Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S+:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6](O)=[CH:5][CH:4]=1.[CH3:11][O:12][S:13]([O-:16])(=[O:15])=[O:14].[C:17](Cl)(=[O:19])[CH3:18].C(N(CC)CC)C>C(#N)C>[CH3:11][O:12][S:13]([O-:16])(=[O:15])=[O:14].[CH3:1][S+:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([CH2:18][C:17]([OH:19])=[O:12])=[CH:5][CH:4]=1
Reactant: C[S+](C)c1ccc(O)cc1
Reactant: CC(=O)Cl
Agent: COS(=O)(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[S+](C)c1ccc(CC(=O)O)cc1

Procedure:
In 30 ml of acetonitrile was dissolved 2.6 g of p-dimethylsulfoniophenol methylsulfate, and 0.8 ml of acetyl chloride and 1.4 ml of triethylamine were dropwise added thereto. The reaction mixture was filtered to remove the deposited triethylamine hydrochloride. The filtrate was concentrated under reduced pressure and the residue was crystallized by adding ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.CN(C)C=O.S(Cl)([Cl:18])=O.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][Cl:18])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: ClCCc1ccc(Cl)cc1
Temperature: 62.5 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
To a 4-L, jacketed glass reactor containing a solution of 2-(4-chlorophenyl)ethanol (Compound II) (591 g, 3774 mmol) dissolved in toluene (1250 mL) and N,N-dimethylformamide (41.4 g, 566 mmol) at 60° C. was charged thionyl chloride (302 mL, 4151 mmol) over 30 min. The addition was exothermic with significant gas evolution. The reaction mixture was stirred for 1.5 h at 60 to 65° C. Reaction conversion was monitored by HPLC and 1H NMR. When the amount of 2-(4-chlorophenyl)ethanol remaining was <1 area % by HPLC, the reaction mixture was cooled to 20 to 25° C. Water (1000 mL) was charged to the reactor and the mixture was stirred for 15 min. The aqueous layer was removed and the organic phase was washed twice with saturated sodium bicarbonate solution (1000 mL). Evaporation of the organic phase afforded the title compound as a colorless to yellow oil (641 g, 97% yield, 100 area % by HPLC). 1H NMR (400 Hz, CDCl3) δ 3.06 (t, J=7.2 Hz, 2H), 3.72 (t, J=7.2 Hz, 2H), 7.19 (d, J=10 Hz, 2H), 7.32 (d, J=10 Hz, 2H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]([O-:35])([O:11][N:12]1[C:18](=[O:19])[N:17]2[CH2:20][C@H:13]1[CH2:14][CH2:15][C@H:16]2[C:21]1[S:22][C:23]([CH2:26][NH:27]C(OC(C)(C)C)=O)=[N:24][N:25]=1)(=[O:10])=[O:9].[Na+]>C(Cl)Cl.CCOCC>[S:8]([OH:35])([O:11][N:12]1[C:18](=[O:19])[N:17]2[CH2:20][C@H:13]1[CH2:14][CH2:15][C@H:16]2[C:21]1[S:22][C:23]([CH2:26][NH2:27])=[N:24][N:25]=1)(=[O:9])=[O:10]
Reactant: CC(C)(C)OC(=O)NCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)[O-])s1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: NCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)O)s1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 81.8 %

Procedure:
TFA (0.30 mL) was added to a mixture of sodium (2S,5R)-2-(5-(((tert-butoxycarbonyl)amino)methyl)-1,3,4-thiadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl sulfate (50 mg) in dry DCM (0.80 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2-3 hrs and then diluted with ether (˜15 mL). The precipitate was collected via centrifugation, washed with ether (3×) and dried under high vacuum to afford (2S,5R)-2-(5-(aminomethyl)-1,3,4-thiadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate (30 mg) as TFA salt. ESI-MS (EI+, m/z): 336.1. 1H NMR (300 MHz, D2O) δ 4.97 (br d, J=6.2 Hz, 1H), 4.68 (s, 2H), 4.19 (br s, 1H), 3.21 (br d, J=13.5 Hz, 1H), 2.94 (d, J=12.2 Hz, 1H), 2.54-2.49 (m, 1H), 2.30-2.07 (m, 2H), 1.98-1.87 (m, 1H).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH:9]([O:11][CH3:12])=[CH2:10].Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:12][O:11][CH:9]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[CH3:10]
