Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:24]=[C:11]3[N:12]=[C:13]([CH3:23])[C:14]([C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19])=[C:15]([I:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:24]=[C:11]3[N:12]=[C:13]([CH3:23])[C:14]([C@H:17]([OH:22])[C:18]([O:20][CH3:21])=[O:19])=[C:15]([I:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1c(C)nc2cc(-c3cccc(Br)c3)nn2c1I
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3cccc(Br)c3)nn2c1I
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
To a stirred yellow solution of methyl 2-(2-(3-bromophenyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (1.7 g, 3.40 mmol) in anhydrous toluene (100 mL) was added 1.1M (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole/toluene (1.236 mL, 1.360 mmol). The mixture was cooled to −35° C. and a solution of catechoborane/toluene (1.166 mL, 4.76 mmol) was added over 5 min. After 30 min, the reaction mixture was slowly warmed to −15° C. and stirred for additional 2 h. and diluted with EtOAc (600 mL) and sat. Na2CO3 (100 mL). The mixture was stirred vigorously for 30 min, and the organic phase washed with sat Na2CO3 (2×100 mL), dried (Na2SO4), filtered, concentrated and the residue was purified by silica gel chromatography (5-100% EtOAc/hexane) to afford desired (S)-methyl 2-(2-(3-bromophenyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (1 g, 1.992 mmol, 58.6% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ: 8.21 (t, J=1.7 Hz, 1H), 7.96 (dt, J=7.8, 1.2 Hz, 1H), 7.59-7.55 (m, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.09 (s, 1H), 5.78 (s, 1H), 3.87 (s, 3H), 3.54 (br. s., 1H), 2.61 (s, 3H). LCMS (M+H)=504.05.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].[Na].OC1C=CC2C(=CC=CC=2)N=1.Cl.Cl[CH2:39][CH2:40][CH2:41][N:42]([CH3:52])[CH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(O)C>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:39][CH2:40][CH2:41][N:42]([CH3:52])[CH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Reactant: CN(CCCCl)CCCc1ccccc1
Agent: Cl
Agent: Oc1ccc2ccccc2n1
Agent: [Na]
Solvent: CCO
Product: CCCC(=O)c1cnc2c(OCCCN(C)CCCc3ccccc3)cccc2c1Nc1ccccc1C
Yield: 31 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.2 g, 10 mmol) was dried by azeotroping with toluene, then dissolved in dry ethanol (20 ml). Sodium (0.23 g, 10 mmol) was dissolved in ethanol (15 ml), and added to the hydroxyquinoline. The resulting solution was evaporated, and the solid redissolved in toluene (50 ml). 3-chloro-N-methyl-N-(3-phenylpropyl)-1-propylamine hydrochloride (1.5 g, 5.7 mmol) was added and the mixture heated at reflux under nitrogen for 3 hours. Evaporation of the solvent, chromatography (silica gel, 0-3% methanolic ammonia in chloroform) and crystallisation from ether gave 3-butyryl-4-(2-methylphenylamino)-8-(3-(N-methyl-N-(3-phenylpropyl)amino)propoxy)quinoline (0.9 g, 18%), m.p. 79°-81°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[C:5]2=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)(=[O:28])=[O:27].O>CN(C=O)C>[F:17][C:15]1[CH:14]=[CH:13][C:12]([O:18][CH3:19])=[C:11]([C:10]2[C:5]3[C:6](=[N:7][C:2]([NH:35][CH:32]4[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]4)=[N:3][CH:4]=3)[NH:8][N:9]=2)[CH:16]=1
Reactant: COc1ccc(F)cc1-c1n[nH]c2nc(Cl)ncc12
Reactant: CS(=O)(=O)N1CCC(N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1-c1n[nH]c2nc(NC3CCN(S(C)(=O)=O)CC3)ncc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 35.3 %

