Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[NH:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[C:21]1([C:27]2[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][CH2:35]Br)[CH2:31][CH:32]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39]>CN(C)C=O.C(Cl)Cl.C(C(C)=O)C>[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39].[CH3:1][N:2]([CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[CH2:35][CH2:34][CH2:33][N:30]1[CH2:29][CH:28]=[C:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:32][CH2:31]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: BrCCCN1CC=C(c2ccccc2)CC1
Reactant: CN(c1ccccc1)C1NC(=O)c2ccccc21
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CN(c1ccccc1)C1c2ccccc2C(=O)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A solution of 3-(N-methyl-N-phenylamino)-1-isoindolinone (10 g) in anhydrous dimethylformamide (200 cc) is added to a suspension of sodium hydride (as a 50% suspension in oil) (2.2 g) in anhydrous dimethylformamide (200 cc) at a temperature close to 20° C. in the course of 30 minutes and agitation is continued for 1 hour. Then, a solution of 3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)-1-bromopropane (13 g) in dimethylformamide (100 cc) is added in the course of 15 minutes, and agitation is continued for a further 20 hours. The solution obtained is evaporated to dryness under reduced pressure (1 mm Hg; 0.1 kPa). The residue obtained is dissolved in methylene chloride (200 cc) and washed with distilled water (3×50 cc). The organic extracts are dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7.kPa) at 40° C. The residue obtained is dissolved in methylene chloride (40 cc) then poured onto silica (800 g) contained in a column of 8 cm diameter. Elution is carried out with a mixture of methylene chloride and methanol (95-5 by volume). The first 2300 cc are eliminated and the next 1100 cc are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is dissolved in methyl ethyl ketone (50 cc). A solution of oxalic acid (1.1 g) in methyl ethyl ketone (15 cc) is added, and agitation continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration. 5.4 g of 3-(N-methyl-N-phenylamino)-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone oxalate are obtained, melting at 159° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([NH:17][CH2:18][CH3:19])=[O:16].NC1C=[N:25][CH:24]=[C:23]([Cl:27])[N:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:27][C:23]1[N:22]=[C:18]([NH:17][C:15]([C:3]2[N:4]([CH3:14])[S:5](=[O:12])(=[O:13])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:16])[CH:19]=[N:25][CH:24]=1
Reactant: Nc1cncc(Cl)n1
Reactant: CCNC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CN1C(C(=O)Nc2cncc(Cl)n2)=C(O)c2ccccc2S1(=O)=O

Procedure:
This compound was prepared from 4-hydroxy-2-methyl-N-ethyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, 2-amino-6-chloro-pyrazine and p-toluenesulfonic acid analogous to Example 14.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[Al+3].[Cl-].[Cl-].[Cl-].Br[C:15]([CH3:20])([CH3:19])[C:16](Br)=[O:17].Cl>C(Cl)Cl>[OH:9][C:3]1[C:4]([CH3:8])=[C:5]2[C:6](=[CH:7][C:2]=1[CH3:1])[C:16](=[O:17])[CH:15]([CH3:20])[CH2:19]2
Reactant: CC(C)(Br)C(=O)Br
Reactant: Cc1cccc(C)c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc2c(c(C)c1O)CC(C)C2=O
Reaction time: 0.33 h

Procedure:
Solution of 2,6-dimethylphenol (36.65 g, 0.3 mol) in CH2Cl2 (100 ml) was added to well stirred suspension of AlCl3 (120 g, 0.9 mol) in CH2Cl2 (200 ml). After 20 min, 2-bromoisobutyryl bromide (69 g, 0.3 mol) was added. Reaction mixture was stirred for 3 days, poured into HCl/crashed ice, organic phase was separated, water phase was extracted by CH2Cl2 (3×100 ml), combined organic fraction was washed by water, dried over MgSO4, and evaporated. Ether (70 ml) and hexane (70 ml) were added, resulting crystalline precipitate was filtered off and dried in vacuo. The yield 15.8 g (27.7%).
Reaction SMILES: C(C1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH:7]([CH3:13])[CH2:6]2)#N.[C:14]([OH:17])(=[O:16])[CH3:15].Cl>C(O)C>[C:14]([C:15]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH:7]([CH3:13])[CH2:6]2)([OH:17])=[O:16]
Reactant: CC1Cc2cc(C#N)ccc2C1=O
Reactant: CC(=O)O
Agent: Cl
Solvent: CCO
Product: CC1Cc2cc(C(=O)O)ccc2C1=O

