Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1(O)[CH:13]2[CH2:14][O:15][CH2:16][CH:12]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:13]2[CH2:14][O:15][CH2:16][CH:12]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1
Reactant: CC1(O)CCCCCCCCCC2COCC21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=CCCCCCCCCC2COCC12
Reaction time: 8 h
Yield: 82.1 %

Procedure:
Crude 4-methyl-dodecahydro-2-oxa-cyclopentacyclododecen-4-ol (133 g) from Step 3 was dissolved in toluene (1 L). p-Toluenesulfonic acid (pTSA) (4 g) was added and the reaction was heated to reflux with a water trap. After 8 hours, there was no more water separated. The reaction was cooled and washed with sodium carbonate solution. Further distillation afforded 13-methyl-3a,4,5,6,7,8,9,10,11,13a-decahydro-1H,3H-2-oxa-cyclopentacyclododecene (101 g, ˜82% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH2:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(=O)[C@H](C1C=CC=CC=1)O.[OH-].[Na+]>C(OC)(C)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH2:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(N)c1ccc(Cl)c(Cl)c1
Agent: O=C(O)[C@@H](O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: C[C@@H](N)c1ccc(Cl)c(Cl)c1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
A solution consisting of 41 g of (RS)-1-(3,4-dichlorophenyl)ethylamine and 78 g of methyl t-butyl ether was heated to 45° C. while stirring, and a mixture of 14.6 g of L-mandelic acid and 90 g of methyl t-butyl ether was added thereto over about 30 minutes, followed by stirring at the same temperature for 30 minutes. Then, after cooled to 20° C. over 6 hours, the precipitated crystals were filtered, washed twice with 40 g of methyl t-butyl ether and dried to obtain 32.9 g of diastereomer salt. 82 g of a 5% aqueous sodium hydroxide solution was added to the crystals, followed by extraction twice with 10 g of methyl t-butyl ether. The solvent was distilled off from the resulting organic layer to obtain 18.2 g of (R)-1-(3,4-dichlorophenyl)ethylamine. This had the optical purity of 87.4%ee.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-])=O)[C:5]=2[N:6]=1.CC(O)=O>CCOC(C)=O.[Fe]>[NH2:13][C:7]1[C:5]2[N:6]=[C:2]([CH3:1])[O:3][C:4]=2[C:10]([C:11]#[N:12])=[CH:9][CH:8]=1
Reactant: Cc1nc2c([N+](=O)[O-])ccc(C#N)c2o1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1nc2c(N)ccc(C#N)c2o1
Temperature: 60 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
To a solution of 11B (0.16 g, 0.79 mmol) in EtOAc (2 mL) was added iron powder (0.1 g), followed by 10% aqueous AcOH (2 mL). The mixture was stirred at 60° C. for 2 h, then allowed to cool to rt and partitioned between saturated NaHCO3 and EtOAc. The separated EtOAc layer was concentrated under reduced pressure to give the title compound (0.14 g) as a solid.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:15])[C:9]([OH:14])=[CH:10][C:11]=2[CH3:13])[CH2:6][CH:5]1[CH3:16])(=[O:3])[CH3:2].Cl[CH2:18][C:19]([CH3:21])=[CH2:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:15])[C:9]([O:14][CH2:20][C:19]([CH3:21])=[CH2:18])=[CH:10][C:11]=2[CH3:13])[CH2:6][CH:5]1[CH3:16])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2c(C)cc(O)c(C)c2CC1C
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)COc1cc(C)c2c(c1C)CC(C)N2C(C)=O
Temperature: 80 °C
Reaction time: 20 h
Yield: 86.3 %

Procedure:
A suspension of 1-acetyl-2,3-dihydro-5-hydroxy-2,4,7-trimethyl-1H-indole (3.3 g, 16.1 mmol), 3-chloro-2-methyl-1-propene (2.6 g, 28.7 mmol) and potassium carbonate (3.5 g, 25.3 mmol) in dimethylformamide (25 ml) was stirred for 20 hours at 80° C. under nitrogen atmosphere. The reaction mixture was combined with water, and extracted twice with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain 3.8 g of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]#[C:9][CH3:10].CN(C)C=O.[CH3:17][N:18]1[C:23](=[O:24])[C:22]2[NH:25][C:26]([N:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)=[N:27][C:21]=2[CH:20]=[N:19]1>O>[CH2:7]([N:25]1[C:22]2[C:23](=[O:24])[N:18]([CH3:17])[N:19]=[CH:20][C:21]=2[N:27]=[C:26]1[N:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)[C:8]#[C:9][CH3:10]
Reactant: CC#CCBr
Reactant: Cn1ncc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)[nH]c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cnn(C)c(=O)c21
Temperature: 25 °C
Reaction time: 22 h

