Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH:13]2[C:17]3[C:18]([CH3:32])=[C:19]([NH:24][C:25](=[O:31])[CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:20]([CH3:23])=[C:21]([CH3:22])[C:16]=3[O:15][CH2:14]2)[CH:10]=[CH:9][C:8]=1[CH:33]([CH3:35])[CH3:34])C.[Li].O>C1COCC1>[OH:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH:13]2[C:17]3[C:18]([CH3:32])=[C:19]([NH:24][C:25](=[O:31])[CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:20]([CH3:23])=[C:21]([CH3:22])[C:16]=3[O:15][CH2:14]2)[CH:10]=[CH:9][C:8]=1[CH:33]([CH3:34])[CH3:35]
Reactant: CCOC(=O)COc1cc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)ccc1C(C)C
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)c(OCCO)c1)CO2
Temperature: 25 °C
Reaction time: 60 h
Yield: 70.6 %

Procedure:
To a solution of ethyl(5-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)-2-isopropylphenoxy)acetate (200 mg, 0.49 mmol) obtained in Example 188 in THF (5 mL) was added with ice-cooling lithium borotetrahydride (43 mg, 2.00 mmol). The reaction solution was warmed to room temperature and stirred for 60 hours. The reaction solution was added to ice and water was added to the reaction solution, and the product was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 157 mg (yield: 71%) of the title compound. Melting point: 155-156° C. (ethyl acetate-hexane).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[CH3:2].[C:38]1([OH:48])[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1.B(F)(F)F>ClCCl>[C:8]([O:7][C@@H:6]1[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:27][C@H:5]1[O:4][C:1]1[C:47]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:43]=[CH:44][CH:2]=1)(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1.[C:38]1([OH:48])[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: FB(F)F
Agent: Oc1cccc2ccccc12
Solvent: ClCCl
Product: O=C(OC[C@H]1O[C@@H](Oc2cccc3ccccc23)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1

Procedure:
A solution 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (500 mg, 0.99 mmol). α-naphthol (428 mg. 3.00 mmol) and boron trifluoride diethyletherate (141 mg, 0.99 mmol, 125 μl) in dry dichloromethane (5 ml) was stirred at room temperature under argon for 16 hours. The mixture was worked up as for Stage 1 of Example 1 and purified by flash chromatography on silica gel (eluting with dichloromethane:hexanes, 3:2) to afford the title compound contaminated with α-naphthol. The latter was removed by dissolving the residue in ethyl acetate and washing with 10% aqueous sodium hydroxide solution, which after conventional processing, gave 136 mg, 23% of product as a yellow gum.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=O.P(Cl)(Cl)(Cl)=O.[N+:14]([C:17]1[N:21]([CH3:22])[C:20]([C:23]2[N:27]3[N:28]=[C:29]([NH2:32])[CH:30]=[CH:31][C:26]3=[N:25][N:24]=2)=[N:19][CH:18]=1)([O-:16])=[O:15]>O1CCOCC1>[N+:14]([C:17]1[N:21]([CH3:22])[C:20]([C:23]2[N:27]3[N:28]=[C:29]([N:32]=[CH:1][N:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)[CH:30]=[CH:31][C:26]3=[N:25][N:24]=2)=[N:19][CH:18]=1)([O-:16])=[O:15]
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N)nn12
Reactant: O=CN1CCCCC1
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N=CN3CCCCC3)nn12
Reaction time: 1.5 h