Procedure:
A stirred mixture of 5-cyano-2-methylindan-1-one (9.36 g), glacial acetic acid (90 ml) and concentrated hydrochloric acid (90 ml) was heated under reflux for 20 hours to afford 5-carboxy-2-methylindan-1-one, m.p. 189°-194° C. (from aqueous ethanol).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[N:14][CH:13]=[C:12](Cl)[N:11]=1>>[CH2:1]([NH:8][C:12]1[CH:13]=[N:14][CH:15]=[C:10]([Cl:9])[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: NCc1ccccc1
Product: Clc1cncc(NCc2ccccc2)n1
Yield: 97.9 %

Procedure:
In a procedure analogous to example 1, reaction of benzylamine (3.21 g, 30.0 mmol) and 2,6-dichloropyrazine (1.49 g, 10.0 mmol) furnished the product (2.15 g, 98%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH:14]=O)=[CH:4][C:5]2[C:9]([CH3:11])([CH3:10])[O:8][B:7]([OH:12])[C:6]=2[CH:13]=1.[NH2:16][OH:17].Cl.CC([O-])=O.[Na+]>C1COCC1.O>[F:1][C:2]1[C:3]([CH:14]=[N:16][OH:17])=[CH:4][C:5]2[C:9]([CH3:11])([CH3:10])[O:8][B:7]([OH:12])[C:6]=2[CH:13]=1
Reactant: NO
Reactant: CC1(C)OB(O)c2cc(F)c(C=O)cc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OB(O)c2cc(F)c(C=NO)cc21
Reaction time: 2 h

Procedure:
To a solution of 6-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde (200 mg, 0.96 mmol) and NH2OH.HCl (79.5 mg, 1.15 mmol) in THF (4 mL) and H2O (1 mL) at rt was added NaOAc (110 mg, 1.34 mmol). The reaction mixture was stirred for 2 h and diluted with H2O. The mixture was extracted with DCM (60 mL×3) and the organic layer was separated. The organic solution was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give crude compound 6-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime as a light yellow solid. It was used in next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.I[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:7]1([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Ic1ccccc1
Reactant: c1cc[nH]c1
Product: c1ccc(-n2cccc2)cc1

Procedure:
Following General Procedure A (90° C., 30 hours), 1H-pyrrole (104 μL, 1.5 mmol) is coupled with iodo-benzene (112 μL, 1.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: hexanes) to provide 130 mg (91% isolated yield) of the desired product as a white solid.
Reaction SMILES: C(O)C=C.ClCC1C=C(C=CC=1)C(O)=O.[H-].[Na+].[CH3:18][C:19](=C)[CH2:20][O:21][CH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([OH:28])=[O:27]>>[CH2:20]([O:21][CH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([OH:28])=[O:27])[CH:19]=[CH2:18]
Reactant: C=C(C)COCc1cccc(C(=O)O)c1
Agent: O=C(O)c1cccc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C=CCO
Product: C=CCOCc1cccc(C(=O)O)c1