Reactant: Oc1ccccc1O
Reactant: C=COC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(C)Oc1ccccc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
110 parts by weight of pyrocatechol is suspended in 100 parts by weight of toluene. At +5° C., 64 parts by weight of vinylmethyl ether at -40° C. is introduced all at once into the suspension and a drop of concentrated hydrochloric acid is then added. The mixture is heated, with stirring, to about +20° C., whereupon the reaction is initiated and the temperature in the flask rises to about 65° C. If necessary, ice water may be used for external cooling. The mixture is kept for 30 minutes at 65° C. and 5 parts by weight of 2N NaOH is then added. After the mixture has been cooled and dried with Na2SO4 the solvent is evaporated in a rotary evaporator and distillation carried out in vacuo.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][CH3:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.[CH3:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[CH2:7]([C:5]1[S:6][C:2]([C:21]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:16])[CH:22]=2)=[C:3]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:4]=1)[CH3:8]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: CCc1nc(-c2ccc(F)cc2)c(Br)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCc1nc(-c2ccc(F)cc2)c(-c2ccnc(C)c2)s1
Temperature: 90 °C

Procedure:
In a microwave reactor, 100 mg (0.35 mmol) of 5-bromo-2-ethyl-4-(4-fluorophenyl)-1,3-thiazole, 100 mg (0.45 mmol) of 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 1 ml of a 1M caesium carbonate solution and 28.7 mg (0.04 mmol) of [1,1′-bis(diphenylphosphino)-ferrocene/palladium(II) dichloride dichloromethane complex] in 2.5 ml of THF are, under argon, heated at 90° C. for 25 min. The reaction mixture is then filtered, the filter cake is washed with ethyl acetate (3×5 ml) and the combined filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (cyclohexane/ethyl acetate). This gives 35 mg (24%) of the desired product; 1H-NMR(MeCN-d3) δ: 8.34 (d, 1H), 7.47 (m, 3H), 7.12 (s, 1H), 7.07 (m, 2H), 6.99 (d, 1H), 3.03 (q, 2H), 2.42 (s, 3H), 1.38 (t, 3H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.CCCCCC.C(OCC)(=O)C.[C:33]([NH:40][C@H:41]([C@H:49]1[O:53][C:52](=[O:54])[CH2:51][CH2:50]1)[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>C1COCC1>[C:33]([NH:40][C@H:41]([C@H:49]1[O:53][C:52](=[O:54])[C@H:51]([CH2:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH2:50]1)[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccc(C#N)cc2)C(=O)O1

Procedure:
In analogy with Example 1h), 1.5 g of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]dihydrofuran-2-(3H)-one, dissolved in 32 ml of THF, are deprotonated with 9.8 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF, and alkylated with 1.0 g of 4-bromomethylbenzonitrile (Fluka; Buchs/Switzerland) dissolved in 3 ml of THF. Column chromatography (SiO2, hexane/ethyl acetate 1:1) affords the pure title compound: TLC Rf (B)=0.33.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:17]=[C:16]([CH2:18][CH3:19])[S:15][C:10]=2[NH:11][CH2:12][CH2:13][N:14]=1.[N:20]1([CH2:26][CH2:27][NH:28][C:29]([Cl:31])=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>N1C=CC=CC=1>[ClH:1].[ClH:31].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:17]=[C:16]([CH2:18][CH3:19])[S:15][C:10]=2[N:11]([C:29](=[O:30])[NH:28][CH2:27][CH2:26][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:12][CH2:13][N:14]=1
