Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([O:8][C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)([C:4]([F:6])([F:5])[F:7])[C:2]([F:16])([F:17])[F:1])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(OS(C)(=O)=O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
5.16 g (20 mmol) of 1,1,1,3,3,3-hexafluoro-2-p-tolylpropan-2-ol were dissolved in 50 ml of methylene chloride, and 2.8 g (28 mmol) of triethylamine were added. 3.2 g (22 mmol) of methanesulfonyl chloride were added dropwise, while stirring, to the solution cooled to 5° C. After warming up to room temperature, the mixture was allowed to stand overnight. The precipitated salt was filtered off and the organic solution was evaporated down. The subsequent chromatography (silica gel/methylene chloride) gave 4.8 g of 2-methanesulfonyloxy-2-p-tolyl-1,1,1,3,3,3-hexafluoropropane (pale yellow oil).
Reaction SMILES: [CH3:1][C@H:2]1[C@:19]([OH:24])([C:20]([CH2:22][OH:23])=[O:21])[C@:18]2([CH3:25])[C@H:4]([C@H:5]3[C@:15]([F:27])([C@@H:16]([OH:26])[CH2:17]2)[C@:14]2([CH3:28])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]2)=[O:11])[CH2:7][CH2:6]3)[CH2:3]1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].Cl>N1C=CC=CC=1>[CH3:1][C@H:2]1[C@:19]([OH:24])([C:20]([CH2:22][OH:23])=[O:21])[C@:18]2([CH3:25])[C@H:4]([C@H:5]3[C@:15]([F:27])([C@@H:16]([OH:26])[CH2:17]2)[C@:14]2([CH3:28])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]2)=[O:11])[CH2:7][CH2:6]3)[CH2:3]1.[S:30]([O-:32])(=[O:11])(=[O:31])[CH3:29]
Reactant: CS(=O)(=O)Cl
Agent: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 200 ml Erlenmeyer flask equipped with a magnetic stir bar and a rubber septum was charged with 5 grams of dexamethasone (12.7 mmol, 1 equivalent) and 16 ml of anhydrous pyridine. The flask was cooled to 0° C. with an ice bath, and 1.2 ml of methanesulfonyl chloride was added. After 1 hour, 0.8 ml of additional methanesulfonyl chloride was added. At two hours, the solution was poured into 100 ml of cold 1M HCl, forming a precipitate. The precipitate was filtered and redissolved in 250 ml of ethanol, and precipitated into 250 ml of 1M HCl. The precipitate was filtered and recrystallized in ethanol, filtered, and dried under vacuum yielding 4.95 g (82.6%) of dexamethasone mesylate.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:27][C:28]1[C:33]([CH:34]=O)=[C:32]([NH:36]C(=O)OC(C)(C)C)[CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:27][C:28]1[N:29]=[CH:30][CH:31]=[C:32]2[C:33]=1[CH:34]=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([C:10]1[CH:11]=[CH:12][C:13]([C:16]3([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:17][CH2:18]3)=[CH:14][CH:15]=1)=[N:36]2
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)Cc3ccccc3)cc2)CC1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(Cl)c4cc3-c3ccccc3)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 33-2 (0.64 g, 2.5 mmol), 3-1 (0.88 g, 2.5 mmol) and potassium carbonate (2.1 g, 15 mmol) in DMF (14 mL) was heated to 120° C. for 4.5 hours. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (1% ethyl acetate/hexane→70% ethyl acetate/hexane) gave the title compound as a foam. MS (M+H+): calculated=471.98, observed=472.1.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][C:23]=3[Cl:24])[NH:20][CH:19]=[C:18]4[CH:25]=[O:26])=[CH:11][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].Cl([O-])=[O:28].[Na+].O.O.OP([O-])(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O.CC(=CC)C>[C:1]([N:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][C:23]=3[Cl:24])[NH:20][CH:19]=[C:18]4[C:25]([OH:28])=[O:26])=[CH:13][CH:14]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(c2ccc(-c3cc4c(C=O)c[nH]c4cc3Cl)cc2)C1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CC(C)(C)O
Product: CC(=O)N1CCC(c2ccc(-c3cc4c(C(=O)O)c[nH]c4cc3Cl)cc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.1 %