Procedure:
The reaction of allyl alcohol and 3-chloromethyl-benzoic acid in the presence of sodium hydride was performed as described for Compound 37 to give 3-Allyloxymethyl-benzoic acid as colorless oil. 1H-NMR (400 MHz, d6-DMSO): 7.90 (m, 1 arom.H); 7.85 (m, 1 arom.H); 7.55 (m, 1 arom.H); 7.47 (m, 1 arom.H); 5.92 (m, —CH═CH2); 5.30, 5.16 (2 d-like, —CH═CH2); 4.52 (s, —OCH2—C6H4); 4.00 (d-like, CH2═CHCH2O). 13C-NMR (100 MHz, d6-DMSO): 167.24 (—C═O); 138.98; 135.04; 131.77; 130.80; 128.56; 128.34; 128.14; 116.60; 70.70; 70.55.
Reaction SMILES: [CH2:1](Cl)/[CH:2]=[CH:3]\[OH:4].C[OH:7].[OH-].[CH3:9][N+:10]([CH3:19])([CH3:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O.C(O)(=O)C=CC1C=CC=CC=1.C1C=CC=CC=1>[C:3]([O-:4])(=[O:7])[CH:2]=[CH:1][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:9][N+:10]([CH3:19])([CH3:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O/C=C\CCl
Reactant: CO
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C(O)C=Cc1ccccc1
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C([O-])C=Cc1ccccc1

Procedure:
A 6.5 g amount of polyepichlorohydrin was dissolved in 227 ml of dimethylformamide while heated under a nitrogen atmosphere. In addition, 13.6 g of cinnamic acid was dissolved in 177 ml of benzene and then 38.3 g of a 40% methanol solution of trimethylbenzyl ammonium hydroxide was admixed with the solution. Trimethylbenzyl ammonium cinnamate was isolated when the benzene solvent was evaporated in addition to the methanol and the water formed by the neutralization reaction. The product obtained was admixed with the solution of polyepichlorohydrin and the mixture was reacted at 80° C for 6.5 hours. The reaction mixture was mixed with methanol and 12 g of a rubber-like white polymer was obtained. Infrared spectrum analysis and elemental analysis of the product indicated that the polymer was a photosensitive resin having units 1 and 2 wherein the ratio of 1 to 2 was 71% to 29%. ##STR6##
Reaction SMILES: [N:1]1[C:11]2[S:10][C:9]3[CH:12]=[C:13]([CH:16]([CH3:20])[C:17](O)=[O:18])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C1([N:27]=C=NC2CCCCC2)CCCCC1.C(Cl)(Cl)Cl.N>C(OCC)(=O)C.C(O)(=O)C>[N:1]1[C:11]2[S:10][C:9]3[CH:12]=[C:13]([CH:16]([CH3:20])[C:17]([NH2:27])=[O:18])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C(=O)O)c1ccc2c(c1)Sc1ncccc1CC2
Agent: N
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C(N)=O)c1ccc2c(c1)Sc1ncccc1CC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
The mixture of 80 mg of 2-(5,6-dihydro benzo[b]pyrido-[3,2-f]thiepin-9-yl)-propionic acid, 120 mg of dicyclohexylcarbodiimide and 5 ml of chloroform was stirred at 0° C. for 20 minutes under a stream of nitrogen. To this was added dropwise 1 ml of chloroform containing excessive amount of ammonia and the resulting mixture was stirred for 2 hours at 0° C., then at room temperature for 1 hour. To this was added 50 g of ice-water and the mixture was acidified with acetic acid and extracted with chloroform. The extract was washed with water, 5% sodium hydrogencarbonate solution, then water, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the residue, which was dissolved in ethyl acetate and filtered. The filtrate was freed of the solvent to obtain the residue, which was chromatographed over silica gel, eluted with chloroform/ethanol(100/1), and there was obtained 63 mg of 2-(5,6-dihydro benzo[b]pyrido[3,2-f]thiepin-9 -yl)-propionamide as colorless glutinous substance.
Reaction SMILES: ClC1[C:7]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)NN=C3)=CC=CN=1.CC1C=C(B(O)O)C=CC=1.Br[C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[Cl:34][C:33]1[C:28]([C:15]2[CH:14]=[CH:10][CH:9]=[C:8]([CH3:7])[CH:16]=2)=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: Clc1cccnc1Br
Reactant: Clc1ncccc1-c1ccc2[nH]ncc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cccc(-c2ncccc2Cl)c1
Yield: 61 %

