Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:6]2.[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH:17]=[CH2:18].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1>[C:21]([O:20][C:16]([CH2:17][CH2:18][N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[C:5]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CCOC(=O)c1cc2c(C)cccc2[nH]1
Reactant: C=CC(=O)OC(C)(C)C
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc2c(C)cccc2n1CCC(=O)OC(C)(C)C
Temperature: 61 °C
Reaction time: 8.5 h
Yield: 87 %

Procedure:
A mixture of ethyl 4-methyl-1H-indole-2-carboxylate (70.0 g, 344 mmol), tert-butyl acrylate (53.0 g, 413 mmol), benzyltrimethylammonium hydroxide (5.76 g, 34.4 mmol) and 1,4-dioxane (1,000 ml) was stirred at 60-62° C. for 8.5 hours. The solvent was distilled off under reduced pressure and water (1,000 ml) and acetic acid (30 ml) were added to the residue, followed by extraction with ethyl acetate (twice). The extract solution was washed with a 5% aqueous sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was crystallized from isopropanol (230 ml) to obtain ethyl 1-(2-tert-butoxycarbonylethyl)-4-methyl-1H-indole-2-carboxylate (99.2 g). M.p. 78-79° C.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=O.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[C:19]([C:21](=[O:23])[CH3:22])[CH:20]=1.[OH-].[K+].Cl>CCO>[ClH:14].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[C:19]([C:21](=[O:23])/[CH:22]=[CH:1]/[C:3]2[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=2)[CH:20]=1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: CC(=O)c1cc(Cl)ccc1N1CCN(C)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCN(c2ccc(Cl)cc2C(=O)/C=C/c2ccc(/C=C/C(=O)O)cc2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 163.5 %

Procedure:
A mixture of 4-formylcinnamic acid (397 mg, 2.25 mmol), 1-[5-chloro-2-(4-methyl-piperazin-1-yl)-phenyl]-ethanone (obtained as described in Preparation 10, 570 mg, 2.25 mmol) and 1.7 M KOH (2.66 ml) in EtOH (25 ml) was stirred at 0° C. for 3 h and then acidified with 10% HCl. The solution was concentrated until formation of a yellow precipitate. The solid was filtered to give 823 mg of (E)-3-(4-{(E)-3-[5-chloro-2-(4-methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH2:25]([NH:29][C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31])[CH:26]([CH3:28])[CH3:27]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:35]4[CH:36]=[CH:37][C:32]([C:30]([NH:29][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:31])=[CH:33][CH:34]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CC(C)CNC(=O)c1ccc(B(O)O)cc1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)CNC(=O)c1ccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(C)C2=O)cc1
Temperature: 120 °C
Yield: 5.1 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-(isobutylcarbamoyl)-phenyl-boronic acid (23 mg, 0.1 mmol). The mixture was heated at 120° C. in a microwave reactor for 30 mins. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 4-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-N-isobutylbenzamide (1.28 mg, 5%). 1H-NMR (MeOD): 0.96 (d, 6H), 1.94 (m, 1H), 2.15 (d, 1H), 2.47 (t, 1H), 3.29 (s, 3H), 3.31 (s, 1H), 3.32 (s, 1H), 5.30 (d, 1H), 7.06 (t, 2H), 7.33 (m, 1H), 7.42 (t, 2H), 7.48 (d, 3H), 7.53 (d, 1H), 7.66 (d, 1H), 7.72 (d, 1H), 7.91 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:20][CH2:19][C@:18]3([CH2:24][CH2:23][NH:22][C:21]3=[O:25])[N:17]2C(OC(C)(C)C)=O)=[CH:12][CH:11]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C@H:16]2[CH2:20][CH2:19][C@:18]3([CH2:24][CH2:23][NH:22][C:21]3=[O:25])[NH:17]2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3F)cc2)CC[C@]12CCNC2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCC[C@]12CC[C@H](c1ccc(OCc3ccccc3F)cc1)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
1,1-Dimethylethyl (2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (D26, 30 mg) was dissolved in dry DCM (1.5 ml). At 0° C. TFA (0.4 ml) was added and the mixture was stirred at room temperature for 1 h. The mixture was evaporated and the residue purified via a SCX cartridge affording the title compound (23 mg) as a yellowish oil. Rt (HPLC) 3.61 min; MS: (ES/+) m/z: 341 [MH+]. C20H21FN2O2 requires 340.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=O)[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([C:25]#[N:26])(C)C>[I-].[Zn+2].[I-].CCOCC>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([C:25]#[N:26])=[CH:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: [I-]
Agent: [Zn+2]
Solvent: CCOCC
Product: N#CC1=CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Reaction time: 15 h
Yield: 44 %