Procedure:
43.9 g of potassium carbonate and 27.8 ml of 2-butynyl bromide were successively added to a 5.5-L N,N-dimethylformamide solution of 88.4 g of t-butyl 4-(6-methyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl)piperazine-1-carboxylate at 15° C. under a nitrogen atmosphere. The reaction solution was stirred at room temperature for 22 hours, and then poured into 10 L of water. The mixture was extracted with 5 L of ethyl acetate. The organic layer was successively washed twice with 5 L of water, and with 5 L of a saturated sodium chloride solution. The aqueous layer was extracted twice with 3 L of ethyl acetate. The organic layers were combined together, and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 54.3 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (3:2 to 3:7).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:16][CH2:15][C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2].C(COC)OC.[CH3:23][NH:24][NH2:25]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:16][CH2:15][C:9]2[N:10]=[N:11][C:12]([N:24]([CH3:23])[NH2:25])=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2nnc(Cl)cc2C1
Reactant: CNN
Solvent: COCCOC
Product: CCOC(=O)N1CCc2nnc(N(C)N)cc2C1

Procedure:
72.6 g of 3-chloro-5,6,7,8-tetrahydro-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester are heated at reflux in 300 cc of methylhydrazine at a bath temperature of 110° for 1 hour while stirring, and the mixture is concentrated, the residue divided between chloroform and water and after concentrating the chloroform phase the title compound is obtained, M.P. 121°-123° (dec., from dimethoxyethane).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH:21]([CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][OH:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:41]1([C:47](Cl)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:15])[CH3:16])[CH2:10][C@H:9]1[CH:21]([CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][O:24][C:47]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(CCO)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(CCOC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2S,4R)-N-tert-butoxycarbonyl-2-(1-tert-butoxycarbonylaminomethyl-3-hydroxypropyl)-4-tert-butyldimethylsiloxypyrrolidine diastereomer B prepared in REFERENCE EXAMPLE 24-1 (1.01 g, 2 mmol) in methylene chloride (20 ml) were added triethylamine (0.307 ml, 2.2 mmol) and triphenylmethyl chloride (584 mg, 2.1 mmol). The mixture was stirred for 3 h at room temperature under a nitrogen atmosphere. The reaction solution was washed successively with water and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate) to give (2S,4S)-N-tert-butoxycarbonyl-2-(1-tert-butoxycarbonylaminomethyl-3-triphenylmethoxypropyl)-4-tert-butyldimethylsiloxypyrrolidine diastereomer B (1.48 g, yield: quantitative).
Reaction SMILES: C([O:4][CH2:5][CH:6]([C:22]1[C:27]([F:28])=[CH:26][C:25](Br)=[CH:24][C:23]=1[F:30])[N:7]1[CH2:21][CH2:20][C:10]2([O:15][CH2:14][C:13](=[O:16])[N:12]([CH:17]3[CH2:19][CH2:18]3)[CH2:11]2)[CH2:9][CH2:8]1)(=O)C.CC1(C)C(C)(C)OB([C:39]2[CH:48]=[C:47]3[C:42]([CH:43]=[CH:44][CH:45]=[N:46]3)=[CH:41][CH:40]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:17]1([N:12]2[CH2:11][C:10]3([CH2:20][CH2:21][N:7]([CH:6]([C:22]4[C:23]([F:30])=[CH:24][C:25]([C:39]5[CH:48]=[C:47]6[C:42]([CH:43]=[CH:44][CH:45]=[N:46]6)=[CH:41][CH:40]=5)=[CH:26][C:27]=4[F:28])[CH2:5][OH:4])[CH2:8][CH2:9]3)[O:15][CH2:14][C:13]2=[O:16])[CH2:18][CH2:19]1
Reactant: CC(=O)OCC(c1c(F)cc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Reactant: CC1(C)OB(c2ccc3cccnc3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1COC2(CCN(C(CO)c3c(F)cc(-c4ccc5cccnc5c4)cc3F)CC2)CN1C1CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
A solution of crude (80% purity) 2-(4-bromo-2,6-difluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl acetate (0.361 mmol) in 1,4-dioxane (2 mL) was treated with 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.397 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.018 mmol), and 2M aq potassium carbonate (1.083 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120° C. for 15 min. The reaction was cooled at which point additional portions of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.08 mmol) and PdCl2(dppf)-CH2Cl2 adduct (0.006 mmol) were added. The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120° C. for 5 min. The black reaction mixture was then concentrated to minimal volume (˜0.5 mL) under a stream of nitrogen at which point it was diluted with a mixture of ethanol and water (2 mL, 1:1). This mixture was stirred in an oil bath at 80° C. overnight. The resulting solution was concentrated to dryness under a stream of nitrogen and then diluted with water (50 mL) and brine (20 mL). This aqueous mixture was extracted four times with ethyl acetate. The combined organic layers were treated with Silicycle Si-thiol (50 mg), dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-7% methanol/dichloromethane) and chiral HPLC (Chromegachiral CC4, methanol) followed by lyophilization from water (w/25% acetonitrile) afforded the title compound as a white solid in >99% ee (29 mg, 15% yield). MS(ES)+ m/e 494.1 [M+H]+. αD=+4 deg (c=0.06, methanol).
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[C:9]2[CH:14]=[C:13]([O:15][C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[CH:12]=[C:11]([OH:27])[CH:10]=2)=[CH:5][CH:4]=[C:3]([OH:28])[CH:2]=1.Cl>O>[C:9]1(/[CH:8]=[CH:7]/[C:6]2[CH:5]=[CH:4][C:3]([OH:28])=[CH:2][CH:1]=2)[CH:14]=[C:13]([OH:15])[CH:12]=[C:11]([OH:27])[CH:10]=1
Reactant: OC[C@H]1O[C@@H](Oc2cc(O)cc(/C=C/c3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: Cl
Solvent: O
Product: Oc1ccc(/C=C/c2cc(O)cc(O)c2)cc1
Temperature: 100 °C
Yield: 97491.9 %