Procedure:
3-Chloro-2-(3-methylphenyl)pyridine was synthesized analogous to the reaction conditions used in the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole by heating the mixture of 3-methylphenyl boronic acid (1.76 g, 12.9 mmol), 2-bromo-3-chloropyridine (2.7 g, 14.2 mmol), Pd(PPh3)4 (0.9 g, 0.77 mmol) and 2M aq. Na2CO3 (16 mL, 32 mmol) in 1,4-dioxane (125 mL) under argon atmosphere for 3 h. Upon work-up of the reaction mixture, as discussed in the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole, the crude concentrate was purified by flash silica gel column chromatography [Combiflash® companion System® with RediSep® silica gel column 40 g, 10-30% EtOAC/hexanes eluting solvent gradient upon liquid loading on to column] to obtain 3-chloro-2-(3-methylphenyl)pyridine (1.62 g, 61%) as a clear liquid. 1H NMR (DMSO-d6): δ 8.60 (dd, 1H, J=1.4 and 4.7 Hz), 8.00 (dd, 1H, J=1.4 and 8.2 Hz), 7.44-7.37 (m, 3H), 7.25 (app d, 1H, J=8.2 Hz), 2.36 (s, 3H).LCMS: 97%, MS (m/e) 204.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:44]2([CH3:45])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:43]2[CH2:42][CH2:41][C@@:40]2([CH3:46])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:24]/[CH:25]=[CH:26]\[C:27]([CH2:38][CH3:39])([O:30][Si](CC)(CC)CC)[CH2:28][CH3:29])[CH3:22])[CH2:12][C@@H:11]([O:47][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:44]2([CH3:45])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:43]2[CH2:42][CH2:41][C@@:40]2([CH3:46])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:24]/[CH:25]=[CH:26]\[C:27]([CH2:38][CH3:39])([OH:30])[CH2:28][CH3:29])[CH3:22])[CH2:12][C@@H:11]([OH:47])[CH2:10]1
Reactant: CCC(/C=C\CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(O)(/C=C\CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C)CC
Yield: 94.5 %

Procedure:
By the same procedure as in Example 9, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{(Z)-(4-ethyl-4-triethylsilyloxy-2-hexenyloxy)}pregna-5,7,16-triene (81.3 mg, 0.102 mmol), tetrahydrofuran (3 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) were reacted (heating under reflux for 5.5 hours) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×1, dichloromethane:ethyl acetate:ethanol=20:80:1, developed once) to give the title compound as a pale yellow oil (44.0 mg, 94%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O.C([O-])(=O)C.[NH4+]>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:25]([C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([Cl:21])[CH:23]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1cccc(Cl)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4cccc(Cl)c4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 53.2 %

Procedure:
In a similar fashion to Compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (86.35 mg, 0.2553 mmol), 3-Chlorobenzaldehyde (39.5 mg, 0.281 mmol) and Ammonium acetate (39.4 mg, 0.511 mmol) were reacted to produce 62.33 mg (53%) of the title compound. (300 MHz, DMSO-d6) 3.42 (s, 1H), 8.18 s, 1H), 8.09 (d, J=8 Hz, 1H), 8.05 (s, 1H), 7.76 (s, 1H), 7.62-7.53 (m, 2H), 7.27-7.22 (m, 2H), 6.38 (m, 2H), 5.19 (t, J=17 Hz, 9 Hz, 1H), 2.90 (s, 1H), 2.79 (s, 1H), 2.63 (d, J=8 Hz, 1H), 2.25 (d, J=8 Hz, 1H), 1.40 (d, J=8 Hz, 1H). MS=460 (M+H), HPLC: 2.75 min. (G Method)
Reaction SMILES: [C:1]1([CH2:11][S:12][CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F:24][Sb-:25]([F:30])([F:29])([F:28])([F:27])[F:26].[CH2:31]([O+](CC)CC)[CH3:32]>C(Cl)Cl>[F:24][Sb-:25]([F:30])([F:29])([F:28])([F:27])[F:26].[C:1]1([CH2:11][S+:12]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:31][CH3:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(CSCc3cccc4ccccc34)cccc2c1
Reactant: CC[O+](CC)CC
Agent: F[Sb-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC[S+](Cc1cccc2ccccc12)Cc1cccc2ccccc12
Yield: 98.5 %