Procedure:
2.85 ml. N-formyl-piperidine in 10 ml. dioxan were stirred with 2.4 ml. phosphorus oxychloride, which was introduced portionwise at 35° - 40° C., for 30 minutes at this temperature, then 1.5 g. crude 3-(5-nitro-1-methyl-2-imidazolyl)-6-amino-s-triazolo[ 4,3-b]pyridazine was added and the reaction mixture was stirred for 1.5 hours at 35° - 40° C. The solution obtained was now poured into 75 ml. ice water, filtered with suction and the clear filtrate was rendered alkaline (about pH 10) with concentrated aqueous ammonia, cooled, left to stand for some time and the resultant crystals (1.28 g.) filtered off with suction and recrystallized from 25 ml. isopropanol, with the addition of charcoal, 0.82 g. of the desired 3-(5-nitro-1-methyl-2-imidazolyl)-6-(1-piperidinyl-methyleneamino)-s-triazolo[ 4,3-b]pyridazine thereby being obtained in the form of yellowish-white crystals which melt at 187° - 189° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([C:14]([OH:16])=O)[O:7][CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:29][O:30][NH:31][CH3:32]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([C:14]([N:31]([CH3:32])[O:30][CH3:29])=[O:16])[O:7][CH2:6][CH2:5]2
Reactant: CNOC
Reactant: COc1cc2c(cc1Br)CCOC2C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COc1cc2c(cc1Br)CCOC2C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-bromo-7-(methyloxy)-3,4-dihydro-1H-isochromene-1-carboxylic acid (5.9 g, 21 mmol) and CDI (4.0 g, 25 mmol) in 60 mL of dry DCM was stirred at r.t. for 0.5 hours and then O,N-dimethyl-hydroxylamine (2.4 g, 25 mmol) was added. The result mixture was stirred overnight. The solvents were removed under vacuum, and the residue was purified by column to give 6-bromo-N-methyl-N,7-bis(methyloxy)-3,4-dihydro-1H-isochromene-1-carboxamide.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[O:25][C:23](=[O:24])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1.[CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:37])[CH3:36])[C:30]=1[N:38]=[C:39]=[O:40])([CH3:28])[CH3:27]>CCOCC>[CH3:28][CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:36])[CH3:37])[C:30]=1[NH:38][C:39]([CH:22]1[CH2:21][CH:20]([C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)[O:25][C:23]1=[O:24])=[O:40])[CH3:27]
Reactant: O=C1CCC(c2ccc(F)cc2)O1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C1CC(c2ccc(F)cc2)OC1=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 71.2 %

Procedure:
To a cooled (-78° C.) solution of diisopropylamine (1.40 g, 0.013 mol) in 90 mL ether, n-BuLi (0.013 mol) was added dropwise followed by 45 mL ether. After stirring for 5 minutes at -78° C. under a nitrogen atmosphere, a solution of γ-(4-fluorophenyl)-γ-butyrolactone (2.50 g, 0.013 mol) in 23 mL ether was added dropwise and the resulting solution was stirred for 20 minutes at -78° C. A solution of 2,6-diisopropylphenyl isocyanate in 23 mL ether was then added dropwise and the reaction mixture was allowed to gradually warm to room temperature and stir for 16 hours under a nitrogen atmosphere (J. F. Wolfe, et al, Synthetic Communications 17, 13 (1987)). The reaction mixture was then quenched with a saturated solution of ammonium chloride and extracted with methylene chloride. The layers were separated and the organic layer was washed two times with water, dried (Na2SO4) and concentrated in vacuo (30° C.) to afford a white residue. The residue was washed with hexane, filtered, and oven-dried (30° C.) to yield a white solid, 3.77 g (0.009 mol, 71.2%) of the title compound, mp 203°-205° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH2:17][C@H:18]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[CH2:19][CH2:20][N:21]2[CH2:24][CH:23]([OH:25])[CH2:22]2)[CH3:16])=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[CH3:41][S:42]([O:25][CH:23]1[CH2:24][N:21]([CH2:20][CH2:19][C@@H:18]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[CH2:17][N:15]([C:13]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:12]=[C:3]([C:1]#[N:2])[CH:4]=2)=[O:14])[CH3:16])[CH2:22]1)(=[O:44])=[O:43]
Reactant: CN(C[C@@H](CCN1CC(O)C1)c1ccc(Cl)c(Cl)c1)C(=O)c1cc(C#N)cc2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C[C@@H](CCN1CC(OS(C)(=O)=O)C1)c1ccc(Cl)c(Cl)c1)C(=O)c1cc(C#N)cc2ccccc12
Reaction time: 1 h
Yield: 91.4 %

