Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:14][CH2:13][CH2:12][N:11]([C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O.[CH3:24][N:25](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2]>[C:17]1([C@H:15]([N:11]2[CH2:10][CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([C:24]#[N:25])=[CH:3][CH:4]=3)[O:14][CH2:13][CH2:12]2)[CH3:16])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)C=O
Reactant: C[C@H](c1ccccc1)N1CCOC(c2ccc(Br)cc2)CC1
Agent: [Fe+2]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: C[C@H](c1ccccc1)N1CCOC(c2ccc(C#N)cc2)CC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of diastereopure 7-(4-bromo-phenyl)-4-((R)-1-phenyl-ethyl)-[1,4]oxazepane (diastereomer type A) (2.0 g, 5.6 mmol), zinc(II) cyanide (0.40 g, 3.4 mmol), tris(dibenzylideneacetane)dipalladium (0.46 g, 0.50 mmol), diphenylphosphinoferrocene (0.67 g, 1.2 mmol) and water (0.02 mL, 1.0 mmol) in dimethylformamide (10 mL) was prepared at room temperature under nitrogen atmosphere. The mixture was heated to 120° C. and stirred for 8 hours. After cooling to room temperature, the reaction was quenched by the addition of 2N ammonia aqueous solution and diluted with ethyl acetate. The organic layer was separated and dried over anhydrous sodium sulfate. Concentration of the solution followed by purification of the residue by flash column chromatography on silica gel (hexane/ethyl acetate=90/10 to 60/40 as eluants) was yield 4-[4-((R)-1-phenyl-ethyl)-[1,4]oxazepan-7-yl]-benzonitrile (diastereomer type A) (0.68 g, 2.2 mmol, 40%) as brown oil.
Reaction SMILES: [OH-].[K+].[CH:3]1([O:8][C:9]2[N:14]=[C:13]([C:15]([O:17]C3CCCC3)=[O:16])[CH:12]=[CH:11][C:10]=2[O:23][CH3:24])[CH2:7][CH2:6][CH2:5][CH2:4]1>O.CO>[CH:3]1([O:8][C:9]2[N:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:23][CH3:24])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COc1ccc(C(=O)OC2CCCC2)nc1OC1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)O)nc1OC1CCCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 49.3 %

Procedure:
Potassium hydroxide (1.98 g) in water (12 mL) is added to a solution of cyclopentyl 6-cyclopentyloxy-5-methoxypyridine-2-carboxylate (3.6 g) in methanol (35 mL) and the mixture stirred at room temperature for 2.5 hours. The solution is concentrated to half of the original volume and diluted with water. The solution is acidified to pH 4 with concentrated hydrochloric acid and the product extracted with ethyl acetate. The extracts are dried (MgSO4) and concentrated to give 6-cyclopentyloxy-5-methoxypyridine-2-carboxylic acid (1.38 g) as a yellow solid, m.p. 96-99° C.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[C:33][C:34]3[CH:35]=[CH:36][C:37]([N:40]4[CH2:44][CH2:43][C:42](=O)[CH2:41]4)=[N:38][CH:39]=3)=[N:30][CH:31]=2)=[CH:22][CH:21]=1.[CH3:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[C:33][C:34]3[CH:35]=[CH:36][C:37]([N:40]4[CH2:44][CH2:43][CH:42]([N:50]5[CH2:51][CH2:52][CH:47]([CH3:46])[CH2:48][CH2:49]5)[CH2:41]4)=[N:38][CH:39]=3)=[N:30][CH:31]=2)=[CH:22][CH:21]=1
Reactant: O=C1CCN(c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cn2)C1
Reactant: CC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1CCN(C2CCN(c3ccc(C#Cc4ccc(-c5ccc(Cl)cc5)cn4)cn3)C2)CC1
Reaction time: 8 h

Procedure:
48 mg (0.22 mmol) NaBH(OAc)3 and 27 μL (0.47 mmol) acetic acid are added to a solution of 100 mg (0.19 mmol, 70% purity) 1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-one and 22 μL 4-methylpiperidine (0.19 mmol) in 5 mL THF. The reaction mixture is stirred overnight and combined with saturated NaHCO3 solution. The organic phase is extracted twice with EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. Further purification is carried out by column chromatography using HPLC-MS.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]1[C:24]2[C:16]3[C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[O:19][C:15]=3[C:14](B(O)O)=[CH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[C:2]1([C:14]2[C:15]3[O:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16]=3[C:24]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: OB(O)c1cc2ccccc2c2c1oc1ccccc12
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: CCO
Solvent: Cc1ccccc1
Product: c1ccc(-c2cc3ccccc3c3c2oc2ccccc23)cc1
Yield: 56 %

