Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5](OB(O)O)=[CH:4][CH:3]=1.Br[C:13]1[CH:27]=[CH:26][C:16]([O:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(OC)(C)C>O.COCCOC.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>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:13]2[CH:27]=[CH:26][C:16]([O:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: OB(O)Oc1ccc(F)nc1
Reactant: Brc1ccc(OCCN2CCOCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: COCCOC
Product: Fc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Temperature: 80 °C
Reaction time: 17 h
Yield: 101 %

Procedure:
A 72 L reactor equipped with reflux condenser, sparging tube, bubbler, and temperature probe was charged with 6-fluoropyridin-3-ylboric acid (2.84 kg, 1.24 equiv.), 4-(2-(4-bromophenoxy)ethyl)morpholine (4.27 kg, 1.0 equiv.), and DME (27 L). Agitation was started and sodium carbonate (4.74 kg, 3.0 equiv.) as a solution in DI water (17.1 L) was then charged to the reaction mixture. Argon was bubbled through the reaction mixture for 50 minutes. Under an argon atmosphere, tetrakis(triphenylphosphine)palladium (750 g, 0.04 equiv.) was added to the reaction mixture as a slurry in DME (1.0 L). The reaction mixture was heated to 75-85° C. and stirred overnight (17 h). The reaction mixture was cooled to between 18-22° C. DI water (26.681 kg) and MTBE (26.681 L) were charged to the reactor and stirred for 5 minutes. The phases were separated and the aqueous phase was extracted with MTBE (2×26.7 L). The combined organics were extracted with 2M HCl (1×15.0 L, 3×21.8 L). The aqueous phase was then charged back to the reactor and ethyl acetate was added (26.7 L). The pH was adjusted to 6.2 using 6 M sodium hydroxide (26.7 L) while maintaining a temperature between 15-25° C. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×26.7 L). The combined organics were dried with magnesium sulfate and concentrated to give 4555 g of a residue (101% crude yield, 67.1% AUC by HPLC).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([CH:15]1[CH2:19][CH2:18][C:17]2([CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[C:16]1=[O:32])[CH2:13][CH3:14].C(N(CC)CC)C>ClCCl>[O:11]=[C:12]([CH:15]1[CH2:19][CH2:18][C:17]2([CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]2)[C:16]1=[O:32])[CH2:13][CH3:14]
Reactant: CCC(O)C1CCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCC(=O)C1CCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 84.1 %

Procedure:
To a solution of oxalyl chloride (1.6 mL, 18.3 mmol) in dichloromethane (150 mL) at −78° C. was slowly added dimethyl sulfoxide (2.6 mL, 37 mmol). After 5 min, a solution of tert-butyl 2-(1-hydroxyprop-1-yl)-1-oxo-8-azaspiro[4.5]decane-8-carboxylate (4.75 g, 15.3 mmol) from Step H in dichloromethane (40 mL) was added via an addition funnel. The reaction mixture was stirred for 45 min at −78° C. and then triethylamine (10.2 mL, 73.2 mmol) was added. After 5 min, the reaction mixture was removed from the cooling bath, allowed to warm to room temperature for 1.5 h, poured into water, and extracted three times with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated to afford 4.65 g. The residue was purified by flash chromatography eluting with 15% ethyl acetate in hexanes to give the title compound (3.98 g) as a pink oil.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[N:7]([CH3:23])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:24]Br.O>C(O)(=O)C>[Br:24][C:9]1[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]([CH3:23])[C:8]=1[NH:10][C:11]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc(OC)ccc1Nc1cc(C(C)(C)C)nn1C
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(OC)ccc1Nc1c(Br)c(C(C)(C)C)nn1C
Reaction time: 0.08 h