Procedure:
The following example illustrates conversion of a β-D-glycosylated stilbene to the aglycone. 200 mg of 90% trans-piceid (3,4′5-trans-trihydroxystilbene -3-β-mono-D-glucoside, BZ1-69-1) was mixed with 5 ml of concentrated hydrochloric acid and 95 ml water (5% HCl v/v) and refluxed with agitation at 100° C. for 90 minutes to yield 114 g (57% yield) trans-resveratrol (trans-3,4′,5-trihydroxystilbene).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[SH:11][CH2:12][C:13]([OH:15])=[O:14]>[OH-].[K+].O>[F:10][C:7]1[CH:8]=[CH:9][C:2]2[S:11][C:12]([C:13]([OH:15])=[O:14])=[CH:4][C:3]=2[CH:6]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: O=C(O)CS
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc2cc(F)ccc2s1
Temperature: 125 °C
Yield: 80.1 %

Procedure:
In a glass pressure bottle, 2,5-difluorobenzaldehyde (11 ml, 0.1 mol) was added to a solution of 2-mercaptoacetic acid (9 ml) in potassium hydroxide (16.5 g) and water (155 ml). The bottle was then sealed and heated in a hot oil bath to 125±5° C. for 1.25 hours. The bottle was then removed from the hot oil bath and cooled. A pale yellow precipitate was obtained in the bottle. At ambient temperature, the bottle was opened and sufficient water was added to dissolve the precipitate. The resultant aqueous material was washed with ether and then acidified with hydrochloric acid to produce a pale yellow solid. The pale yellow solid was collected on a filter, washed with water and dried, to produce 15.5 g of 5-fluoro-2-benzo-[b]thiophenecarboxylic acid (80.1% yield, mp>300° C.).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1.Cl.Cl.O.O1CCCC1>CO>[S:16]1[C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:2]=[O:1])=[CH:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]1=2
Reactant: c1ccc(C2OCCO2)c(-c2cc3ccccc3s2)c1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccccc1-c1cc2ccccc2s1