Procedure:
Into a 200 mL three-neck flask were placed 0.90 g (5.7 mmol) of bromobenzene and 1.5 g (5.7 mol) of benzo[b]naphtho[1,2-d]furan-6-boronic acid, and the air in the flask was replaced with nitrogen. To this mixture were added 20 mL of toluene, 10 mL of ethanol, and 6.0 mL of an aqueous solution of sodium carbonate (2.0 mol/L). While the pressure was reduced, this mixture was stirred to be degassed. To this mixture was added 0.33 g (0.28 mmol) of tetrakis(triphenylphosphine)palladium(0), and the mixture was stirred at 80° C. for 2 hours under a nitrogen stream. After that, the aqueous layer of this mixture was subjected to extraction with toluene, and the obtained solution of the extract and the organic layer were combined and washed with saturated brine. The organic layer was dried with magnesium sulfate, and this mixture was gravity-filtered. An oily substance obtained by concentration of the obtained filtrate was purified by silica gel column chromatography (a developing solvent in which the ratio of hexane to toluene was 19:1) to give a white solid. The obtained solid was recrystallized with a mixed solvent of toluene and hexane, so that 0.95 g of white needle-like crystals of the object of the synthesis were obtained in 56% yield. The reaction scheme is illustrated in (R-1).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)=[O:4].[N+:18]([C:21]1[CH:51]=[CH:50][C:24]([CH2:25][O:26][C:27]([N:29]=[C:30]([NH:36][C:37](=[O:49])[O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)N2C=CC=N2)=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19].C(OCC)(=O)C>O1CCCC1>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][O:26][C:27]([N:29]=[C:30]([NH:36][C:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)=[O:49])[NH:1][CH2:2][C:3]([NH:5][C@H:6]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)=[O:4])=[O:28])=[CH:50][CH:51]=1)([O-:20])=[O:19]
Reactant: O=C(N=C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)n1cccn1)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)CN)C1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)CNC(=NC(=O)OCc2ccc([N+](=O)[O-])cc2)NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (3S)-3-(2-aminoacetylamino)-1-pyrrolidinecarboxylate (3.07 g) in anhydrous tetrahydrofuran (45 ml), a solution of 4-nitrobenzyl [(4-nitrobenzyloxy)carbonylimino-pyrazol-1-ylmethyl]carbamate (5.38 g) in tetrahydrofuran (35 ml) was added under ice cooling, followed by stirring at room temperature for 30 minutes. Ethyl acetate was added to the reaction mixture. The resulting mixture was washed with water, an aqueous solution of potassium hydrogensulfate and saturated saline, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column (ethyl acetate-dichloromethane), whereby the title compound (7.82 g) was obtained as an amorphous substance.
Reaction SMILES: [N:1]1([C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O[CH:21](N(C)C)[N:22]([CH3:24])[CH3:23])(C)(C)C>>[CH3:21][N:22]([CH3:24])[CH:23]=[C:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:8])[C:10]1=[O:15]
Reactant: O=C1CCCCC1C(=O)N1CCOCC1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=C1CCCC(C(=O)N2CCOCC2)C1=O

Procedure:
2-(Morpholine-4-carbonyl)-cyclohexanone (17 mg, 0.08 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (16 mg) as a yellow oil which was used directly in the next step. MS ISP (m/e): 267.5 (100) [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH2:32][C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[C:16]([NH:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:21][CH:20]=2)=[O:17])[C:11](=[O:39])[CH:10]=1.C(O)(C(F)(F)F)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH2:32][C:33]2[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=2)[C:16]([NH:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[O:17])[C:11](=[O:39])[CH:10]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)C(Cc2ccncc2)n2ccc(-c3cc(Cl)ccc3Br)cc2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(NC(=O)C(Cc2ccncc2)n2ccc(-c3cc(Cl)ccc3Br)cc2=O)cc1