Procedure:
To a solution of 2-(5-tert-butyl-2-methyl-2H-pyrazol-3-ylamino)-5-methoxy-benzoic acid methyl ester (Example 155, 1.34 g, 4.22 mmol) in acetic acid (27 mL), was added dropwise a solution of Br2 (6.74 g, 4.22 mmol) in acetic acid (5 mL). The reaction was stirred for 5 min, and then water (100 mL) was added. The aqueous phase was extracted with EtOAc, and the combined organic layers were washed with water, and then with NaHCO3 (10% aqueous solution) 10 times. The organic layer was then dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 5 to 10% EtOAc in hexane) to give the title compound as a light yellow solid. (1.49 g, 89%). 1H NMR (400 MHz, CDCl3) δ 1.40 (s, 9H), 3.66 (s, 3H), 3.78 (s, 3H), 4.05 (s, 3H), 6.32 (d, 1H), 7.06 (dd, 1H), 7.48 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH2:11][C:12]([CH:15]=[CH2:16])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>O1CCCC1.C(OC(C)C)(C)C>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH2:11][C:12]([CH2:15][CH2:16][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC1=NC=C(OCc2ccccc2)C(=O)C1
Reactant: C1CCNC1
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: O=C1CC(CCN2CCCC2)=NC=C1OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 5-benzyloxy-2-vinyl-4-pyridone (2.90 g) and pyrrolidine (5.33 ml) was heated and refluxed for an hour. The mixture was cooled and diluted with tetrahydrofuran (20 ml) and diisopropyl ether (80 ml). After being stirred for an hour at ambient temperature, the resulting precipitate was collected by filtration, washed with diisopropyl ether and air-dried at ambient temperature to give 5-benzyloxy-2-[2-(1-pyrrolidinyl)ethyl]-4-pyridone (3.79 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[O:5][CH2:6][CH2:7][N:8]([CH3:22])[CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:18]=[C:17]([C:19](N)=[O:20])[CH:16]=[CH:15][N:14]=1.Cl.[CH3:28][OH:29]>>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[O:5][CH2:6][CH2:7][N:8]([CH3:22])[CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:18]=[C:17]([C:19]([O:29][CH3:28])=[O:20])[CH:16]=[CH:15][N:14]=1
Reactant: CO
Reactant: COc1ccccc1OCCN(C)CCCNc1nccc(C(N)=O)n1
Agent: Cl
Product: COC(=O)c1ccnc(NCCCN(C)CCOc2ccccc2OC)n1

Procedure:
12.7 g (35.3 mmol) of 2-[[3-[[2-(2-methoxyphenoxy)ethyl]methylamino]propyl]amino]pyrimidine-4-carboxamide and 300 ml of methanol are introduced into a 0.5 l round-bottomedflask, a stream of gaseous hydrochloric acid is passed through for a few minutes and the mixture is heated at the reflux temperature of the methanol for 4 h.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:24](O)=[O:25]>>[CH:24]([C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])=[O:25].[CH:24]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[OH:1])=[O:25]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1cccc(O)c1
Agent: C1N2CN3CN1CN(C2)C3
Product: COC(=O)c1ccc(C=O)c(O)c1
Product: COC(=O)c1cccc(O)c1C=O

Procedure:
Methyl 3-hydroxybenzoate (75.5 g) is dissolved in trifluoroacetic acid (2 L), thereto is added hexamethylenetetramine (141.4 g) at room temperature and the mixture is heated under reflux for 3 hours. The reaction solution is concentrated under reduced pressure, to the resulting residue is added water, the mixture is adjusted to pH 8 with potassium carbonate and sodium hydrogen carbonate, diluted with water and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: hexane/ethyl acetate=8/1, 5/1 followed by 2/1) to give methyl 2-formyl-3-hydroxybenzoate (54.6 g) (ESI-MS m/z: 179[M−H]−) and methyl 4-formyl-3-hydroxybenzoate (4.4 g)
Reaction SMILES: NC(N)=[S:3].[ClH:5].Cl.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26]Cl)[CH2:20][CH2:19]2)=[CH:10][CH:9]=1.C(O)C.[OH-].[Na+]>O>[ClH:7].[ClH:5].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][SH:3])[CH2:20][CH2:19]2)=[CH:10][CH:9]=1
Reactant: ClCCCN1CCN(CCCCc2ccc(Cl)cc2)CC1
Reactant: NC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: SCCCN1CCN(CCCCc2ccc(Cl)cc2)CC1
Yield: 30.2 %

