized. By filtration, the final product was obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[N:11]=2)[C:6](=[O:14])[C:5]([C:15]([OH:17])=O)=[CH:4]1)[CH3:2].[NH2:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[N:11]=2)[C:6](=[O:14])[C:5]([C:15]([NH:18][C:19]2[NH:23][N:22]=[N:21][N:20]=2)=[O:17])=[CH:4]1)[CH3:2]
Reactant: Nc1nnn[nH]1
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(C)nc21
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)Nc2nnn[nH]2)c(=O)c2ccc(C)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (4.1g) and N,N'-carbonyldiimidazole (2.85g) in dimethylformamide (30 ml) were stirred and heated at 100° for 3 hours and cooled. 5-Amino-1H-tetrazole (3.6 g) was added and the mixture was stirred at room temperature for 16 hours. The solid was collected and dissolved in aqueous dimethylaminoethanol and the solution was acidified to pH2 with dilute hydrochloric acid. The solid was filtered off and dried, m.p. above 289° (d), (60%)
Reaction SMILES: FC(F)(F)S(O[C:7]1[C@@H:8]([C:31]([O:33][CH3:34])=[O:32])[N:9]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH:11]=1)(=O)=O.[F:37][C:38]([F:49])([F:48])[C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1>CO>[F:37][C:38]([F:49])([F:48])[C:39]1[CH:44]=[CH:43][C:42]([C:7]2[C@@H:8]([C:31]([O:33][CH3:34])=[O:32])[N:9]([C:12]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:10][CH:11]=2)=[CH:41][CH:40]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)[C@@H]1C(OS(=O)(=O)C(F)(F)F)=CCN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)[C@@H]1C(c2ccc(C(F)(F)F)cc2)=CCN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 85 °C
Yield: 62.5 %

Procedure:
To a stirred mixture of (S)-methyl 3-(trifluoromethylsulfonyloxy)-1-trityl-2,5-dihydro-1H-pyrrole-2-carboxylate ((Tetrahedron Lett. 2001, 8571) 1.71 g, 3.3 mmol), 4-(trifluoromethyl)phenylboronic acid (1.3 g, 6.6 mmol), K2CO3 (0.68 mg, 5.0 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]dichloride palladium(II) DCM adduct (0.12 g, 0.16 mmol) was added toluene (10 mL) and MeOH (1.0 mL). The mixture was stirred under nitrogen at 85° C. 15 hours. The mixture was cooled and evaporated in vacuo. The residue was dissolved in DCM, adsorbed onto silica gel and purified by flash column chromatography (eluting first with 1:5 EtOAc in hexanes and second with a gradient of hexanes to 30% DCM in hexanes) to give (S)-methyl 3-(4-(trifluoromethyl)phenyl)-1-trityl-2,5-dihydro-1H-pyrrole-2-carboxylate as a white solid (1.06 g, 62%). LCMS (M+H) 514.5 calc. for C32H27F3NO2 514.2. 1H NMR (400 MHz, CDCl3): δ ppm 6.67-8.21 (a series of m, 19H) 5.85 (s, 1H) 5.01 (d, J=4.11 Hz, 1H) 4.39 (dd, J=17.61, 2.54 Hz, 1H) 3.82 (dd, J=17.70, 2.64 Hz, 1H) 3.64 (s, 3H).