Reactant: CCc1cc2c(s1)NCCN=C2c1ccccc1Cl
Reactant: O=C(Cl)NCCN1CCCCC1
Solvent: c1ccncc1
Product: CCc1cc2c(s1)N(C(=O)NCCN1CCCCC1)CCN=C2c1ccccc1Cl
Product: Cl
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a solution of 5.8 g of 5-o-chlorophenyl-7-ethyl-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine in 50 ml of pyridine is added 4.2 g of 2-piperidinoethylcarbamoyl chloride, and the mixture is stirred for 24 hours at 60° C. Then pyridine is evaporated under reduced pressure, and to the residue is added acetone to crystallize. The crude crystals obtained are recrystallized from ethanol to give 5-o-chlorophenyl-7-ethyl-1-(2-piperidinoethylcarbamoyl)-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine dihydrochloride 1/2hydrate as yellow crystals, melting at 215°-216° C with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.Cl.CN(C)CCCN=C=NCC.O.O[N:28]1[C:32]2C=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=N1>CN(C)C=O>[ClH:1].[NH2:28][C@@H:32]1[CH2:34][CH2:35][CH2:36][C@H:31]1[NH:30][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: N[C@@H]1CCC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 23 h
Yield: 188.6 %

Procedure:
The compound obtained in Referential Example 61 (1.40 g) was dissolved in N,N-dimethylformamide (15 mL), and to the solution were added 5-chloroindole-2-carboxylic acid (1.64 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.68 g), and 1-hydroxybenzotriazole monohydrate (473 mg), followed by stirring at room temperature for 23 hours. The solvent was distilled away under reduced pressure, and to the residue were added methylene chloride and saturated aqueous sodium hydrogencarbonate. The resultant precipitate was collected by filtration, and the precipitate was washed with ethyl acetate, methylene chloride, and methanol. Aside from this, the filtrate was partitioned, and the organic layer was separated, followed by drying over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel flash column chromatography (methylene chloride:methanol=19:1), to thereby give a pale-yellow solid. This pale-yellow solid was combined with the precipitate collected by the above-described filtration, and this mixture was dissolved in methylene chloride (10 mL). Trifluoroacetic acid (10 mL) was added thereto, and the thus-obtained mixture was stirred at room temperature for 3 hours. The solvent was distilled away under reduced pressure, and to the residue were added methylene chloride and 1N aqueous sodium hydroxide. The resultant precipitate was collected by filtration. The organic layer of the filtrate was separated, and was dried over sodium sulfate anhydrate. To the solution was added the precipitate collected by the above-described filtration, and a 4N HCl-dioxane solution (20 mL) was added thereto. The solvent was distilled away under reduced pressure, and after methylene chloride (10 mL) and a 4N HCl-dioxane solution (10 mL) were added to the residue, the solvent was distilled away again under reduced pressure. Ethyl acetate was added to the residue, and the resultant precipitate was collected by filtration, to thereby give the title compound (1.83 g).