Procedure:
For example, the 2-(2-[1,3]dioxolan-2-yl-phenyl) benzo[b]thiophene (3) product is treated with a suitable acid, such as a hydrochloric acid, preferably an aqueous acid, such as a hydrochloric acid/water mixture. The reaction is carried out in a suitable organic solvent such as tetrahydrofuran or methanol. The reaction is heated to reflux for a period of time ranging from about 20 minutes to about 6 hours. The reaction is then quenched with a weak base such as, for example, sodium bicarbonate. The solvent is removed and the resulting mixture may be extracted, concentrated and purified according to techniques well known in the art, to provide benzo[b]thiophen-2-yl-benzaldehyde (4).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:6]=1[F:17])[OH:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][O:29][CH3:30]>C(#N)C>[F:19][C:2]([F:1])([F:18])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:12][CH2:13][N:14]([CH2:27][CH2:28][O:29][CH3:30])[CH2:15][CH2:16]2)[C:6]=1[F:17])[OH:4]
Reactant: COCCBr
Reactant: OC(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN1CCC(c2cccc(C(O)C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 2,2,2-trifluoro-1-(2-fluoro-3-piperidin-4-ylphenyl)ethanol (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 1-bromo-2-methoxyethane (0.01 g). MS m/z (rel. intensity, 70 eV) 335 (M+, 1), 291 (15), 290 (bp), 207 (4), 149 (7).
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH2:18][CH:19]2[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20]2)=[CH:12][C:11]=1[N+:26]([O-:28])=[O:27])(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:24][C:21]1([CH3:25])[O:20][CH:19]([CH2:18][C:13]2[C:14]([O:16][CH3:17])=[CH:15][C:10]([CH2:9][OH:8])=[C:11]([N+:26]([O-:28])=[O:27])[CH:12]=2)[CH2:23][O:22]1
Reactant: COc1cc(CO[Si](C)(C)C(C)(C)C)c([N+](=O)[O-])cc1CC1COC(C)(C)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(CO)c([N+](=O)[O-])cc1CC1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
358 mg of t-butyl(4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-5-methoxy-2-nitrobenzyloxy)dimethylsilane was dissolved in 10 ml of tetrahydrofuran. While cooling on ice, 1 ml of a tetrahydrofuran solution containing 1.0 M tetrabutyl ammonium fluoride was added to the reaction solution, and the obtained mixture was then stirred at room temperature for 3 hours. Thereafter, the reaction solution was diluted with ethyl acetate and then washed with a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain 253 mg of (4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-5-methoxy-2-nitrophenyl)methanol.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[C:5]([CH3:7])[N:6]=1.CS[C:17]1[S:18][CH2:19][CH2:20][N:21]=1.Cl.C(=O)([O-])O.[Na+]>COC(O)C.O1CCOCC1>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][C:17]2[S:18][CH2:19][CH2:20][N:21]=2)[S:3][C:4]=1[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=1
Reactant: CSC1=NCCS1
Reactant: Cc1ccnc(-c2sc(N)nc2C)c1
Agent: COC(C)O
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: Cc1ccnc(-c2sc(NC3=NCCS3)nc2C)c1