Procedure:
To a solution of 5-[4-(1-acetylpyrrolidin-3-yl)phenyl]-6-chloro-1H-indole-3-carbaldehyde (60 mg, 0.163 mmol) in acetonitrile (3 mL) and tert-butanol (3 mL) was added 2-methyl-2-butene (3 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (164 mg, 1.8 mmol) and sodium phosphate monobasic dihydrate (381 mg, 2.445 mmol) in water (1.5 mL). The reaction mixture was stirred for 2 hours at room temperature and treated with additional sodium chlorite (218 mg, 2.4 mmol) and sodium phosphate monobasic dihydrate (509 g, 3.26 mmol) in water (1.5 mL) and 2-methyl-2-butene (0.5 mL). The resulting mixture was stirred at room temperature for an additional 16 h. The reaction mixture was evaporated in vacuo and the aqueous residue was extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in DMSO and purified via prep-HPLC to give 5-[4-(1-acetylpyrrolidin-3-yl)phenyl]-6-chloro-1H-indole-3-carboxylic acid (25 mg) as a white solid. MS (ES+) 383.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.96 (br, 1H), 8.08 (d, 1H), 7.93 (s, 1H), 7.64 (s, 1H), 7.38 (m, 4H), 3.1-3.9 (m, 5H), 2.2-2.5 (m, 1H), 1.9-2.1 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:7]=1.[C:19](OC(=O)CC)(=O)[CH2:20][CH3:21].Cl>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:18][C:19]([CH2:20][CH3:21])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[C:8]2=[O:17]
Reactant: O=C(Cc1cccc(F)c1)c1cc(Br)ccc1O
Reactant: CCC(=O)OC(=O)CC
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1oc2ccc(Br)cc2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Yield: 38.6 %

Procedure:
Intermediate 33 (3.0 g, 9.70 mmoles) was taken in a RB flask and to this triethylamine (30 ml) and propionic anhydride (3.94 g, 30.37 mmoles) were added and the mixture was refluxed for 24 h. After cooling to RT, the reaction mixture was acidified by the addition of 1N HCl solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried with sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as off-white solid (1.30 g, 39% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 6 8.10(d, J=2.3 Hz, 1H), 7.99(dd, J=8.9,2.4 Hz, 1H), 7.69(d, J=8.9 Hz, 1H), 7.51(q, J=7.9 Hz, 1H), 7.25(dt, J=10.8,2.4 Hz, 1H), 7.15(t, J=12.2 Hz, 2H), 2.57(q, J=7.6 Hz, 2H), 1.20(t, J=7.5 Hz, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[CH:7]=1)=[O:4].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:24][NH2:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[Cl:13][C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:25][CH2:24][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=2)[CH:11]=[C:10]([Cl:12])[CH:9]=1
Reactant: O=C(CCl)Nc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(CN)cc1OC
Product: COc1ccc(CNCC(=O)Nc2cc(Cl)cc(Cl)c2)cc1OC