Reaction SMILES: [C:1]([CH:4]([C:15](=[O:17])[CH3:16])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2].[Cl-].[Mg+2].[Cl-].N1C=CC=CC=1.[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)#[N:28]>ClCCl>[C:1]([C:4]([C:33](=[O:34])[C:32]1[CH:36]=[CH:37][C:29]([C:27]#[N:28])=[CH:30][CH:31]=1)([C:15](=[O:17])[CH3:16])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCCCC(C(C)=O)C(C)=O
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CCCCCC(C(C)=O)(C(C)=O)C(=O)c1ccc(C#N)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 5740.9 %

Procedure:
To a mixture of ethyl 7-acetyl-8-oxononanoate (4.0 g) and magnesium chloride (1.27 g) in dichloromethane (70 ml) was added pyridine (2.15 ml) at 0° C. The mixture was stirred at 20° C. for 1 hour, then a solution of 4-cyanobenzoyl chloride (2.87 g) in dichloromethane (10 ml) was added. After stirring for 3 hours at 20° C., the mixture was partitioned between ether and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 7-acetyl-7-(4-cyanobenzoyl)-8-oxononanoate (352 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][CH:9]=1)=[O:4].[CH2:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:12]#[CH:13].CCN(CC)CC>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.CC#N>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13]#[C:12][CH2:11][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:8][CH:9]=1)=[O:4]
Reactant: C#CCNS(C)(=O)=O
Reactant: COC(=O)c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccc(C#CCNS(C)(=O)=O)s1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
To a solution of 5-bromo-thiophene-2-carboxylic Acid methyl ester (1.66 g, 8.0 mmol), N-prop-2-ynyl-methanesulfonamide (1.09 g, 8.2 mmol), Et3N (1.7 mL, 12.1 mmol), and CH3CN (30 mL) was added Pd(PPh3)4 (462 mg, 0.4 mmol) followed by Cul (76 mg, 0.4 mmol). The reaction was heated at reflux for 24 h and was cooled to room temperature. The volatiles were removed in vacuo and the residue was purified via flash chromatography (20% EtOAc in hexanes to 33% EtOAc in hexanes) to yield 5-(3-methanesulfonylamino-prop-1-ynyl)-thiophene-2-carboxylic Acid methyl ester as a pale yellow solid (1.1 g). 1H NMR (300 MHz, CDCl3) δ 7.64 (d, 1H), 7.14 (d, 1H), 4.60 (m, 1H), 4.22 (d, 2H), 3.88 (s, 3H), 3.10 (s, 3H); MS 274 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][CH:14]1[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]1.[CH:21]([C:24]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[NH:26][N:25]=1)([CH3:23])[CH3:22]>>[ClH:1].[CH:21]([C:24]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[N:26]([C:2]2[N:11]=[C:10]([NH:20][CH:17]3[CH2:18][CH2:19][CH:14]([CH3:13])[CH2:15][CH2:16]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[N:25]=1)([CH3:23])[CH3:22]
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CC(C)c1cc(C(C)C)[nH]n1
Reactant: CC1CCC(N)CC1
Product: CC1CCC(Nc2nc(-n3nc(C(C)C)cc3C(C)C)nc3ccccc23)CC1
Product: Cl

Procedure:
Was prepared according to Method A from 2,4-dichloroquinazoline, 4-methylcyclohexylamine and 3,5-diisopropylpyrazole. Mp. 134.6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([N:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.Br[CH2:37][CH2:38][OH:39]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([N:23]5[CH2:24][CH2:25][N:26]([CH2:37][CH2:38][OH:39])[CH2:27][CH2:28]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: OCCBr