Procedure:
6-Benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one from Preparation 1 above (4.0 g, 14 mmol), trimethylsilyl cyanide (10.0 g, 100 mmol) and Zinc Iodide (0.25 g) were combined and stirred under nitrogen for 15 hours. The reaction mixture was then diluted by addition of 200 mL of Et2O, washed with cold water, and the organic layer was dried (MgSO4) and evaporated under reduced pressure to an oil. The oil was dissolved in 250 mL of toluene, and 0.5 g of paratoluene sulfonic acid was added. The reaction mixture was refluxed for three hours, cooled, and the the solvent was removed under reduced pressure. The crude product was eluted through silica under medium pressure with 5% EtOAc in hexanes to yield 1.8 g (6.1 mmol, 44%) of (racemic) 6-benzenesulfonyl-3,4-dihydro-naphthalene-1-carbonitrile as an oil. MS: 296 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([NH2:19])=[CH:17][C:6]2[CH2:7][CH2:8][CH:9]([NH:12][CH2:13][CH2:14][O:15][CH3:16])[CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[C:38]3[CH2:37][N:36]([S:39]([CH3:42])(=[O:41])=[O:40])[CH2:35][C:34](=[O:43])[NH:33][C:32]=3[CH:31]=[CH:30][C:29]=2[O:44][CH3:45])[C:24]([Cl:46])=[CH:23][N:22]=1>>[Cl:46][C:24]1[C:25]([NH:27][C:28]2[C:38]3[CH2:37][N:36]([S:39]([CH3:42])(=[O:41])=[O:40])[CH2:35][C:34](=[O:43])[NH:33][C:32]=3[CH:31]=[CH:30][C:29]=2[O:44][CH3:45])=[N:26][C:21]([NH:19][C:18]2[C:3]([O:2][CH3:1])=[CH:4][C:5]3[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][O:15][CH3:16])[CH2:8][CH2:7][C:6]=3[CH:17]=2)=[N:22][CH:23]=1
Reactant: COCCNC1CCc2cc(N)c(OC)cc2CC1
Reactant: COc1ccc2c(c1Nc1nc(Cl)ncc1Cl)CN(S(C)(=O)=O)CC(=O)N2
Product: COCCNC1CCc2cc(Nc3ncc(Cl)c(Nc4c(OC)ccc5c4CN(S(C)(=O)=O)CC(=O)N5)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 3-Methoxy-N*7*-(2-methoxy-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine and 6-(2,5-Dichloro-pyrimidin-4-ylamino)-4-methanesulfonyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one in an analogous manner to example 730 (0.017 g, 11%). Mp 110-114° C.; LCMS (m/e) 660 (M); 1H-NMR (DMSO, 400 MHz) δ 10.28 (br, 1H), 8.58 (s, 1H), 8.05 (s, 1H), 7.42 (s, 1H), 7.35 (s, 1H), 7.20-7.14 (q, 2H, J=5.81 Hz), 6.70 (s, 1H), 6.56 (s, 1H), 6.39 (s, 1H), 4.40-4.24 (br, 3H), 3.74 (s, 3H), 3.70 (s, 6H), 3.98-3.45 (q, 3H, J=5.05 Hz), 3.25 (s, 2H), 2.80 (s, 2H), 2.79-2.70 (br, 2H), 2.70-2.57 (br, 2H), 2.35-2.10 (br, 2H), 1.98-1.81 (br, 3H), 1.25-0.90 (br, 4H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[C:22]2[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:21]=2[N:20]=1)[CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:12]([O:11][CH2:10][CH2:9][C@H:8]([NH2:7])[C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[C:22]2[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:21]=2[N:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)c1nc2ccc(F)cc2n1-c1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CCOCc1ccccc1)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [(S)-3-benzyloxy-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)propyl]carbamic acid tert-butyl ester (546 mg, 1.1 mmol) in DCM (10 mL) was added TFA (5 mL) and the mixture was stirred at RT for 1 h. The volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The crude material was used in the following step without further purification. Colourless oil (355 mg, 86%). LCMS (Method B): RT 1.89 min [M+H]+ 377.3.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9](/[CH:15]=[C:16](/[C:21]([O:23][CH3:24])=[O:22])\[CH2:17][C:18]([OH:20])=[O:19])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:25](Cl)(=O)C(Cl)=O>C(Cl)Cl>[CH3:24][O:23][C:21](/[C:16](=[CH:15]/[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1)/[CH2:17][C:18]([O:20][CH3:25])=[O:19])=[O:22]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)/C(=C/c1ccc(OC)c(OC2CCCC2)c1)CC(=O)O
Solvent: ClCCl
Product: COC(=O)C/C(=C\c1ccc(OC)c(OC2CCCC2)c1)C(=O)OC
Temperature: 25 °C