Procedure:
3-Cyano-N-[(2S)-2-(3,4-dichlorophenyl)-4-(3-hydroxyazetidin-1-yl)butyl]-N-methyl-1-naphthamide (0.20 g, 0.41 mmol) was dissolved in CH2Cl2 and to the resultant solution was added triethylamine (0.17 mL, 0.41 mmol). The mixture was cooled to 0° C. before careful addition of methanesulfonyl chloride (0.03 mL, 0.41 mmol). The mixture was stirred with cooling for 30 min and then at room temperature for 1 h. The reaction mixture was diluted with CH2Cl2 and then washed with hydrochloric acid (1M), saturated NaHCO3 and then with brine. The organic solution was dried over MgSO4 and the solvent removed by evaporation. There was obtained 0.21 g (92%) of 1-[(3S)-4-[(3-cyano-1-naphthoyl)(methyl)amino]-3-(3,4-dichlorophenyl)butyl]azetidin-3-yl methanesulfonate as a solid. LCMS: m/z 560 (M+)+.
Reaction SMILES: [ClH:1].C(OC([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[C:11]([CH2:20][O:21][CH3:22])([CH3:19])[CH2:10]1)=O)(C)(C)C>CCOC(C)=O>[ClH:1].[Br:18][C:15]1[CH:16]=[C:17]2[C:12]([C:11]([CH2:20][O:21][CH3:22])([CH3:19])[CH2:10][NH:9]2)=[CH:13][CH:14]=1
Reactant: COCC1(C)CN(C(=O)OC(C)(C)C)c2cc(Br)ccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: COCC1(C)CNc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Saturated HCl in EtOAc (10 mL) was added to 6-bromo-3-methoxymethyl-3-methyl-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (300 mg, 0.84 mmol) and the mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo, the solid was washed with Et2O and dried in vacuo to give the title compound (220 mg) as a yellow semi-solid. MS: [M+H]+=256.
Reaction SMILES: CS([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[N:15]([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[N:14]=[C:13]([C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])[CH:12]=2)[CH:6]=1)(=O)=O.[C-:32]#[N:33].[K+]>CN(C)C=O>[C:32]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[N:15]([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[N:14]=[C:13]([C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])[CH:12]=2)[CH:6]=1)#[N:33]
Reactant: COc1ccc(-n2nc(C(=O)N3CCCCC3)cc2-c2cc(S(C)(=O)=O)ccn2)cn1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(C(=O)N3CCCCC3)cc2-c2cc(C#N)ccn2)cn1
Temperature: 120 °C
Reaction time: 37 h
Yield: 83.5 %

Procedure:
To a solution of 1-[5-(4-methanesulfonyl-2-pyridyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]piperidine (0.60 g) obtained in Example 97 in N,N-dimethylformamide (12 mL), potassium cyanide (97.3 mg) was added at room temperature. The mixture was stirred at 120° C. for 37 hours, and then potassium cyanide (97.3 mg) was further added thereto. The mixture was further stirred at 120° C. for 4 hours, and then cooled in air. The reaction mixture was partitioned between saturated brine and ethyl acetate. The organic layer was dried over sodium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (chloroform-ethyl acetate), to thereby give the title compound as a solid (0.441 g, 84%).
Reaction SMILES: B.C1COCC1.[Br:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=O)[CH:21]([F:23])[F:22])[CH2:15]2)=[N:12][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].FC(F)(F)C(O)=O>O1CCCC1.ClCCl>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][CH2:20][CH:21]([F:23])[F:22])[CH2:15]2)=[N:12][CH:13]=1
Reactant: O=C(N[C@H]1CCN(c2ccc(Br)cn2)C1)C(F)F
Agent: B
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: FC(F)CN[C@H]1CCN(c2ccc(Br)cn2)C1
Reaction time: 8 h
Yield: 83.4 %