Procedure:
The procedure described in Example 1(b) was followed, using 1.0 g of thiourea, 4.0 g of 1-[4-(4-chlorophenyl)butyl]-4-(3-chloropropyl)piperazine dihydrochloride and 50 ml of reagent ethanol. The hydrolysis was effected with 4.0 g of sodium hydroxide in 50 ml of water. Work-up of the free base, as described above followed by purification on a silica gel column (methylene chloride:methanol, 97:3), precipitation as the hydrochloride salt and recrystallization from reagent ethanol, gave 0.6 g (16% of theory) of 3-{4-[4-(4-chlorophenyl)butyl]piperazin-1-yl}propanethiol dihydrochloride as a white crystalline solid, M.p. 254°-259° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[C:22]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:21]=[CH:20][C:19]([CH2:18][N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2](=[O:1])[C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4]2)=[CH:24][CH:23]=1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)c1c[nH]c2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(-c3ccccc3)cc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (6.11 g, 28.1 mmol), 4-(bromomethyl)biphenyl (9.04 g, 36.6 mmol, 1.3 equiv), potassium iodide (467 mg, 2.81 mmol, 0.1 equiv) and potassium carbonate (9.72 g, 70.3 mmol, 2.5 equiv) were combined in N,N-dimethylformamide (10 mL) and stirred at ambient temperature for 18 hours. The mixture was poured into water (100 mL) and ethyl acetate (100 mL) and aged for 2 hours. The mixture was filtered, the filtrate discarded and the solid was dissolved in dichloromethane (100 mL), dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9](Cl)=[O:10])[CH2:5][CH2:4]1.[CH2:12]([O:14][C:15]#[CH:16])[CH3:13]>>[CH2:15]([O:14][C:12]1[C:6]2([CH2:7][CH2:8][CH:3]([O:2][CH3:1])[CH2:4][CH2:5]2)[C:9](=[O:10])[CH:13]=1)[CH3:16]
Reactant: C#COCC
Reactant: COC1CCC(C(=O)Cl)CC1
Product: CCOC1=CC(=O)C12CCC(OC)CC2