Procedure:
1.67 g (0.005 mol) of (3E)-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-(methoxycarbonyl)-3-butenoic acid are suspended in 8 ml of methylene chloride. 0.36 ml of N,N-DMF (0.005 mol), are added under stirring at room temperature, the solution is cooled to 0° C. and 0.87 ml (0.01 mol) of oxalyl chloride is added.
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=[O:2].[CH2:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH3:13].[H-].[Na+].[C:26]1([CH3:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:12]([N:14]([CH2:32][CH:26]1[CH2:31][CH2:30][C:29](=[O:2])[CH2:28][CH2:27]1)[C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)[CH3:13]
Reactant: Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CCNc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Product: CCN(CC1CCC(=O)CC1)c1ccc([N+](=O)[O-])cc1

Procedure:
In a manner similar to Preparation 23 react 4-(hydroxymethyl)cyclohexanone with p-toluenesulfonyl chloride in pyridine to obtain the tosylate. The tosylate is further reacted with N-ethyl-4-nitrobenzenamine and sodium hydride in toluene as in Preparation 12 to obtain the title compound.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[OH-].[Na+].[CH3:21][C:22]1[S:23][C:24]([SH:27])=[N:25][N:26]=1.Cl>CC(C)=O.O>[CH3:21][C:22]1[S:23][C:24]([S:27][CH2:5][C:6]2[CH2:15][S:14][CH:9]3[N:8]([C:11](=[O:12])[CH:10]3[NH2:13])[C:7]=2[C:16]([OH:18])=[O:17])=[N:25][N:26]=1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cc1nnc(S)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)C3SC2)s1

Procedure:
A mixture of 13.6 g. (0.5 M) of 7-aminocephalosporanic acid (7-ACA) in 100 ml. of water and 50 ml. of acetone are brought to pH 8 with sodium hydroxide while stirring. 9.8 g. (0.57 M) of 2-methyl-1,3,4-thiadiazole-5-thiol are added and the mixture is heated at 80° for four hours. After cooling to 5°, this is acidified to pH 3.5 with dilute hydrochloric acid and stirred for 15 minutes. The precipitated solid is filtered under suction and washed with acetone. This 3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]-methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is purified by dissolving in sodium bicarbonate solution and reprecipitating with 2N hydrochloric acid; yield 12.7 g., m.p. 206°.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][NH:9][C:10](=[O:27])[C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16](=[O:26])[C@@H:17]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH2:18])=[CH:6][CH:5]=1)#[N:3].[CH:30]([NH:33][S:34](Cl)(=[O:36])=[O:35])([CH3:32])[CH3:31]>>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10](=[O:27])[C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16](=[O:26])[C@@H:17]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:18][S:34]([NH:33][CH:30]([CH3:32])[CH3:31])(=[O:36])=[O:35])=[CH:28][CH:29]=1)#[N:3]
Reactant: N#Cc1ccc(CNC(=O)[C@@H]2CCCN2C(=O)[C@H](N)Cc2ccccc2)cc1
Reactant: CC(C)NS(=O)(=O)Cl
Agent: Cl
Product: CC(C)NS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc(C#N)cc1

Procedure:
D-Phenylalanylproline (p-cyanobenzyl)amide hydrochloride was reacted with isopropylaminosulfonyl chloride as in Example 1c.
Reaction SMILES: [OH:1][N:2]1C(=O)C2=CC=CC=C2C1=O.[CH2:13]1[O:17][C:16]2[CH:18]=[C:19]([Cl:24])[C:20]([CH2:22][Cl:23])=[CH:21][C:15]=2[O:14]1>>[ClH:23].[Cl:24][C:19]1[C:20]([CH2:22][O:1][NH2:2])=[CH:21][C:15]2[O:14][CH2:13][O:17][C:16]=2[CH:18]=1
Reactant: ClCc1cc2c(cc1Cl)OCO2
Reactant: O=C1c2ccccc2C(=O)N1O
Product: Cl
Product: NOCc1cc2c(cc1Cl)OCO2