Procedure:
5.0 g (15.9 mmol) of bis(1-naphthylmethyl) sulfide and 5.93 g (17.5 mmol) of triethyloxonium hexafluoroantimonate in 30 ml of methylene chloride are reacted according to Example 1(a) to give 9.07 g (98% of theory) of bis(1-naphthylmethyl)ethylsulfonium hexafluoroantimonate in the form of white crystals of melting point 101°-105° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH2:5].[N:13](OCCC(C)C)=O.C(O)(=O)C>C1C=CC=CC=1>[N+:5](=[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:3]([O:2][CH3:1])=[O:12])=[N-:13]
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Reactant: CC(C)CCON=O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COC(=O)CCC(=[N+]=[N-])C(=O)OC

Procedure:
A solution of L-glutamic acid dimethyl ester (2.6 g, 14.8 mmol), isoamyl nitrite (2.13 mL, 15.9 mmol) and acetic acid (0.22 mL) in benzene (150 mL) is heated to reflux for one hour. The solution is washed with IN aqueous sulfuric acid, water, saturated sodium hydrogen carbonate solution, water and brine (50 mL each). The solvent is removed in vacuo to yield dimethyl 2-diazopentane-1,5-dioate which can be further purified by column chromatography.
Reaction SMILES: [CH3:1][NH2:2].Br[CH:4]1[CH2:8][CH2:7][N:6]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:5]1>C(O)C>[CH:9]1([N:6]2[CH2:7][CH2:8][CH:4]([NH:2][CH3:1])[CH2:5]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: BrC1CCN(C2CCCCC2)C1
Reactant: CN
Solvent: CCO
Product: CNC1CCN(C2CCCCC2)C1

Procedure:
A mixture of 40% aqueous methylamine (93 g), ethanol (200 ml) and 3-bromo-1-cyclohexylpyrrolidine (92.8 g, 0.4 mol) was heated to 150° C. in a steel bomb for 20 hr. After cooling, the mixture was concentrated and the residue partitioned between dilute sodium hydroxide and chloroform. The chloroform solution was dried (sodium sulfate), concentrated, and the residue distilled to obtain 40 g (55%), bp 172°-176° C./40 mm. A portion of the distillate was converted to the fumarate salt which was recrystallized from ethanol-water. This was converted back to the free base and distilled, bp 75°-80° C./0.1 mm.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([CH3:13])[C:7](=[O:14])[CH2:6][CH2:5]2.[OH:15][C@:16]1([C:23]2[CH:24]=[C:25]([SH:28])[S:26][CH:27]=2)[CH2:21][CH2:20][O:19][C@@H:18]([CH3:22])[CH2:17]1>>[OH:15][C@:16]1([C:23]2[CH:24]=[C:25]([S:28][C:2]3[CH:3]=[C:4]4[C:9](=[C:10]([CH3:12])[CH:11]=3)[N:8]([CH3:13])[C:7](=[O:14])[CH2:6][CH2:5]4)[S:26][CH:27]=2)[CH2:21][CH2:20][O:19][C@@H:18]([CH3:22])[CH2:17]1
Reactant: C[C@H]1C[C@@](O)(c2csc(S)c2)CCO1
Reactant: Cc1cc(I)cc2c1N(C)C(=O)CC2
Product: Cc1cc(Sc2cc([C@@]3(O)CCO[C@@H](C)C3)cs2)cc2c1N(C)C(=O)CC2
Yield: 60 %