Procedure:
734 mg (purity 92%, 1.11 mmol) of tert-butyl 4-({2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]-3-(pyridin-4-yl)propanoyl}amino)benzoate (racemate) (Example 10.2C) were hydrolysed with TFA according to General Method 2. Yield: 126 mg (21% of theory)
Reaction SMILES: [OH:1]O.[NH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5](=[O:15])C1=O.Cl>[OH-].[Na+]>[NH2:3][C:14]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[C:5]([OH:15])=[O:1]
Reactant: OO
Reactant: O=C1Nc2cc3c(cc2C1=O)CCC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc2c(cc1C(=O)O)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
Add 30% aqueous hydrogen peroxide solution (3 mL) to a solution of 1,5,6,7-tetrahydro-1-aza-s-indacene-2,3-dione (2.18 g, 11.66 mmol) in 2 N NaOH (23 mL) over a period of 5 minutes, stir the mixture at room temperature for 3 h. Add 1N hydrochloric acid to pH=5 and extract with ethyl acetate (3×20 mL). Wash with brine, dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure to afford 6-amino-indan-5-carboxylic acid (1.7 g, 86%). Dissolve in ethyl acetate (2 mL) and ethanol (2 mL) and add (trimethylsilyl) diazomethane (9.6 mL, 19.2 mmol, 2 M in hexane) at room temperature and stir the solution for 16 h. Remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with hexanes/ethyl acetate (9:1), to afford the title compound (1.19 g, 66%). 1H NMR (CDCl3, 300 MHz) δ 2.05 (quintuplet, J=7.3 Hz, 2H), 2.80 (q, J=7.7 Hz, 4H), 6.59 (s, 1H), 7.69 (s, 1H). MS (ES+): 192 (M+H).
Reaction SMILES: C[N:2](C)/[CH:3]=[N:4]\[C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[CH3:21])[CH:8]=[CH:7][N:6]=1.N1C=CC=CC=1.N(S(O)(=O)=O)O>CO>[CH3:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:11][C:9]1[CH:8]=[CH:7][N:6]2[N:2]=[CH:3][N:4]=[C:5]2[CH:10]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1Oc1ccnc(/N=C\N(C)C)c1
Agent: O=S(=O)(O)NO
Solvent: CO
Solvent: c1ccncc1
Product: Cc1cc([N+](=O)[O-])ccc1Oc1ccn2ncnc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.1 %

Procedure:
To a cooled (0° C.) solution of (Z)-N,N-dimethyl-N′-(4-(2-methyl-4-nitrophenoxy)pyridin-2-yl)formamidine (1.00 g, 3.33 mmol) in methanol (5 mL) was added pyridine (0.54 mL, 6.66 mmol) and hydroxylamine sulfonic acid (0.427 g, 3.66 mmol). After stirring at room temperature for 2 hours, the precipitate was filtered to provide the product (0.442 g, 49%) as white solid.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[CH3:13][CH:14]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][C:16](OC)=[O:17].C(O)(=O)C>C1COCC1.O>[CH3:13][C@@H:14]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][C:16](=[O:17])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCCCC(C)CC(=O)OC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCCC[C@H](C)CC(=O)CP(=O)(OC)OC
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a solution of dimethyl methylphosphonate (32.5 g, 0.262 mol) in anhydrous THF (480 ml) was dropwise added 1.63N n-butyl lithium (160 ml, 0.261 mol) at -78° C. After stirring for 30 minutes, a solution of methyl l-3-methylheptanoate (16.5 g, 0.104 mol) in anhydrous THF (25 ml) was added dropwise, and the mixture was stirred at -78° C. for one hour and at room temperature for 2 hours. Acetic acid (19 ml) and water (100 ml) were added to the reaction mixture. After distilling off THF, the residue was extracted with ether (500 ml×3). The combined organic layers were washed with brine (250 ml×2), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled under reduced pressure to give dimethyl (4S)-4-methyl-2-oxo-octylphosphonate (23.6 g, 0.094 mol, 90%, b.p.=124°-125° C./0.5 mmHg). The structure was confirmed by the following data.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:31][OH:32].C(N(CC)CC)C>C(O)C>[Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=[N:31][OH:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCCCC2=O)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCCCC2=NO)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C