Procedure:
To a suspension of 2-amino-4-methyl-5-(4-methylpyridin-2-yl)-thiazole and 2-(methylthio)-2-thiazoline (127 mg) in methoxyethanol (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 0.23 ml). The mixture was refluxed for 20 hours, poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate twice. The combined organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 25 g, 5% methanol in dichloromethane) and recrystallized from chloroform (1 ml)-diisopropyl ether (3 ml) to give 2-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-ylamino)-2-thiazoline (110 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15](OC)=[O:16])=[CH:13][C:12]([C:19]([F:22])([F:21])[F:20])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+]>C1COCC1.CO.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH2:15][OH:16])=[CH:13][C:12]([C:19]([F:22])([F:21])[F:20])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1cc(C(F)(F)F)nn1-c1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2nc(C(F)(F)F)cc2CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
Intermediate 18 (0.662 g, 2.1 mmol) dissolved in a mixture of THF (5 ml) and MeOH (5 ml) and added sodium borohydride (79 mg, 2.1 mmol). Colour of the reaction mixture changed to pink and then two drops of water added to it. Reaction mixture allowed to stir at rt for 1 h and at this stage colour changed to pink to pale yellow. Reaction mixture was allowed to stir further overnight. Work up (AcOEt/H2O) and evaporation of organic layer on vacuum afforded the title compound (558 mg) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.42 (d, J 8.9, 2H), 8.01 (d, J 8.9, 2H), 7.01 (s, 1H), 5.77 (t, J 5.4, 1H), 4.63 (d, J 5.4, 2H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Br:18][CH2:19][C:20](Br)=[O:21].Cl>C(Cl)CCl>[Br:18][CH2:19][C:20]([C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:8]=[CH:7][C:6]([F:5])=[CH:11][CH:10]=2)=[CH:13][CH:14]=1)=[O:21]
Reactant: Fc1ccc(-c2ccccc2)cc1
Reactant: O=C(Br)CBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(CBr)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
44 gm (0.33 mol) of aluminum chloride were added in small portions to a solution of 51.7 gm (0.3 mol) of 4-fluoro-biphenyl and 66.6 gm (0.33 mol) of bromoacetyl bromide in 150 cc of ethylene chloride, while cooling the solution on an ice-salt bath, and the mixture was then stirred at room temperature for two hours. Thereafter, the reaction mixture was admixed with ice and hydrochloric acid, and the organic phase was separated, washed with water, dried with sodium sulfate and evaporated. The residue was recrystallized from 250 cc of carbon tetrachloride, yielding 53 gm (60% of theory) of 2-bromo-4'-(4-fluoro-phenyl)-acetophenone, m.p. 102°-103° C.
Reaction SMILES: C(N(CC)C(C1C=CC=CC=1[S:12]([C:15]1[C@H:16]([CH3:46])[C@@H:17]2[C@@H:34]([C@H:35]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH3:36])[C:33](=[O:45])[N:18]2[C:19]=1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:21])(=O)=O)=O)C.[CH3:49][N:50]([CH3:72])[C:51]([C@@H:53]1[CH2:57][C@H:56](S)[CH2:55][N:54]1[C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][C:66]([N+:69]([O-:71])=[O:70])=[CH:65][CH:64]=1)=[O:60])=[O:52]>>[CH3:49][N:50]([CH3:72])[C:51]([C@@H:53]1[CH2:57][C@H:56]([S:12][C:15]2[C@H:16]([CH3:46])[C@@H:17]3[C@@H:34]([C@H:35]([O:37][Si:38]([C:41]([CH3:42])([CH3:43])[CH3:44])([CH3:39])[CH3:40])[CH3:36])[C:33](=[O:45])[N:18]3[C:19]=2[C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)=[O:21])[CH2:55][N:54]1[C:59]([O:61][CH2:62][C:63]1[CH:64]=[CH:65][C:66]([N+:69]([O-:71])=[O:70])=[CH:67][CH:68]=1)=[O:60])=[O:52]
Reactant: CN(C)C(=O)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)C(=O)c1ccccc1S(=O)(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2[C@H]1C
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N(C)C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 78 %

Procedure:
Following a procedure similar to that described in Example 18, but using 76 mg of 4-nitrobenzyl (1R, 5S,6S)-2-(2-diethylcarbamoylphenylsulfonyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described it Example 42) and 46 mg of (2S,4S)-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-4-mercaptopyrrolidine, the title compound was obtained in a yield of 78%.
Reaction SMILES: [OH:1][C@@H:2]([CH3:6])[C:3](N)=O.F[B-](F)(F)F.C([O+](CC)CC)C.[NH2:19][C:20]1[C:21]([NH:29][C@@H:30]2[CH2:35][O:34][C@@H:33]([CH2:36][OH:37])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>C1COCC1.C(O)C.CO>[OH:37][CH2:36][C@@H:33]1[O:34][CH2:35][C@@H:30]([N:29]2[C:21]3=[C:22]4[S:28][CH:27]=[CH:26][C:23]4=[N:24][CH:25]=[C:20]3[N:19]=[C:3]2[C@@H:2]([OH:1])[CH3:6])[CH2:31][CH2:32]1
Reactant: C[C@H](O)C(N)=O
Reactant: Nc1cnc2ccsc2c1N[C@H]1CC[C@H](CO)OC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CO)OC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
A mixture of (2S)-2-hydroxypropanamide (86.6 mg, 0.972 mmol) and triethyloxonium tetrafluoroborate (185 mg, 0.972 mmol) in THF (2 mL) was stirred at room temperature for 2 h. The solvent was removed and the residue dissolved in ethanol (0.50 mL) and added to a suspension of {(2R,5S)-5-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]tetrahydro-2H-pyran-2-yl}methanol (65.0 mg, 0.233 mmol) in ethanol (1.8 mL). The mixture was stirred at 80° C. for 1 h. The mixture was cooled to room temperature, diluted with methanol, and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product as white solid (45 mg, 58%). LCMS calculated for C16H20N3O3S (M+H)+: m/z=334.1. Found: 334.