Procedure:
Using an analogous procedure to that described in Example 5, 6-iodo-1,8-dimethyl-1,2,3,4-tetrahydroquinolin-2-one was reacted with (2S,4R)-4-hydroxy-4-(2-mercaptothien-4-yl)-2-methyltetrahydropyran to give (2S,4R)-4-hydroxy-2-methyl-4-[2-(1,8-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)thien-4-yl]tetrahydropyran in 60% yield as a foam;
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][C:9]2[C:19]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14][C:13]=3[CH:12]=[CH:11][C:10]=2[Cl:27])[N:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][C:9]2[C:19]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][C:13]=3[CH:12]=[CH:11][C:10]=2[Cl:27])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3nsc(N)n3)c2CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(SCc2c(Cl)ccc3c2CCNCC3)ns1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
To a solution of 6-(5-amino-[1,2,4]thiadiazol-3-ylthiomethyl)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.186 g, 0.436 mmol) in anhydrous DCM (10 mL) at room temperature add trifluoroacetic acid (10 mL) and stir the solution at room temperature overnight. Concentrate in vacuo and elute the residue through a SCX column (20 g). Dissolve the residue in DCM/methanol, add silica gel (5 g) and concentrate to a powder. Load the powder on to a dry column attached to a RediSep® column (40 g) and purify the crude mixture by preparative liquid chromatography (100:0 to 80:20 DCM/2M ammonia in methanol over 33 min; 80:20 DCM/2M ammonia in methanol over 33 min; 35 mL/min) to afford 6-(5-amino-[1,2,4]thiadiazol-3-ylthiomethyl)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.102 g, 72%). MS (ES+) m/z: 327.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][N:5]=[C:4]1[C:8]1([OH:12])[CH2:11][CH2:10][CH2:9]1.Cl[CH2:14][O:15][CH3:16]>CN(C)C=O>[CH3:14][O:15][CH2:16][O:12][C:8]1([C:4]2[S:3][CH:7]=[CH:6][N:5]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: COCCl
Reactant: OC1(c2nccs2)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOC1(c2nccs2)CCC1
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) suspension of sodium hydride (1.07 g, 44.4 mmol) in N,N-dimethylformamide (50 mL) was added a solution of 1-(thiazol-2-yl)cyclobutanol (Example 1A) (5.3 g, 34.1 mmol) in N,N-dimethylformamide (18 mL). After 0.5 hours, chloro(methoxy)methane (3.89 ml, 51.2 mmol) was added, and the reaction was stirred for 16 hours. The reaction was quenched by the addition of ether and water. The layers were separated, and the aqueous layer was extracted with additional ether. The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 50% ethyl acetate in hexane, to give the title compound. MS ESI(+) m/z 200 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:27](=[O:28])[N:4]2[C:5]([C:24]([O-:26])=[O:25])=[C:6]([CH2:9][N+:10]3[N:11]([CH2:18][CH2:19][CH2:20][O:21]C=O)[C:12]([NH:15]C=O)=[CH:13][CH:14]=3)[CH2:7][S:8][C@H:3]12.CO.[ClH:31]>C(OCC)(=O)C>[ClH:31].[ClH:31].[ClH:31].[NH2:1][C@@H:2]1[C:27](=[O:28])[N:4]2[C:5]([C:24]([O-:26])=[O:25])=[C:6]([CH2:9][N+:10]3[N:11]([CH2:18][CH2:19][CH2:20][OH:21])[C:12]([NH2:15])=[CH:13][CH:14]=3)[CH2:7][S:8][C@H:3]12
Reactant: N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc(NC=O)n3CCCOC=O)CS[C@H]12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cc[n+](CC2=C(C(=O)[O-])N3C(=O)[C@@H](N)[C@H]3SC2)n1CCCO
Temperature: 25 °C

Procedure:
Bis(trifluoroacetic acid salts) of 7β-amino-3-[3-formamido-2-(3-formyloxypropyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (5.30 g) was added to methanol (31.8 ml). Concentrated hydrochloric acid was added dropwise thereto with stirring at room temperature. The mixture was stirred for 3 hours. The reaction mixture was pulverized with ethyl acetate (400 ml) to give 7β-amino-3-[3-amino-2-(3-hydroxypropyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate trihydrochloride.