Procedure:
Was prepared from 4-methoxy cyclohexanecarbonyl chloride (10 g, 52.1 mmol) and ethoxyacetylene (7.5 g, 0.10 mol) according to the method of Intermediate 1 to give the title compound as an approx. 1:1 mixture of isomers, as a pale yellow oil (7.2 g, 34.4 mmol, 65%). δH (CDCl3, 300K) 4.81-4.79 (1H, s), 4.22-4.20 (2H q, J 7.1 Hz), 3.34-3.32 (3H, s), 3.31-3.22 (1H, m), 2.04-1.56 (8H, m), 1.44-1.43 (3H t, J 7.1 Hz); m/z (ES+, 70V) 211.0 (MH+).
Reaction SMILES: [CH:1]([C:4]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([CH:12]([CH3:14])[CH3:13])[C:5]=1[NH2:6])([CH3:3])[CH3:2].C(N(CC)C1C=CC=CC=1)C.[Br:26][CH2:27][C:28](Br)=[O:29]>O>[Br:26][CH2:27][C:28]([NH:6][C:5]1[C:7]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:9]=[C:10]([F:11])[C:4]=1[CH:1]([CH3:3])[CH3:2])=[O:29]
Reactant: O=C(Br)CBr
Reactant: CC(C)c1ccc(F)c(C(C)C)c1N
Solvent: CCN(CC)c1ccccc1
Solvent: O
Product: CC(C)c1ccc(F)c(C(C)C)c1NC(=O)CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 2,6-diisopropyl-3-fluoroaniline (synthesized by the method described in the Japanese Patent Application Laid open No. Sho. 63-208556) (550 mg, 2.82 mmol) indichloromethane (20 ml) were added N,N-diethylaniline (478 mg, 3.94 mmol) and bromoacetyl bromide (649 mg, 3.22 mmol) successively with ice-cooling, and stirred at room temperature for 2 hours. The reaction solution was diluted with water and extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (silica gel 50 g, developing solvent; hexane:ethyl acetate=7:1 3:1) to provide 730 mg (yield 82%) of 2-bromo-N-(2,6-diisopropyl-3-fluorophenyl)acetamide as colorless prisms.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([NH:20][C:21]#[N:22])=[N:9][C:10]2[CH:19]=[CH:18]C=[C:16]3[C:11]=2C=CC=[N:15]3)=[CH:4][CH:3]=1.[S:25](Cl)([C:28]1[C:40]2[CH:39]=[CH:38][CH:37]=[C:33]([N:34]([CH3:36])[CH3:35])[C:32]=2[CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26]>N1C=CC=CC=1.C(OCC)(=O)C>[C:21]([N:20]=[C:8]([NH:9][C:10]1[CH:11]=[CH:16][N:15]=[CH:18][CH:19]=1)[NH:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:25]([C:28]2[C:40]3[C:32](=[C:33]([N:34]([CH3:36])[CH3:35])[CH:37]=[CH:38][CH:39]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[CH:24][CH:23]=1)#[N:22]
Reactant: N#CNC(=Nc1cccc2ncccc12)NCc1ccc(N)cc1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CN(C)c1cccc2c(S(=O)(=O)Nc3ccc(CNC(=NC#N)Nc4ccncc4)cc3)cccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
N-(4-Amino-benzyl)-N′-cyano-N″-quinolin-5-yl-guanidine (400 mg, 1.50 mmol) and dansyl chloride (405 mg, 1.50 mmol) were combined in pyridine (15 mL). An exothermic reaction occurred and the suspension became homogeneous. This solution was shaken at room temperature for 12 hours. The reaction mixture was then diluted with ethyl acetate (80 mL) and washed with water (40 mL×3). The organic phase was dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give a solid product which was purified by HPLC (yield=60%). 1H NMR (DMSO-d6, ppm): 10.73 (s, 1H), 9.09 (bs, 1H), 8.57 (d, 2H), 8.44 (d, 2H), 8.36 (d, 1H), 8.21 (d, 1H), 7.61 (m, 3H), 7.50 (s, 2H), 7.27 (d, 1H), 7.17 (d, 2H), 7.03 (d, 2H), 4.38 (d, 2H).
Reaction SMILES: C([O-])=O.[Na+].[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])[CH3:6]>C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.C(O)=O>[C:8]1([C@@H:5]([OH:7])[CH3:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)c1ccccc1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Product: C[C@H](O)c1ccccc1
Temperature: 30 °C
Reaction time: 20 h
Yield: 96.4 %