Procedure:
In a manner similar to Preparation 12, react 2-chloro-N-(3,5-dichlorophenyl)acetamide with (3,4-dimethoxyphenyl)methanamine to obtain the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C:22]=3[CH2:27][CH:28]=[CH2:29])([CH3:20])[C@@H:18]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:38][C:39]([F:66])([C:56]([F:65])([F:64])[C:57]([F:63])([F:62])[C:58]([F:61])([F:60])[F:59])[CH2:40][CH2:41][CH:42]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]C=C)[C:43]([O:45][CH2:46][CH3:47])=[O:44]>ClCCl.C(P(C1CCCCC1)(C1CCCCC1)C1CCCCC1)(P(C1CCCCC1)(C1CCCCC1)C1CCCCC1)C1C=CC=CC=1.Cl[Ru]Cl>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C:22]=3[CH2:27][CH:28]=[CH:29][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH:42]([CH2:41][CH2:40][C:39]([F:38])([F:66])[C:56]([F:64])([F:65])[C:57]([F:62])([F:63])[C:58]([F:59])([F:61])[F:60])[C:43]([O:45][CH2:46][CH3:47])=[O:44])([CH3:20])[C@@H:18]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Reactant: C=CCC1=C2c3ccc(OCc4ccccc4)cc3CC[C@H]2[C@@H]2CC[C@H](OCc3ccccc3)[C@@]2(C)C1
Agent: Cl[Ru]Cl
Agent: c1ccc(C([PH](C2CCCCC2)(C2CCCCC2)C2CCCCC2)[PH](C2CCCCC2)(C2CCCCC2)C2CCCCC2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(CCCCCCC=CCC1=C2c3ccc(OCc4ccccc4)cc3CC[C@H]2[C@@H]2CC[C@H](OCc3ccccc3)[C@@]2(C)C1)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 47.6 %

Procedure:
Benzylidenebis(tricyclohexylphosphine)-dichlororuthenium (90 mg, 0.1 mmol) was added to a solution of 3,17β-bis(benzyloxy)-11-(2-propenyl)estra-1,3,5(10),9(11)-tetraene (1.0 g, 2.0 mmol) and ethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-decenoate (1.81 g, 4.1 mmol) in dichloromethane (20 ml), followed by heating under reflux for 5 hours under nitrogen atmosphere. After cooling, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel flash chromatography (eluent: hexane/ethyl acetate=4/1) to give ethyl 11-[3,17β-bis(benzyloxy)estra-1,3,5(10),9(11)-tetraen-11-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-undecenoate (863 mg, Yield 48%).
Reaction SMILES: [NH2:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([F:14])=[C:7]([F:13])[CH:8]=2)[N:3]=1.[CH3:15][O-:16].[Na+]>O1CCCC1.CO>[NH2:1][C:2]1[C:11]([O:16][CH3:15])=[N:10][C:9]2[C:4](=[CH:5][C:6]([F:14])=[C:7]([F:13])[CH:8]=2)[N:3]=1
Reactant: C[O-]
Reactant: Nc1nc2cc(F)c(F)cc2nc1Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc2cc(F)c(F)cc2nc1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.4 %

Procedure:
To 2-amino-3-chloro-6,7-di fluoroquinoxaline (610 mg, 2.83 mmol) dissolved in tetrahydrofuran (40 ml), 25 wt % sodium methoxide (6.12 g, 28.3 mmol) in methanol was added at room temperature and stirred further at room temperature for 1.5 hour. The resulting mixture was concentrated under the reduced pressure to remove the solvent. The product was extracted with ethyl acetate and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 570 mg of the titled compound (yield, 95%).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:20])[CH:3]=1.[C:21]1([CH2:27][C:28](Cl)=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH2:31](N(CC)CC)C.C1COCC1>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[OH:1][C:2]1[CH2:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][C:4](=[O:20])[C:3]=1[CH2:31][CH2:28][CH2:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=C1C=C(O)CC(c2ccccc2)(c2ccccc2)O1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1CCCc1ccccc1

Procedure:
The title compound was prepared as described in General Method 5 using 2.5 mmol of 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one, 2.7 mmol of phenylacetyl chloride, 2.8 mmol of triethylamine, and 20 mL of THF, followed by 20 mL of toluene and catalytic DMAP. Chromatography of the residue afforded 1.0 mmol of the intermediate 3-acyl compound. Reduction of this acyl derivative was accomplished with 3 mmol of sodium cyanoborohydride. The product was triturated from ether to give the title compound (m.p. 61°-63° C.). 1H NMR (DMSO-d6) δ 1.35 (m, 2 H), 2.05 (t, 2 H), 2.14 (t, 2 H), 3.42 (bs, 2 H), 6.92 (m, 2 H), 7.17-7.40 (m, 13 H).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]1=[O:19])([F:8])[F:7].[C:20](OCC)(=O)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.CCCCCC>[CH3:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[CH:11][C:10]([OH:19])=[C:9]2[C:6]([F:7])([F:8])[F:5]
Reactant: O=C1C=Cc2ccccc2C1C(F)(F)F
Reactant: CCOC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CCCCCC
Product: Cc1cccc2c(C(F)(F)F)c(O)ccc12
Temperature: 25 °C
Yield: 100 %