Procedure:
Prepared by a similar procedure as described for preparation 18, starting from N-hydroxyphthalimide and 6-chloropiperonyl chloride (Aldrich). 13C-NMR (DMSO-d6) δ 148.9, 146.5, 126.2, 124.2, 111.1, 109.8, 102.3, 72.7.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].O>CC#N>[O:19]([CH2:18][CH2:17][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(C=O)cc1
Yield: 79.5 %

Procedure:
To a stirred suspension of 4-hydroxybenzaldehyde (0.500 g, 4.012 mmol) and anhydrous potassium carbonate (0.833 g, 6.019 mmol) in dry MeCN (15 ml) at room temperature was added 2-bromo-1-tert-butyldimethylsiloxyethane (83%, 1.730 g, 6.019 mmol), and the reaction mixture was heated under reflux for 20.5 h. Water (25 ml) was added and the reaction mixture was extracted with Et2O (4×25 ml). The combined organic extracts were washed with brine (50 ml), dried (Na2SO4), and the solvent was removed under reduced pressure to give a pale yellow oil that was purified by flash chromatography (3:1 Hexane/Et2O) to give the title compound (0.895 g, 79.5%) as a colourless oil.
Reaction SMILES: [Br:1][C:2]([Br:12])=[CH:3][C@@H:4]1[C@H:6]([C:7](Cl)=[O:8])[C:5]1([CH3:11])[CH3:10].[C:13]1([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH:22]([OH:28])[CH2:23]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1.C1(C)C=CC=CC=1>O>[Br:1][C:2]([Br:12])=[CH:3][C@@H:4]1[C@H:6]([C:7]([O:28][CH:22]2[CH2:21][C:20]3[C:24](=[CH:25][CH:26]=[CH:27][C:19]=3[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:23]2)=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: CC1(C)[C@H](C=C(Br)Br)[C@@H]1C(=O)Cl
Reactant: OC1Cc2cccc(-c3ccccc3)c2C1
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)[C@H](C=C(Br)Br)[C@@H]1C(=O)OC1Cc2cccc(-c3ccccc3)c2C1

Procedure:
In a manner similar to Example 12A, the reaction of 0.51 g (0.0016 mole) of (+)-cis-3-(2,2-dibromoethenyl)-2,2-dimethylcyclopropanecarbonyl chloride (an additional four drops were added 1 hour after original addition) with 0.33 g (0.0016 mole) of (+)-4-phenyl-2-indanol (EE 50%), 0.16 g (0.002 mole) of pyridine and toluene produced an oil. The oil was subjected to vacuum column chromatography, whereby the oil was placed on silica gel packed in a sintered glass suction funnel, and the eluant was drawn through by water aspirator vacuum. Elution was accomplished with hexane, then 24:1 hexane/ethyl acetate to give (+)-4-phenyl-2-indanyl (+)-cis-3-(2,2-dibromoethenyl)-2,2-dimethylcyclopropanecarboxylate as an oil, EE 50% (alcohol moiety). The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [OH-:1].[Na+].Cl.[NH2:4]O.[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH:10]=O>O.C(O)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH:10]=[N:4][OH:1]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: NO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.7 %

Procedure:
A solution of 34.3 g of sodium hydroxide in 50 ml of water was slowly added to a solution prepared by mixing a solution of 47.5 g of hydroxylamine hydrochloride in 60 ml of water with a solution of 100 g of 3,4-dichlorobenzaldehyde in 300 ml of ethanol. The mixture was heated at reflux on a steam bath for half an hour, then stirred at ambient temperature for 16 hours. The separated solid was collected and the filtrate was poured into 600 ml of ice. Carbon dioxide was bubbled into the cold aqueous mixture for 30 minutes and the solid which separated was collected by filtration. The solids were triturated with hot methylene chloride and the methylene chloride removed to give 83.3 g of crude 3,4-dichlorobenzaldoxime which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[Br:19][CH:20]([CH2:24][CH2:25][Br:26])[C:21](Cl)=[O:22]>O1CCCC1.Cl>[Br:19][CH:20]([CH2:24][CH2:25][Br:26])[C:21]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][N:3]=1)=[O:22]
Reactant: Nc1cc(C(F)(F)F)ccn1
Reactant: O=C(Cl)C(Br)CCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cc(C(F)(F)F)ccn1)C(Br)CCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
A solution of 2-amino-4-trifluoromethylpyridine (5.00 g) and triethylamine (3.43 g) in dry tetrahydrofuran (50 ml) was added dropwise, over ten minutes, to a stirred solution of 2,4-dibromobutanoyl chloride (9.51 g) in dry tetrahydrofuran (50 ml), whilst maintaining the temperature below 5° C. The mixture was allowed to stir overnight at room temperature, diluted with hydrochloric acid (1M) and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, using hexane-ethyl acetate (5:1) as eluant, to give the title compound (10.09 g, yellow gum) sufficiently pure for use in Step 2 below. Rechromatographed material had NMR (CDCl3): δ 2.57(1H,m); 2.74(1H,m); 3.62(2H,m); 4.71(1H,dd); 7.33(1H,dd); 8.49(3H,d+s); 8.84(1H,bs). MS: M+ 388.
Reaction SMILES: [C:1](=[N:9][OH:10])([C:3]1[O:4][C:5]([CH3:8])=[CH:6][CH:7]=1)[CH3:2].C(C1[O:15][C:16](C)=CC=1)(=O)C.Cl.[NH2:21]O>C(O)C.N1C=CC=CC=1.O>[OH:10][N:9]([CH:1]([C:3]1[O:4][C:5]([CH3:8])=[CH:6][CH:7]=1)[CH3:2])[C:16]([NH2:21])=[O:15]
Reactant: CC(=NO)c1ccc(C)o1
Reactant: CC(=O)c1ccc(C)o1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1ccc(C(C)N(O)C(N)=O)o1
Temperature: 50 °C