Procedure:
Culture fluid was obtained by cultivating E. coli HB101 (pNCMFT) in a similar manner to Example 9. In a 100-mL portion of the culture fluid, 2.8 g of sodium formate, 3 mg of NAD+, and 10 g of acetophenone were added, and the mixture was stirred at 30° C. for 20 hours while controlling the pH of the reaction mixture to 6.0 with 5 N aqueous formic acid, which was added dropwise to the mixture. After the reaction, the reaction mixture was extracted with toluene, and combined organic layer was dried over anhydrous sodium sulfate. Removal of sodium sulfate, and evaporation of organic solvents from the organic layer under reduced pressure yielded 9.8 g of (S)-phenylethanol. The product (S)-phenylethanol was analyzed in accordance with the [Analysis condition (1) for gas chromatography] as described above, and found that the optical purity of the product was 99.9% e.e. or higher.
Reaction SMILES: P([O-])([O-])([O-])=[O:2].[O:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.C(#N)C.[N+](C1C=CC(COC(C2N3[C@H](SC=2)C(C(OC(=O)C)[C:34]2C=[C:37]4[S:38][CH2:39][CH2:40][N:36]4[N:35]=2)(Br)C3=O)=O)=CC=1)([O-])=O>[Zn].C(OCC)(=O)C>[CH2:10]([O:6][C:7]([C:8]1[CH:34]=[N:35][N:36]2[CH2:40][CH2:39][S:38][C:37]=12)=[O:2])[CH3:9]
Reactant: C1CCOC1
Reactant: O=P([O-])([O-])[O-]
Reactant: CC(=O)OC(c1cc2n(n1)CCS2)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Agent: [Zn]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn2c1SCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 39.2 %

Procedure:
Freshly activated Zn dust (37.4 g) was added rapidly with 0.5 mol/l phosphate buffer (pH 6.5, 196 ml) to tetrahydrofuran (134 ml) and acetonitrile (62 ml) solution of (5R)-6-[acetoxy-(2,3-dihydropyrazolo[5,1-b]thiazol-6-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid p-nitrobenzyl ester. The reaction vessel was covered with foil to exclude light. The reaction mixture was vigorously stirred for 1.5 hours at room temperature. The reaction mixture was cooled at 0° C., and then the pH was adjusted to 8.0. ethyl acetate (100 ml) was added to the reaction mixture. The mixture was filtered through a pad of Celite and the pad was washed with water (300 ml). The aqueous layer was separated and then the organic layer was extracted with 0.5 mol/l phosphate buffer (pH 6.5, 2×50 ml). The pH of the combined aqueous layer was adjusted to 8.0 and the mixture was concentrated to 426 g. The concentrate was adjust pH to 8.0 and applied to Diaion HP-21 resin (540 ml, Mitsubishi Kasei Co. Ltd.) column chromatography. After adsorbing, the column was eluted with water (1 bed volume) and then 5% (2 bed volume), 10% (2 bed volume) and 20% acetonitrile aqueous solution. The combined active fractions were concentrated under high vacuum at 35° C. and lyophilized to give the title compound as a orange amorphous solid (2.09 g, 39.2%, pH 7.10).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:28])([CH3:27])[CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=2)=[CH:6][CH:5]=1)[CH3:2].ClC1C=C(C(C)(C)COCC2C=CC=C(OC3C=CC=CC=3)C=2)C=CC=1OCC>[C].[Pd]>[O:20]([C:16]1[CH:15]=[C:14]([CH3:13])[CH:19]=[CH:18][CH:17]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1.[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:27])([CH3:28])[CH2:11][OH:12])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C(C)(C)COCc2cccc(Oc3ccccc3)c2)cc1
Agent: [Pd]
Agent: CCOc1ccc(C(C)(C)COCc2cccc(Oc3ccccc3)c2)cc1Cl
Product: CCOc1ccc(C(C)(C)CO)cc1
Product: Cc1cccc(Oc2ccccc2)c1

Procedure:
The dechlorination reaction was carried out in the same manner as in Example 1 except that 1.44 g of 10%-palladium-alumina (100% dry) was used instead of the 5%-palladium-carbon used as the hydrogenation catalyst in Example 1, and an oily product was obtained by carrying out the post-treatment in the same manner as in Example 1. From the results of the analysis of the oily product by gas chromatography according to the internal standard method, it was found that the oily product comprised 97.4% of 3-phenoxybenzyl 2-(4-ethoxyphenyl)-2-methylpropyl ether and 0.5% of unreacted starting 3-phenoxybenzyl 2-(3-chloro-4-ethoxyphenyl)-2-methylpropyl ether, and that the content of each of 3-phenoxytoluene and 4-ethoxyneophyl alcohol formed by cleaving of the ether linkage was lower than 0.7%. The amount of the obtained oily product was 52.0 g and the yield was 93.2%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]([CH:25]=O)[CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[BH3-]C#N.[Na+]>CC(O)=O.CO>[CH2:8]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]([CH2:25][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:19]1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=CC1CCCCN(C(=O)OCc2ccccc2)C1
Reactant: Nc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CCCCC(CNc2ccccc2)C1
Reaction time: 0.33 h