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1N1CCNCC1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1N1CCN(CCO)CC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[4-(2-hydroxyethyl)piperazin-1-yl]-1,3-thiazolidine-2,4-dione was prepared from ((5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-piperazin-1-yl-1,3-thiazolidine-2,4-dione (Example 351) and 2-bromoethanol following General Procedure S.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1C=CN=C1)=[O:2].[F:13][C:14]([F:32])([F:31])[C:15]1[CH:16]=[C:17]([S:21]([N:24]2[CH2:28][CH2:27][C@H:26]([O:29]N)[CH2:25]2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1.[CH2:33](N(CC)CC)C.C(N)CC>C(Cl)Cl>[CH2:12]([NH:8][C:1]([NH:3][O:29][C@H:26]1[CH2:27][CH2:28][N:24]([S:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:32])([F:31])[F:13])[CH:16]=2)(=[O:23])=[O:22])[CH2:25]1)=[O:2])[CH2:11][CH3:33]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCN(CC)CC
Reactant: NO[C@H]1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)C1
Solvent: ClCCl
Solvent: CCCN
Product: CCCNC(=O)NO[C@H]1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.7 %

Procedure:
1,1′-Carbonyldiimidazole (162 mg, 1.00 mmol) was added to a solution of (S)—O-(1-(3-(trifluoromethyl)phenylsulfonyl)pyrrolidin-3-yl)hydroxyl amine (155 mg, 0.50 mmol) and triethylamine (101 mg, 1.00 mmol) in CH2Cl2 (15 ml) and stirred at room temperature for 24 hours. Propan-1-amine (35.0 mg, 0.60 mmol) was added to the reaction mixture and stirred at room temperature for another 17 hours. The reaction mixture was washed with aqueous 0.1 N HCl solution (15 ml), H2O (20 ml×3) and brine (20 ml), dried over Na2SO4 filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether: 50/50) to give (S)-1-propyl-3-(1-(3-(trifluoromethyl)phenylsulfonyl)pyrrolidin-3-yloxy)urea (120 mg, 61%) as pale yellow oil: LCMS: 396 [M+1]+. 1H NMR (DMSO-d6) δ: 0.76-0.81 (3H, t), 1.34-1.41 (2H, m), 1.77-1.83 (1H, m), 2.01-2.06 (1H, m), 2.90-2.97 (2H, m), 3.16-3.28 (3H, m), 3.50-3.54 (1H, d), 4.22 (1H, s), 6.64-6.68 (1H, t), 7.83-7.89 (1H, t), 8.01 (1H, s), 8.07-8.13 (1H, t), 8.92 (1H, s).
Reaction SMILES: C[Si](NS([O:9][Si:10]([CH3:13])([CH3:12])[CH3:11])(=O)=O)(C)C.[C:14]([NH:22][CH:23]1[C:35](=[O:36])[N:25]2[C:26]([C:32](O)=[O:33])=[C:27]([CH3:31])[CH2:28][S:29](=[O:30])[C@H:24]12)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Br:37]N1C(=O)CCC1=O>ClCCl>[C:14]([NH:22][CH:23]1[C:35](=[O:36])[N:25]2[C:26]([C:32]([O:9][Si:10]([CH3:11])([CH3:12])[CH3:13])=[O:33])=[C:27]([CH2:31][Br:37])[CH2:28][S:29](=[O:30])[C@H:24]12)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)c3ccccc3)[C@H]2S(=O)C1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[Si](C)(C)NS(=O)(=O)O[Si](C)(C)C
Solvent: ClCCl
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)c3ccccc3)C(=O)N12
Temperature: 40 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
207 mg (0.86 mmoles) of trimethylsilyl trimethylsilylamidosulfonate were added to a suspension of 353 mg (1.06 mmoles) of 7-benzamido-3-methyl-3-cephem-4-carboxylic acid-1-oxide in 25 ml of dichloromethane and the mixture was stirred at 40° C. for 3 hours. The colorless translucent suspension was cooled in an ice-bath and bromination was carried out in half an hour using 277 mg of N-bromosuccinimide (1.56 mmoles) as the brominating agent to obtain a 49% yield of trimethylsilyl 7-benzamido-3-bromomethyl-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: [OH:1][C@H:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C@@H:3]([NH:5]C(=O)OC(C)(C)C)[CH3:4].O.C(O)(C(F)(F)F)=O>ClCCl>[NH2:5][C@@H:3]([CH3:4])[C@@H:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[OH:1]