Procedure:
To a stirred solution of 6-chloro-3-(5-fluoro-2-methoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 24, 97 mg, 0.35 mmol) in DMF (4 mL), sodium bicarbonate (60 mg) and 1-methanesulfonyl-piperidin-4-ylamine (93 mg, 0.52 mmol) were added and the mixture was stirred at 100° C. for 4 hours. The reaction was cooled and the mixture was poured into water (60 mL). The solid was filtered and dried to give a yellow solid, which was purified by reverse phase HPLC to give 52 mg pale yellow solid. Yield, 35%. MS (M+H)+, 421.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].Cl[C@H:6]1[CH2:23][CH2:22][C@@:21]2([CH2:24][OH:25])[C:8](=[CH:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]2=[O:26])[CH2:7]1.[Li].N.C(O)C>O1CCCC1>[C:1]([OH:4])(=[O:3])[CH3:2].[OH:25][CH2:24][C@@:21]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:26])[CH2:14][CH2:13]4)[CH2:10][CH:9]=[C:8]1[CH2:7][CH2:6][CH2:23][CH2:22]2
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](Cl)CC[C@@]43CO)[C@@H]1CCC2=O
Agent: N
Agent: [Li]
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4CCCC[C@@]43CO)[C@@H]1CCC2=O
Reaction time: 2 h

Procedure:
A solution of 3β-chloro-19-hydroxy-5-androsten-17-one acetate in anhydrous tetrahydrofuran is added with stirring to a solution of lithium in liquid ammonia. After approximately two hours of stirring, 95% ethanol is added via dropwise addition. The residue obtained after evaporation of the ammonia is treated with water and ether. The ether extract is washed with water, dried over magnesium sulfate and concentrated under vacuum. The residue which remains is crystallized from an acetone-hexane solution to yield 19-hyroxy-5-androsten-17-one acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=1.[CH2:22]([O:29][CH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:22]([O:29][CH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][N:35]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C@@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=2)[CH2:34][CH2:33]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Reactant: c1ccc(COCCC2CCNCC2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CCC(CCOCc3ccccc3)CC2)c1
Temperature: 99 °C

Procedure:
To a mixture of 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (72 mg, 0.20 mmol) and 4-[2-(benzyloxy)ethyl]piperidine (44 mg, 0.20 mmol) in anhydrous toluene (2.0 mL) were added successively sodium tert-butoxide (29 mg, 0.30 mmol, 1.5 equiv.), tris(dibenzylideneacetone)dipalladium(0) (3.7 mg, 4.0 μmol, 0.02 equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 6.9 mg, 12 μmol, 0.06 equiv.). The mixture was degassed and purged with Ar (3 cycles), then warmed to 98-100° C. for 4 h. After cooling to room temperature, the mixture was diluted with EtOAc and washed with brine. The solution was dried over Na2SO4 and evaporated, and the residue was purified by CC (SiO2, CH2Cl2/EtOAc 4:1 followed by CH2Cl2/MeOH 10:1) to recover first unreacted 3-bromo-5-[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (14 mg) and subsequently 3-[4-[2-(benzyloxy)ethyl]-1-piperidinyl]-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (67 mg, 85%) as a pale yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.91-7.78 (m, 2H), 7.37-7.21 (m, 5H), 6.86-6.68 (m, 1H), 4.51 (s, 2H), 4.15 (m, 2H), 3.93-3.82 (m, 1H), 3.67 (m, 2H), 3.54 (t, 2H, J=6.0 Hz), 3.41 (m, 2H), 2.74 (m, 2H), 2.02-1.83 (m, 4H), 1.80-1.62 (m, 2H), 1.61-1.58 (m, 3H), 1.47 (s, 9H), 1.38-1.26 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[OH-].[Ca+2:27].[OH-]>O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O-:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Ca+2:27].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O-:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
7-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.15 g.) was added to an aqueous solution of calcium hydroxide (0.111 g.) in water (100 ml.), and the solution was stirred at room temperature for 10 minutes. After the solution was filtered, the filtrate was lyophilized to give calcium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 1.2 g.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][C:9](N)=[O:10]>>[C:2]1([NH:1][C:9]([NH:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: NC(N)=O
Product: O=C(Nc1ccccc1)Nc1ccccc1
Reaction time: 0.75 h