Procedure:
Aniline (0.126 mL, 1.38 mmol) was added to a solution of 3-formyl-azepane-1-carboxylic acid benzyl ester (147) (0.300 g, 1.15 mmol) in 5% HOAc in MeOH (11.5 mL). The reaction was stirred for approx. 20 minutes, then NaBH3CN (0.2164 g, 3.44 mmol) was slowly added and the reaction was stirred at room temperature overnight. The reaction was then concentrated in vacuo and EtOAc and a few drops of 10% NaOH were added. The organic was washed with saturated NaCl (aq), dried with Na2SO4, concentrated in vacuo, to give crude 3-phenylaminomethyl-azepane-1-carboxylic acid benzyl ester (148). Compound 148 was used in the next step without further purification.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:16]CC)(=[O:15])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:19]1[CH2:24][CH2:23][CH:22]([CH:25]=O)[CH2:21][CH2:20]1>C(O)(C)(C)C>[CH2:13]([O:12][C:10](=[O:11])[C:9](=[CH:25][CH:22]1[CH2:23][CH2:24][CH2:19][CH2:20][CH2:21]1)[CH2:8][C:7]([OH:16])=[O:15])[CH3:14]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: O=CC1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)C(=CC1CCCCC1)CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 11.2 g (0.1 mol) potassium tert-butoxide in 100 ml tert-butanol was added a mixture of 17.4 g (0.1 mol) diethyl succinate and 11.2 g (0.1 mol) cyclohexylcarboxaldehyde over a period of 30 min. The mixture was allowed to stir at room temperature for one hour and heated to 50° C. for an additional hour. The solvent was removed under reduced pressure, the residue was dissolved in 100 ml water and transferred into a separation funnel. The solution was extracted twice with 50 ml ethyl acetate to remove neutral impurities, acidified with 6M HCl and extracted again twice with 20 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure, to give 18.9 g (79%) of a yellow brown oil. 1H-NMR: 66% E-isomer, 13% Z-isomer, 15% cyclohexenyl-isomer, 6% other unsaturated olefelinic compound.
Reaction SMILES: S(=O)(=O)(O)O.[C-:6]#[N:7].[Na+].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:12][C:11]=1[C:20]([F:23])([F:22])[F:21].[OH-:24].[Na+]>C(O)(=O)C>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([NH:7][CH:6]=[O:24])([CH3:19])[CH3:18])=[CH:12][C:11]=1[C:20]([F:21])([F:22])[F:23]
Reactant: [C-]#N
Reactant: [OH-]
Reactant: CC(C)=Cc1ccc(F)c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(Cc1ccc(F)c(C(F)(F)F)c1)NC=O
Temperature: 55 °C
Reaction time: 1 h

Procedure:
A solution of 30 mL conc. sulphuric acid and 15 mL glacial acetic acid is added dropwise to 1.0 g (20.4 mmol) sodium cyanide in 15 mL glacial acetic acid, while the temperature rises to approx. 30° C. Then 3.4 g (15.6 mmol) 1-fluoro-4-(2-methyl-propenyl)-2-trifluoromethyl-benzene, dissolved in 15 mL glacial acetic acid, are added and the mixture is stirred for 1 hour at 50-60° C. After cooling to ambient temperature the mixture is poured onto ice water and made alkaline with sodium hydroxide solution. It is extracted with diethyl ether and the organic phases are washed with water, dried with sodium sulphate and evaporated down. 3.64 g of a brown oil are obtained.