Reactant: COc1cccc([C@@H](O)[C@H](C)NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1cccc([C@@H](O)[C@H](C)N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl [(1S,2R)-2-hydroxy-2-(3-methoxyphenyl)-1-methylethyl]carbamate (317 mg, 1.13 mmol) in dichloromethane (3 ml) was added water (3 ml), and TFA (5 ml), so that a clear solution has been obtained. The mixture was stirred at r.t. for 1 h, than poured into water (30 ml). The aqueous layer was washed with dichloromethane (30 ml), and made alkaline (pH≈10) by addition of 10 N aqueous NaOH. Brine (20 ml) was added, and the solution was extracted with dichloromethane (3×30 ml). The extracts were dried with Na2SO4, and the solvent was removed under reduced pressure to afford the subtitle compound as colourless oil. Yield 179 mg (88%).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8](O)=[O:9])[NH:5][C:4]2[C:11](=[O:19])[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:3]1=2.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1>CN(C)C=O>[O:1]=[C:2]1[CH:7]=[C:6]([C:8]([NH:33][C:34]2[NH:38][N:37]=[N:36][N:35]=2)=[O:9])[NH:5][C:4]2[C:11](=[O:19])[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:3]1=2
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1cc(=O)c2c([nH]1)c(=O)oc1ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nnn[nH]1)c1cc(=O)c2c([nH]1)c(=O)oc1ccccc12
Yield: 46.6 %

Procedure:
A mixture of 1,5-dihydro-1,5-dioxo-4H-1-benzopyrano[3,4-b]pyridine-3-carboxylic acid (2.57 g, 0.01 mole) and 1,1'-carbonyldiimidazole (3.24 g, 0.02 mole) in dimethylformamide (50 ml) is heated at 100 for 60 minutes under nitrogen. The reaction mixture is cooled. 5-aminotetrazole monohydrate (1.03 g, 0.01 mole) is added and the resulting mixture is heated at 100 for 60 minutes, cooled and filtered. The product is recrystallized from dimethylformamide to give white crystals (1.51 g, 39%) mp 265-270. The product crystallizes as a 1:1 salt or complex with 1H-imidazole.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].N1C=CN=C1.[C:10]([Si:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)Cl)([CH3:13])([CH3:12])[CH3:11].[Cl-].[Na+]>CN(C)C=O>[Br:1][CH2:2][CH2:3][O:4][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCBr
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCBr)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
2.50 g (corresponding to 20.0 mmol) of 2-bromoethanol and 2.72 g (corresponding to 40.0 mmol) of imidazole were dissolved in 10 mL of N,N-dimethylformamide (DMF), and cooled to 0° C. Then, 5.50 g (corresponding to 20.0 mmol) of t-butyldiphenylchlorosilane (TBDPSCl) was added thereto. After the reaction mixture was stirred at room temperature for 18 hours, a saturated aqueous sodium chloride solution was added, and extracted three times with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1) to obtain 7.04 g (corresponding to 19.4 mmol) of 1-bromo-2-(t-butyldiphenylsiloxy)ethane (FIG. 7, Step 1).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O1C=CCCC1.C(NCC=C)C=C>C(N(CC)CC)C>[N:3]1[CH:4]=[C:5]2[C:9]([N:8]=[CH:7][NH:6]2)=[N:10][CH:2]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C1=COCCC1
Agent: C=CCNCC=C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: c1ncc2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 203 %

Procedure:
In a 100 ml three-mouth bottle, 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt of paratoluenesulfonic acid (0.2 g) are mixed. The above mixture is stirred and heated to a temperature of 35° C., 2,3-dihydropyrane (12 ml) is added thereto within 5 min. The above mixture is reacted at 50˜60° C. for 3 h. The completion of reaction is checked with TCL analysis. Triethylamine (8 ml) is added to the bottle, and diallylamine (11.4 ml) is added thereto at the temperature within 20 min, the above mixture is reacted at the temperature for 0.5 h. The completion of reaction is checked with TCL analysis. The above mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethyl acetate, and a filtrate is washed with water for 3 times and delaminated. Organic layer is concentrated till large amount of solid is separated out. After filtration, a filter cake is washed with ethyl acetate for 3 times and then dried in vacuum at 50° C. for 5 h to obtain solid purin (12.9 g). The yield is about 73.1%.