Procedure:
After 45 minutes at 160° C., the solution contained 0.050 mole each of methyl N-phenyl carbamate and aniline, representing quantitative urea alcoholysis.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[N:18]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(O)C>CN1C(=O)CCC1>[CH2:27]([O:26][C:24]([N:18]1[CH2:19][CH2:20][N:21]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH2:22][CH2:23]1)=[O:25])[CH3:28]
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cccc(F)c1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)N1CCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 120 °C
Yield: 37.8 %

Procedure:
To a solution of 3-fluoro-1-nitrobenzene (3.37 ml; 31.6 mmol) in NMP (5 ml) was added triethylamine (4.38 ml; 31.6 mmol) and ethyl 1-piperazinecarboxylate (4.63 ml; 31.6 mmol) and the mixture was heated to 120° C. for five days. The cooled mixture was poured into ice-water and a small volume of ethanol was added. Vigorous stirring caused the product to precipitate. The product was filtered off, washed with petroleum ether and dried to leave 6p (3.34 g; 38%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:16]2[CH2:15][CH2:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2].FC(F)(F)C([O-])=O.[Tl+].[I-:30].[K+].C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O.O.C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[C:16]2[CH2:15][CH2:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[C:11](=[O:21])[C:10]=2[C:9]([I:30])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: [I-]
Reactant: CC(=O)OCc1cccc2c1CCc1ccccc1C2=O
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)OCc1ccc(I)c2c1CCc1ccccc1C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4.4 g of (5-oxo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-1-yl)methyl acetate prepared in Example 1-f was dissolved in 30 ml of trifluoroacetic acid, and 5.0 g of thallium trifluoroacetate was added at room temperature in an atmosphere of nitrogen gas. The mixture was stirred at room temperature for 4 hours, followed by stirring at 50° C. for 2 hours. After the starting material disappeared, 3 ml of an aqueous solution of 1.5 g of potassium iodide was added to the reaction mixture and the mixture was stirred at room temperature for 0.5 hour. To the reaction mixture were added ethyl acetate and water, and the mixture was neutralized with sodium hydrogencarbonate and filtered through Celite. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:20), to give 4.1 g of a 3:1 mixture of the title compounds as a colorless oil.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:10][CH:9]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:7])(C)(C)C.Cl>ClCCl.O1CCOCC1>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:9]1[CH2:10][CH:8]1[C:6]([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)C1CC1c1ccccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)C1CC1c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-pyridin-2-yl-cyclopropanecarboxylic acid tert-butyl ester (1.6 g, 7.3 mmol) in dichloromethane (30 mL) was added a solution of anhydrous HCl in dioxane (4.0M, 15 mL). The solution was allowed to stir at ambient temperature overnight then evaporated to yield the product as a yellow oil.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[NH2:20][CH:21]1[CH2:25][CH2:24][O:23][CH2:22]1.C(N(CC)CC)C>CO>[OH:17][CH2:16][C@@H:14]1[C@H:13]([OH:18])[C@H:12]([OH:19])[C@H:11]([N:10]2[CH:9]=[N:8][C:4]3[C:3]2=[N:2][CH:1]=[N:6][C:5]=3[NH:20][CH:21]2[CH2:25][CH2:24][O:23][CH2:22]2)[O:15]1
Reactant: NC1CCOC1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CO
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NC4CCOC4)ncnc32)[C@@H](O)[C@H]1O
Temperature: 80 °C
Yield: 46 %

Procedure:
A mixture of 6-chloropurine riboside (0.5 gm, 1.74 mmol), 3-aminotetrahydrofuran (0.325 gm, 2.6 mmol) and triethylamine (0.73 ml, 5.22 mmol) in methanol (10 ml) was heated to 80° C. for 40 hours. The mixture was cooled and concentrated under reduced pressure. The residue was chromatographed on a short column of silica gel, eluting with methylene chloride/methanol/propylamine (90/10/1). The fractions containing the product were combined and concentrated under reduced pressure. The residue was chromatographed on a chromatotron (2 mm plate, 92.5/7.5/1, methylene chloride/methanol/propylamine). The resulting white solid was recrystallized from methanol/ethyl acetate to give 0.27 gm of (4S,2R,3R,5R)-2-hydroxymethyl-5-[6-(tetrahydrofuran-3-ylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol as white crystals (mp 128° C.-130° C.).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][C:14](=[NH:17])OC)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:18][S:19]([NH2:22])(=[O:21])=[O:20]>CO>[CH3:18][S:19]([NH:22][C:14](=[NH:17])[CH2:13][CH2:12][S:11][CH2:10][C:8]1[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=1)(=[O:21])=[O:20]
Reactant: COC(=N)CCSCc1csc(NC(=N)N)n1
Reactant: CS(N)(=O)=O
Solvent: CO
Product: CS(=O)(=O)NC(=N)CCSCc1csc(NC(=N)N)n1
Reaction time: 48 h
Yield: 92.1 %