Procedure:
Add via syringe 1M BH3-THF (78 mL, 78 mmol) to a solution of N—[(S)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-yl]-2,2-difluoro-acetamide (8.3 g, 25 mmol) in tetrahydrofuran (65 mL) and heat the mixture at reflux overnight. Cool the reaction to 0° C. and slowly quench with 5N NaOH until no gas evolution is observed. Concentrate the material in vacuo to remove THF. Dilute the residue with water (150 mL) and extract with CH2Cl2 (3×150 mL). Dry the combined organics over Na2SO4, filter, and concentrate to dryness. Add sodium triacetoxyborohydride (35.4 g, 167 mmol) to the residue in dichloromethane (75 mL). Add dropwise trifluoroacetic acid (150 mL) with vigorous stirring. After 10 min concentrate the mixture in vacuo and dilute with CH2Cl2 (150 mL). Cool the mixture in an ice bath and slowly basify to pH 9 with 5N NaOH. Stir the basic mixture overnight. Dilute the mixture with water (200 mL) and extract with CH2Cl2 (3×150 mL). Dry the combined organics over Na2SO4, filter, and concentrate to dryness. Purify by chromatography to afford 6.38 g (85%) of the title compound. MS/ES m/z (79Br) 306.0 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:46]=[CH:45][C:12]2[NH:13][C:14]([NH:16][C@H:17]([C:38]([O:40]C(C)(C)C)=[O:39])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][C:29](=[O:37])[NH:30][C:31]4[NH:32][CH2:33][CH2:34][CH2:35][N:36]=4)=[CH:21][CH:20]=3)=[N:15][C:11]=2[CH:10]=1.C1(C)C=CC=CC=1>ClCCl>[CH3:8][C:9]1[CH:46]=[CH:45][C:12]2[NH:13][C:14]([NH:16][C@H:17]([C:38]([OH:40])=[O:39])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][C:29](=[O:37])[NH:30][C:31]4[NH:32][CH2:33][CH2:34][CH2:35][N:36]=4)=[CH:21][CH:20]=3)=[N:15][C:11]=2[CH:10]=1
Reactant: Cc1ccc2[nH]c(N[C@@H](Cc3ccc(OCCCC(=O)NC4=NCCCN4)cc3)C(=O)OC(C)(C)C)nc2c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2[nH]c(N[C@@H](Cc3ccc(OCCCC(=O)NC4=NCCCN4)cc3)C(=O)O)nc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.8 %

Procedure:
1 ml of trifluoroacetic acid is added to 20 mg of the ester 4-5b in 3 ml of dichloromethane, followed by agitating for 5 hours at ambient temperature then adding toluene. After evaporating under reduced pressure, taking up in dichloromethane and crystallizing by adding an Et2O/pentane mixture, 15 mg of 4-6b is obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH2:9][S:8][CH2:7]1.Cl.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[ClH:14].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[CH2:9][S:8][CH2:7]3)[CH2:23][CH2:22]2)=[CH:19][CH:20]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=C1CSCN1CCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CSCN1CCCCN1CCN(c2ccc(Cl)cc2)CC1

Procedure:
To a solution of 3-(4-bromobutyl)-4-thiazolidinone (3.0 g) and 1-(4-chlorophenyl)piperazine dihydrochloride (3.4 g) in 100 ml of anhydrous CH3CN were added K2CO3 (8.7 g) and KI (200 mg). The mixture was heated to 80° with stirring under N2.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[NH2:16])=[CH:10]/[C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.C([BH3-])#N.[Na+]>CO>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH2:16])[CH2:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1
Reactant: N/C(=C\c1nccs1)c1ccc(Cl)cc1
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: NC(Cc1nccs1)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 89.5 %