Procedure:
To a round bottomed flask equipped with magnetic stirrer was added 4-{2,4-bis [tert-butyl(dimethyl)silyloxy]phenyl cyclohexanone (100 mg, 0.23 mmol) and ethanol (5 ml). To the stirred suspension was added hydroxylamine hydrochloride (32 mg, 0.46 mmol) and triethylamine (103 μl, 0.74 mmol), then the solution was heated under reflux temperature for 2.5 hr. The solution was allowed to cool to room temperature then evaporated to dryness in vacuo. The residue was partitioned between ethyl acetate (20 ml) and water (10 ml) and the layers separated. The aqueous layer was extracted with ethyl acetate (3×20 ml) and the combined organic layers washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The title compound was isolated (103 mg, 100%) as a white. δH (CDCl3) 0.19 (6H, s), 0.24 (6H, s), 0.95 (9H, s), 1.02 (9H, s), 1.43-1.62 (2H, m), 1.77-1.87 (1H, m), 1.93-2.04 (2H, m), 2.18-2.24 (1H, m), 2.46-2.53 (1H, m), 3.05-3.15 (1H, m), 3.41-3.50 (1H, m), 6.30 (1H, d), 6.40 (1H, dd), 6.79 (1H, br), 6.92 (1H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C([Li])CCC.[CH3:17][N:18]1C(=O)O[C:21](=[O:22])[C:20]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:19]12.O>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH3:11])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[C:21]([C:20]1[CH:26]=[CH:27][CH:28]=[CH:29][C:19]=1[NH:18][CH3:17])=[O:22]
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Reactant: COc1cc(C)cc(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CNc1ccccc1C(=O)c1c(OC)cc(C)cc1OC
Temperature: -20 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 30 g of 3,5-dimethoxytoluene in 400 ml of tetrahydrofuran are added, at a temperature in the region of -20° C., 129 ml of 1.6M butyllithium in hexane. Once the introduction is complete, the reaction mixture is brought to a temperature of 0° C. and is then stirred for 1 hour. It is cooled to -20° C. and 36.67 g of N-methylisatoic anhydride are added portionwise. The mixture is allowed to return to room temperature and is stirred over 2 hours, followed by addition of 500 ml of water and extraction with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and evaporated under vacuum. The residue is purified by chromatography on silica gel, eluent: toluene/ethyl acetate 9/1. The fractions of pure product are concentrated under vacuum and the residue is crystallized from isopropyl ether, filtered and dried. Beige crystals melting at 215° C. are obtained; Yield=78%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1.[H-].[Na+].[CH3:18]I.O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:18])=[C:4]([C:9]2([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1
Reactant: CI
Reactant: CC1(c2cc(Br)ccc2O)CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Br)cc1C1(C)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
The 4-bromo-2-(1-methylcyclohexyl) phenol (9.26 g, 34.4 mmoles) is dissolved in 50 ml of THF. The solution is cooled to 0° C. and there is added in small fractions sodium hydride (80% in oil, 1.14 g, 37.8 mmoles). The reaction mixture is stirred for 30 minutes at ambient temperature and 5.37 g (37.8 mmoles) of methyl iodide are slowly added. Stirring is continued for 16 hours at which point water (300 ml) is added and the reaction mixture is extracted with ether (3×300 ml). The organic phase is washed with a saturated sodium bicarbonate solution and then with a saturated sodium chloride solution. The reaction mixture is dried on MgSO4, filtered and the solvents are evaporated. The residue is purified by chromatography on a silica column, eluted by a 20/80 mixture of dichloromethane and hexane, yielding 9 g (92% yield) of 4-bromo-2-(1-methylcyclohexyl) anisole in the form of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([F:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[NH:14]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]2[CH:21]=[CH:22][CH:23]=[CH:24][C:15]1=2.C(N(CC)CC)C.O>C(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([F:12])=[C:6]([S:8]([N:14]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]3[CH:21]=[CH:22][CH:23]=[CH:24][C:15]2=3)(=[O:10])=[O:9])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)cc1F
Reactant: c1ccc2c(c1)CCCCN2
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1cc(Br)c(Cl)cc1F)N1CCCCc2ccccc21
Reaction time: 16 h