Procedure:
In 10.2 ml of methanol were dissolved 1.27 g of methyl 3-[(2-guanidinothiazol-4-yl)methylthio]propionimidate and 0.86 g of methanesulfonamide and after reacting for 48 hours at room temperature, the solvent was distilled off under reduced pressure. Then, the residue formed was purified by a silica gel column chromatography using a mixture of chloroform and methanol (20:1→10:1) to provide 1.44 g amorphous N-methanesulfonyl-3-[(2-guanidinothiazol-4-yl)-methylthio]propionamidine. The product shows the following physicochemical properties:
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])(=[O:16])=[O:15])[CH2:11][NH:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH2:25]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:39][CH2:38][CH:37]2[C:40]([O-])=[O:41])[CH2:32][CH2:31]1)=[O:29])[CH3:26].[Li+]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])(=[O:16])=[O:15])[CH2:11][N:10]2[C:40]([CH:37]2[CH2:38][CH2:39][N:36]2[CH:33]2[CH2:32][CH2:31][N:30]([C:28]([O:27][CH2:25][CH3:26])=[O:29])[CH2:35][CH2:34]2)=[O:41])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: COc1ccccc1S(=O)(=O)[C@H]1CN[C@H](C(=O)NC2(C#N)CC2)C1
Reactant: CCOC(=O)N1CCC(N2CCC2C(=O)[O-])CC1
Agent: [Li+]
Product: CCOC(=O)N1CCC(N2CCC2C(=O)N2C[C@H](S(=O)(=O)c3ccccc3OC)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
The reaction of (2S,4R)-N-(1-cyanocyclopropyl)-4-(2-methoxyphenylsulfonyl)pyrrolidine-2-carboxamide 7C and lithium 1-(1-(ethoxycarbonyl)piperidin-4-yl)azetidine-2-carboxylate 20J carried out according to the general procedure L yielded ethyl 4-(2-((2S,4R)-2-(1-cyanocyclopropylcarbamoyl)-4-(2-methoxyphenylsulfonyl)pyrrolidine-1-carbonyl)azetidin-1-yl)piperidine-1-carboxylate 1:1 epimers as a white solid (76%). MS ISP (m/e): 588.2 (100) [(M+H)]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][CH2:7]O.CN1CCOCC1.CS(Cl)(=O)=O.[CH2:24]([NH2:27])[CH2:25][NH2:26]>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][CH2:7][NH:26][CH2:25][CH2:24][NH2:27]
Reactant: OCCOc1cccc(Br)c1
Reactant: NCCN
Agent: CS(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: NCCNCCOc1cccc(Br)c1

Procedure:
To a magnetically stirred, ambient temperature solution of 2-(3-bromo-phenoxy)-ethanol (3.6 g, 16.7 mmol) and N-methylmorpholine [109-02-4] (2.2 mL, 20.0 mmol) in ethyl acetate (200 mL) was added methanesulfonyl chloride [124-63-0] (1.3 mL, 16.8 mmol). The reaction was stirred over night then washed with brine and the phase separated ethyl acetate extract dried (MgSO4) and added to a stirred ambient temperature solution of ethylenediamine [107-15-3] (33.3 mL, 497.0 mmol) in ethyl acetate (300 mL) from a pressure equalizing addition funnel over the course of 15 minutes. The addition funnel was replaced with a condenser and the reaction refluxed for 4 h then cooled and washed with brine. The ethyl acetate phase was dried (CaSO4) and evaporated to obtain N1-(2-(3-bromophenoxy)ethyl)ethane-1,2-diamine as 4.7 g of clear yellow liquid. LRMS (ESI) m/z 259.1/261.1 [(M+H)]+, calc'd for C10H15BrN2O: 259.15.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:16][CH2:15]2)=[CH:10][C:9]=1[NH2:17])([CH3:4])([CH3:3])[CH3:2].[N:19]1([C:24]2[CH:25]=[C:26]([C:30]3[O:35]C(C)(C)[O:33][C:32](=O)[CH:31]=3)[CH:27]=[CH:28][CH:29]=2)[CH:23]=[CH:22][N:21]=[CH:20]1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:16][CH2:15]2)=[CH:10][C:9]=1[NH:17][C:32](=[O:33])[CH2:31][C:30]([C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH:25]=1)=[O:35])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CC2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(C2CC2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1