Procedure:
Thionyl chloride (0.33 mL, 4.52 mmol) was added dropwise at about 5° C. to a stirred solution of 3,4-dihydro-1-hydroxy-5-methyl-1-(trifluoromethyl-2(1H)-naphthalenone (1.04 g, 4.26 mmol) and 4-(dimethylamino)pyridine (3.5 mg) in pyridine (0.73 mL) under dry nitrogen. The reaction mixture was stirred and allowed to warm slowly to 25° C. (about 45 min). The reaction was judged to be complete by tlc using silica gel thin layer plates and 20% (v/v) ethyl acetate in hexane as the mobile phase. The reaction mixture was poured onto ice and extracted with diethyl ether. The ether extract was washed with water and a saturated solution of NaHCO3 in water, dried (MgSO4) and concentrated under reduced pressure to give the title compound (961 mg, 100% yield). A small sample, purified by sublimation (30°-34° C., 0.05 mm), had mp 83°-84° C.; nmr (CDCl3) δ 2.65 (s, 3H), 7.1 (d, J=9 Hz, 1H), 7.25 (m, 1H), 7.35 (q, J=8 Hz, 1H), 7.85 (m, 1H), 8.05 (d, J=9 Hz, 1H); uvλmax (MeOH) 335 nm (ε 2,770), 322 (2,420), 293 (4,050), 281 (4,680), 222 (46,400); Anal Calcd for C12H9F3O: C, 63.72% H, 4,01%; Found: C, 63.47% H, 3.96%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]1[C:14]([CH2:15][N:16]([CH3:18])[CH3:17])=[C:13]([CH3:19])[N:12]=[C:7]12.[S:20]([O:25]C)([O:23][CH3:24])(=[O:22])=[O:21]>O1CCCC1>[CH3:24][O:23][S:20]([O-:25])(=[O:22])=[O:21].[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]1[C:14]([CH2:15][N+:16]([CH3:24])([CH3:18])[CH3:17])=[C:13]([CH3:19])[N:12]=[C:7]12
Reactant: Cc1nc2c3cccc(Cl)c3ccn2c1CN(C)C
Reactant: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: COS(=O)(=O)[O-]
Product: Cc1nc2c3cccc(Cl)c3ccn2c1C[N+](C)(C)C

Procedure:
A solution of 7-chloro-3-dimethylaminomethyl-2-methylimidazo[2,1-a]isoquinoline (3.4 g) in tetrahydrofuran (30 ml) was added dropwise to a solution of dimethyl sulfate (3.5 ml) in tetrahydrofuran (20 ml) with ice-cooling and stirring. After being stirred for 2 hours under the same conditions, the resulting precipitates were collected by filtration and washed with tetrahydrofuran and then ethanol to give 7-chloro-2-methyl-3-trimethylammoniomethylimidazo[2,1-a]isoquinoline methylsulfate (4.4 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16](O)=[O:17])[CH:14]=3)[N:9]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:8]=2)=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[NH2:61][CH:62]1[CH2:67][CH:66]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH2:65][N:64]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[CH2:63]1>CN(C=O)C>[C:68]1([CH:66]2[CH2:67][CH:62]([NH:61][C:16]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[N:9]([C:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:8]=[C:7]4[C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[O:17])[CH2:63][N:64]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[CH2:65]2)[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1
Reactant: O=C(O)c1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(N)CC(c2ccccc2)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(NC(=O)c2ccc3c(c2)c(-c2ccncc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CC(c2ccccc2)C1
Temperature: 45 °C
Reaction time: 4 h