Procedure:
A 2N solution of hydrochloric acid in MeOH at room temperature, was added dropwise to (Z)-1-(4-chlorophenyl)-2-(thiazol-2-yl)ethenamine (Intermediate 94) (1.45 g, 6.13 mmol) and traces of bromocresol green dissolved in MeOH (45 mL) until the solution turned from dark blue to orange. Sodium cyanoborohydride (0.481 g, 7.66 mmol) was added in one portion to the stirred solution and orange color was maintained by adding dropwise the 2N solution of hydrochloric acid in methanol at room temperature. After 1 h stirring, solvent was removed under vacuum. the crude was taken up into water, pH was adjusted around 2 by adding a few drops of the 2N solution of hydrochloric acid in methanol. The aqueous phase was washed with diethyl ether twice then pH was adjusted to 14 by adding a 6N aqueous solution of sodium hydroxide and the basic aqueous phase was extracted with diethyl ether twice. The organic phases were washed with brine dried over magnesium sulphate and concentrated to afford 1-(4-chlorophenyl)-2-(thiazol-2-yl)ethanamine (1.310 g, 90%) as a colorless oil.
Reaction SMILES: [O:1]1[C:6]([C:7](=[N:34][O:35][CH2:36][CH2:37][CH3:38])[C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[C:14]([C:19]([O:21]CC4C=CC([N+]([O-])=O)=CC=4)=[O:20])=[C:15]([Cl:18])[CH2:16][S:17][C@H:12]23)=[O:9])=[CH:5][S:4][CH2:3][CH2:2]1.C(O)(=O)C.O.O1CCCC1>[C].[Pd].CO>[O:1]1[C:6]([C:7](=[N:34][O:35][CH2:36][CH2:37][CH3:38])[C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[C:14]([C:19]([OH:21])=[O:20])=[C:15]([Cl:18])[CH2:16][S:17][C@H:12]23)=[O:9])=[CH:5][S:4][CH2:3][CH2:2]1
Reactant: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)C1=CSCCO1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)C1=CSCCO1
Yield: 43 %

Procedure:
4-Nitrobenzyl 7-[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-propoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 7.0 g.), acetic acid (2 ml.), water (10 ml.), 10% palladium-carbon (3.5 g.). tetrahydrofuran (100 ml.) and methanol (100 ml.) were treated in a similar manner to that of Example 19-(2). The obtained crystals were recrystallized from methylene chloride (20 ml.) to give 7-[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-propoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 2.31 g.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7](=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10].[CH2:16](Br)[CH:17]=[CH2:18]>>[CH2:18]([O:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[CH:7]=[O:15])[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1ccccc1C=O
Yield: 91.1 %

Procedure:
Potassium carbonate (24.0 g, 173.9 mmol), was added to an ethanolic solution containing salicylaldehyde (19.0 g, 155.7 mmol), and allyl bromide (22.0 g, 181.8 mmol). The resulting suspension was heated to reflux overnight. The precipitated inorganic salt was filtered off. The filtrate was evaporated under reduced pressure to give the desired product, 2-allyloxy-benzaldehyde 23.0 g, yield 91%).
Reaction SMILES: Br[CH2:2][C:3]([CH3:16])=[CH:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1.[Na].[CH2:18]([S:22][O-])[CH:19]([CH3:21])[CH3:20]>C1C=CC=CC=1>[CH2:18]([S:22][CH2:2][C:3]([CH3:16])=[CH:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1)[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)CS[O-]
Reactant: CC(=CCOc1ccc2c(c1)OCO2)CBr
Agent: [Na]
Solvent: c1ccccc1
Product: CC(=CCOc1ccc2c(c1)OCO2)CSCC(C)C