Procedure:
2-Acetyl-5-methylfuran oxime. 2-Acetyl 5-methylfuran (5 g, 40.3 mmole) and hydroxylamine hydrochloride (4.2 g, 60.4 mmole) were dissolved in a mixture of ethanol (20mL) and pyridine (6.5 mL) and heated at 50° C. for 2 hours. The reaction mixture was diluted with water (300 mL) and extracted twice with ethyl acetate. The organic layer was washed with 2N HCl and brine, dried over MgSO4 and concentrated in vacuo to provided 4.31 g of the desired product.
Reaction SMILES: [C:1]([CH2:6][NH:7][CH2:8][CH2:9][N:10]1[C:14]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[N:13][N:12]=[N:11]1)([O:3][CH2:4][CH3:5])=[O:2].[CH2:25](N(CC)CC)C.CI>O1CCCC1>[C:1]([CH2:6][N:7]([CH3:25])[CH2:8][CH2:9][N:10]1[C:14]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[N:13][N:12]=[N:11]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CNCCn1nnnc1SCc1ccc(OC)cc1
Reactant: CCN(CC)CC
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)CN(C)CCn1nnnc1SCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 10 mmol of 1-[2-[[(carbethoxy)methyl]amino]ethyl]-5-[(4-methoxybenzyl)thio]-1H-tetrazole and 10 mmol of triethylamine in 20 ml. of dry tetrahydrofuran is added 10 mmol of methyliodide. After stirring at room temperature for 24 hours, the mixture is filtered. The filtrate is stripped in vacuo to dryness, and the residue is dissolved in chloroform and chromatographed on silica gel eluting with a gradient of ethylacetate in chloroform. Evaporation of the product-containing fractions gives 1-[2-[[(carbethoxy)methyl]methylamino]ethyl]-5-[(4-methoxylbenzyl)thio]-1H-tetrazole. Deblocking with mercuric acetate as above gives 1-[2-[(carboxymethyl)methylamino]ethyl]-1,4-dihydro-5H-tetrazole-5-thione which when substituted in the reaction with 7-D-mandelamidocephalosporanic acid gives 7-D-mandelamido-3-[1-[2-[(carboxymethyl)methylamino]ethyl]-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[C:6]([NH:8][C:9]1[C:10]([CH3:20])=[N:11][NH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13]3[NH:12][N:11]=[C:10]([CH3:20])[C:9]=3[N:8]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: COc1cccc(C(=O)Nc2c(C)n[nH]c2-c2ccccc2)c1
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc(-c2nc3c(C)n[nH]c3c3ccccc23)c1
Temperature: 160 °C
Reaction time: 0.25 h

Procedure:
128 mg of 3-methoxy-N-(3-methyl-5-phenyl-1H-pyrazol-4-yl)benzamide (4) were suspended in 5 ml of xylene and the suspension was boiled at 160° C.; 119 mg of phosphorus pentoxide were then added and the mixture was subsequently stirred at 160° C. for 15 min. 27 μl of phosphorus oxychloride were added dropwise to the suspension, which was then stirred at 160° C. for 12 h; a saturated solution of sodium hydrogen carbonate was then added and the whole was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, concentrated under reduced pressure and purified by means of HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The following was obtained: 3.