Procedure:
To a microwave vial equipped with a stir bar was added 3-pyridin-4-yl-1-trityl-1H indazole-5-carboxylic acid (155.4 mg, 0.323 mmol), HOBT (74.1 mg, 0.484 mmol), EDC (93 mg, 0.484 mmol), DIPEA (225 μl, 1.291 mmol), tert-butyl 3-amino-5-phenylpiperidine-1-carboxylate (89 mg, 0.323 mmol), and DMF (3227 μl). The vial was sealed and heated to 45° C. The LCMS taken after 4 hours indicates formation of the desired product. The material was filtered through a column pre-packed with celite and was concentrated under reduced pressure. A column was run from 100% hexanes to 100% ethyl acetate. The desired product eluted and fractions were collected and concentrated in vacuo. The material was dissolved in acetonitrile and water and was dried on the lyophilizer.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])=O.[NH2:18][NH:19][C:20]([NH2:22])=[S:21].C(O)(=O)C>C(O)C>[CH:1](=[N:18][NH:19][C:20]([NH2:22])=[S:21])[C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]
Reactant: CCOP(=O)(Cc1ccccc1C=O)OCC
Reactant: NNC(N)=S
Solvent: CC(=O)O
Solvent: CCO
Product: CCOP(=O)(Cc1ccccc1C=NNC(N)=S)OCC

Procedure:
2.0 g (8 mmol) of the compound A and 0.73 g of thiosemicarbazide were dissolved or suspended in 200 ml of absolute ethanol. 2 ml of acetic acid were added and the mixture was boiled under reflux for 3 h. In the course of the slow cooling, the product D precipitated in crystalline form.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5]S([O-])(=O)=O.C[S+](C)C.[Cl:14][C:15]1[CH:30]=[CH:29][C:18]([O:19][CH2:20][C:21]([C:23]2([CH3:28])[CH2:25][C:24]2([F:27])[F:26])=O)=[CH:17][CH:16]=1.O>C(#N)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]2([C:23]3([CH3:28])[CH2:25][C:24]3([F:26])[F:27])[CH2:4][O:5]2)=[CH:29][CH:30]=1
Reactant: COS(=O)(=O)[O-]
Reactant: CC1(C(=O)COc2ccc(Cl)cc2)CC1(F)F
Agent: C[O-]
Agent: C[S+](C)C
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC1(C2(COc3ccc(Cl)cc3)CO2)CC1(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.4 g (0.044 mol) of sodium methoxide are added to the solution of 30 ml (0.04 mol) of a 1.36-molar solution of trimethylsulphonium methylsulphate in acetonitrile, and the mixture is stirred at room temperature for 30 minutes. 5.8 g (0.022 mol) of 1-(4-chlorophenoxyacetyl)-1-methyl-2,2-difluorocyclopropane are then added, and the mixture is stirred for 16 hours at 20° C. The reaction mixture is poured into 200 ml of water and extracted using methylene chloride, and the organic phase is washed with water and concentrated. 4.3 g (GC content of 73%; 71.6% of theory) of 2-(4-chlorophenoxymethyl)-2-(2,2-difluoro-1-methylcyclopropyl)-oxirane are obtained as a viscous resin which is reacted further directly. ##STR79##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:12]([Si:15]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])Cl)([CH3:14])[CH3:13].[NH4+].[Cl-].CCOCC>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([Si:15]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:12]([CH3:14])[CH3:13])[CH:6]=[CH:5]2
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Fc1cc(F)c2[nH]ccc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(F)cc(F)c21
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
N-butyl lithium (2.7 ml, 2.5 M, 6.9 mmol) was added to 10 mL dry THF at −70° C. 5,7-difluoro-1H-indole (1.0 g, 6.5 mmol) in 5 mL THF was added in portions to the this solution and the mixture was stirred for 30 min at −75° C. Triisopropylchlorosilane (1.5 mL, 1.3 g, 6.9 mmol) was added, stirring was continued for 1 h at −75° C. and then the mixture was allowed to warm to −5° C. over 2 h. After treatment with 5 mL sat. NH4Cl, the mixture was mixed with 30 mL ether and the organic phase was washed with 5 mL sat. NaCl, dried (Na2SO4) and evaporated. The product was purified by flash chromatography (SiO2; hexanes) to provide the title compound as a clear oil (1.5 g; 74%): 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J=3.1 Hz, 1H), 7.07 (dd, J=8.7, 2.3 Hz, 1H), 6.69 (m, 1H), 6.59 (t, J=3.1 Hz, 1H), 1.67 (m, 3H), 1.13 (d, J=7.6 Hz, 18H). 19F NMR (376 MHz, CDCl3) δ −120.64, −120.65, −122.49, −122.49. EIMS m/z 309.
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]=1[O:29][CH2:30][CH2:31][NH2:32])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[C:33]1(=[O:39])[O:38][C:36](=[O:37])[CH2:35][CH2:34]1>C1(C)C=CC=CC=1>[CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]=1[O:29][CH2:30][CH2:31][NH:32][C:33](=[O:39])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=C1CCC(=O)O1
Reactant: CC[C@H](NC(=O)c1c(OCCN)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Solvent: Cc1ccccc1
Product: CC[C@H](NC(=O)c1c(OCCNC(=O)CCC(=O)O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Yield: 56.7 %