Procedure:
A solution of 4.3 g (0.015 mol) of 5-(4-bromo-3-methyl-2-butenyloxy)-1,3-benzodioxol in 50 cc of benzene is added at 25° to 1.7 g (0.015 mol) of sodium-isobutylthio alcoholate in 30 cc of benzene. The mixture is kept at reflux temperature for 13 hours, is subsequently filtered, washed with saturated salt solution and evaporated. The remaining yellow oil is chromatographed with hexane/ethyl acetate 7:1 on silica gel, whereby colourless 5-(4-isobutylthio-3-methyl-2-butenyloxy)-1,3-benzodioxol is obtained. nD20 = 1.5463.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[Li]CCCC.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[CH3:7][C:4]1[N:3]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH2:15][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: C[Si](C)(C)Cl
Reactant: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C[Si](C)(C)C)nc(-n2c(C)ccc2C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 8 (6.0 g, 30 mmol) in THF (100 mL) at 0° C. was added n-BuLi (1.6 M in hexanes, 21 mL, 33 mmol). The solution turned dark red during the addition. After stirring at the same temperature for an additional 2 h, chlorotrimethylsilane (4.2 mL, 33 mmol) was added dropwise to the reaction mixture. The reaction was warmed to room temperature and allowed to stir for an additional 1 h. The resulting bright yellow slurry was partitioned between EtOAc (200 mL) and H2O (100 mL). The organic layer was washed with brine (100 mL), dried over NaSO4, and concentrated. The crude product was purified by flash column chromatography (EtOAc/hexanes, 1:19-1:9) to give 9 (7.7 g, 28.5 mmol, 95%) as a pale yellow oil: 1H NMR (500 MHz, CDCl3) δ 0.10 (s, 9H), 2.13 (s, 6H), 2.39 (s, 3H), 2.41 (s, 3H), 5.89 (s, 2H), 6.78 (s, 1H), 6.85 (s, 1H); 13C NMR (125 MHz, CDCl3) δ−1.5, 13.1, 20.9, 29.8, 106.2, 118.7, 121.9, 128.3, 148.8, 151.5, 161.4; LCQ-MS (M+H+) calcd for C16H25N2Si 273. found 273; LC-TOF-MS (M+H+) calcd for C16H25N2Si 273.17870. found 273.17735.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:11]2([CH2:13][CH2:12]2)[C:10]2(OCC[O:15]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([N:26]1[CH2:32][C:31](=[O:33])[C:28]2([CH2:30][CH2:29]2)[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+]>CO>[CH2:1]([N:8]1[CH2:9][C:10](=[O:15])[C:11]2([CH2:12][CH2:13]2)[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:19]([N:26]1[CH2:32][CH:31]([OH:33])[C:28]2([CH2:29][CH2:30]2)[CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(CN2CC3(CC3)C3(C2)OCCO3)cc1
Agent: O=C1CN(Cc2ccccc2)CC12CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CN(Cc2ccccc2)CC12CC2
Temperature: 25 °C

Procedure:
5-benzyl-5-azaspiro[2.4]heptan-7-one was prepared by similar manner to Example 3, starting from 10-benzyl-5,8-Dioxa-10-azadispiro[2.0.4.3]undecane (A). 5-benzyl-5-azaspiro[2.4]heptan-7-one (100 mg) then was dissolved into Methanol (8 ml) and stirred at RT. NaBH4 (100 mg) was added to the reaction and stirred at RT for 30 minutes. The reaction was evaporated and purified by column chromatography to give 5-benzyl-5-azaspiro[2.4]heptan-7-ol (85 mg) that was mixed with Pd—C (10%, 100 mg) in EtOH (15 ml) and hydrogenated under H2 at 50 psi for 5 hour. The reaction was filtered through Celite and evaporated to give the title compound as an oil. Mass: (M+1), 115
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:13](=O)(=[O:16])([OH:15])[OH:14].OS(O)(=O)=O.O=S(=O)=O.[Na+:27].[Cl-]>>[Na+:27].[CH:7]1([C:1]2[CH:2]=[CH:3][C:4]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:5][CH:6]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: c1ccc(C2CCCCC2)cc1
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Agent: [Cl-]
Agent: [Na+]
Product: O=S(=O)([O-])c1ccc(C2CCCCC2)cc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Cyclohexyl benzene (500 gm, 3.12M) is stirred in a five liter 3-necked flask equipped with a condenser and a thermowatch, and is warmed to 70° C. Sulfuric acid (381 gm, 3.74M) and 30% oleum (38.2 gm) are added dropwise to the stirred reaction at a rate sufficient to maintain a temperature of approximately 70°-75° C. When the addition is complete, the reaction is aged at 70° C. for three hours and then cooled. The resulting reaction mixture, which is deep red in color, then is drowned in two liters of a saturated NaCl solution that is cooled to approximately 5° C. The solid precipitated in the salt solution then is filtered and washed with hexane, following which the precipitate is dried in a vacuum oven at 75° C.