Procedure:
To a solution of DCM (20 mL) containing 5-bromo-4-chloro-2-fluoro-benzenesulfonyl chloride (2.82 g, 9.2 mmol) was added 2,3,4,5-tetrahydro-1H-benzo[b]azepine (1.35 g, 9.2 mmol) and triethylamine (2.8 mL, 21 mmol). The mixture was stirred for 16 hrs. The mixture was then diluted with 50 mL of DCM and repartioned with 50 mL of water. The organic layer was further washed with water (2×30 mL) and dried over MgSO4. Concentration and purification by silica gel column chromatography eluting with hexane/ethyl acetate (9/1 to 6/1) yielded 1-(5-bromo-4-chloro-2-fluoro-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine as the pale yellow solid (2.70 g). NMR (CDCl3), δ, 8.059 (1H, d, J=7.2 Hz), 7.404 (1H, d, J=9.3 Hz), 7.202-7.218 (2H, q), 7.073-7.129 (1H, m), 7.860 (1H, d, J=7.8 Hz), 3.746 (2H, m), 2.750-2.813 (2H, m), 1.906-1.982 (2H, m), 1.639-1.678 (2H, m).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[CH2:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(O)C>[CH3:11][C:9]1[O:10][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[C:7]=2[CH:8]=1
Reactant: Cc1cc2c(O)cccc2o1
Reactant: CCOC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1ccc(COc2cccc3oc(C)cc23)cc1

Procedure:
4-Hydroxy-2-methylbenzofuran (7.4 g, 0.05 M), ethyl 4-bromomethylbenzoate (12.15 g, 0.05 M), anhydrous potassium carbonate (7.59 g), sodium iodide (0.3 g), and 95% ethanol were reacted together in an analogous manner to that described in example 5(A) to give ethyl 4-(2-methyl-4-benzofuranyloxymethyl)benzoate which was recrystallised from ethanol/water, m.p. 59°-61° C. (Found: C, 73.73; H, 6.03. C19H18O4 requires C, 73.55; H, 5.81%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:52])[C:19]([C:27]3[N:28]=[C:29]([NH:32]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:30][CH:31]=3)=[N:20][O:21][CH2:22][CH2:23][N:24]=[N+:25]=[N-:26])[C:15](=[O:53])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C(NCC)C>C(O)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:52])[C:19]([C:27]3[N:28]=[C:29]([NH2:32])[S:30][CH:31]=3)=[N:20][O:21][CH2:22][CH2:23][N:24]=[N+:25]=[N-:26])[C:15](=[O:53])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN=[N+]=[N-])c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Solvent: CCNCC
Solvent: O=CO
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN=[N+]=[N-])c3csc(N)n3)[C@H]2SC1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1.238 g of the product of Step C and 6 ml of 70% aqueous formic acid was stirred at 50° C. for 15 minutes and was the vacuum filtered to remove triphenylcarbinol. The filtrate was evaporated to dryness under reduced pressure and the residue was taken up in water with efflorescence. The mixture was vacuum filtered and the recovered product was dried to obtain 0.358 g of the syn isomer of 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-(2-azidoethoxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[C:9]1[NH:13][N:12]=[N:11][N:10]=1.[C:14](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH3:14])[N:13]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1cccc(I)c1-c1nnn[nH]1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nnc(-c2c(F)cccc2I)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5-(2-fluoro-6-iodophenyl)-1H-tetrazole (23.48 g, 80.97 mmol), potassium carbonate (16.79 g, 0.121 mol), and iodomethane (16.09 g, 0.113 mol) in 25 mL DMF was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water, and the organic extract was washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 0-10% ethyl acetate in hexanes to provide 5-(2-fluoro-6-iodophenyl)-2-methyl-2H-tetrazole that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 305.06 for M+H+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[N-:12]=[N+:13]=[N-:14].[Na+].O>CO>[N:12]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CCCCCBr
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CCCCCN=[N+]=[N-]
Yield: 103.5 %

Procedure:
A solution of ethyl 6-bromohexanoate (10.0 g, 44.8 mmol), NaN3 (5.83 g, 89.6 mmol) and 25 ml of water in 75 ml of MeOH was refluxed for 3.5 hrs. The MeOH was removed in vacuo and the residue was partitioned between CHCl3 (200 ml) and water (50 ml). The organic layer was separated and washed with water. After drying (Na2SO4) and evaporation of solvent, ethyl 6-azidohexanoate (8.59 g, 100%) was obtained as a colorless oil.