Procedure:
2.0 g (4.7 mmol) of (S)-N-(α-ethylbenzyl)-3-(2-aminoethoxy)-2-phenylquinoline-4-carboxamide (compound of Description 4) and 0.6 g (6.2 mmol) of succinic anhydride were dissolved in 50 ml of toluene; some triturated molecular sieves were added and the reaction mixture was refluxed in a Dean Stark apparatus for 4 hours. The reaction mixture was evaporated in vacuo to dryness, dissolved in 100 ml of CH2Cl2 and washed with sat. sol. NaCl, 20% citric acid and sat. sol. NaCl. The organic layer was dried over Na2SO4 and evaporated in vacuo to dryness to yield 2.3 g of the crude product which was purified by flash column chromatography on 230-400 mesh silica gel, eluting initially with a mixture of CH2Cl2/MeOH 9:1 and then with a mixture of CH2Cl2/MeOH 8:2. The crude solid obtained was triturated with i-Pr2O/i-PrOH, washed and dried to yield 1.4 g of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C:32](=[O:33])[N:4]2[C:5]([C:16]([O:18]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:17])=[C:6]([S:9][CH2:10][C:11]3[N:12]=[N:13][S:14][CH:15]=3)[CH2:7][S:8][C@H:3]12.[ClH:34].CC(C)=O.C(OCC)(=O)C>C(O)=O>[ClH:34].[NH2:1][C@@H:2]1[C:32](=[O:33])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([S:9][CH2:10][C:11]3[N:12]=[N:13][S:14][CH:15]=3)[CH2:7][S:8][C@H:3]12
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3csnn3)CS[C@H]12
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O=CO
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(SCc3csnn3)CS[C@H]12
Reaction time: 1.5 h

Procedure:
To a solution of diphenylmethyl 7β-amino-3-[(1,2,3-thiadiazol-4-yl)methylthio]-3-cephem-4-carboxylate (4.68 g, 9.42 m mol) in formic acid (18.7 ml) was added conc. HCl (3.93 ml) at room temperature and the mixture was stirred at the same temperature for 1.5 hours. The mixture was poured into a cooled mixture of acetone (140 ml) and ethyl acetate (280 ml) and the precipitates were collected by filtration, washed with acetone and dried in vacuo to give 7β-amino-3-[(1,2,3-thiadiazol-4-yl)methylthio]-3-cephem-4-carboxylic acid hydrochloride (2.63 g).