Procedure:
Prepared from (2-amino-4-cyclopropyl-phenyl)-carbamic acid tert.-butyl ester (Example G48) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10) according to the general procedure K. Obtained as a light yellow solid (79 mg).
Reaction SMILES: [CH3:1][N:2]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH3:17])=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[OH-].[Na+].O.O.O.O.O.O.[Ni:26](Cl)Cl>O>[CH3:1][N:2]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH3:17])=[CH:12][CH:13]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH3:1][N:2]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH3:17])=[CH:12][CH:13]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[Ni:26]
Reactant: Cl[Ni]Cl
Agent: CCCCc1ccc(N(C)CCC(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: [Ni]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of N-methyl-p-n-butylphenyl-β-alanine (7.85 g., 0.03 mole) in 250 ml of water was added 15 ml. of 2N sodium hydroxide solution. The hazy solution was clarified by filtration, and a solution of nickel chloride hexahydrate (3.58 g., 0.015 mole) in 50 ml of water was added dropwise to the filtrate. The nickel salt precipitated from solution during the addition, and after the addition was completed the mixture was stirred at room temperature for three hours. The precipitated nickel salt was filtered off and washed with water. After drying for 72 hours over P2O5 the salt was dissolved in benzene. The benzene solution was filtered, the filtrate evaporated and the green residue thus obtained heated at 80°-85° at 0.01 mm for 17 hours to give 7 g (90%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O-:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:27]([O:33][CH:34](I)[CH3:35])(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29].[I-].[Na+]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O:20][CH:34]([O:33][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:35])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Reactant: CC(I)OC(=O)C(C)(C)C
Agent: [I-]
Agent: [Na+]
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)OC(=O)C(C)(C)C)=CCS[C@H]12)c1csc(N)n1

Procedure:
In the same manner as Example 1, sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer) was reacted with 1-iodoethyl pivalate in the presence of sodium iodide to give 1-pivaloyloxyethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer), mp 110°-115° C. (decompn.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:11])[O:9]2)=[CH:4][CH:3]=1.[Cl:18][S:19](O)(=[O:21])=[O:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:11])[O:9]2)=[CH:6][C:7]=1[S:19]([Cl:18])(=[O:21])=[O:20]
Reactant: O=C1OC(c2ccc(Cl)cc2)c2ccccc21
Reactant: O=S(=O)(O)Cl
Product: O=C1OC(c2ccc(Cl)c(S(=O)(=O)Cl)c2)c2ccccc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A three-liter, 3-neck flask equipped with a condensor and drying tube, magnetic spin-bar, thermometer and temperature controller was charged with 48.9 grams (0.2 mol) of the 3-(4'-chlorophenyl)phthalide of Example 1 and with chlorosulfonic acid (1467 ml--about 30 ml/gram of reactant). The resulting dark-purple mixture was stirred and heated at about 70° C. for about 21/2 hours. The mixture was subsequently added, dropwise, over a period of about 21/2 hours, to a stirred ice-water mixture in order to decompose the chlorosulfonic acid. 3 Kg of ice were initially present in the mixture, and an additional 9.5 Kg of ice were added during the dropwise addition. The solid precipitate formed was recovered by filtration, dissolved in dichloromethane (1000 ml), the solution dried over Na2SO4, filtered, diluted with hexane and concentrated by distillation until buff-colored crystalline needles began to appear. The crystalline solid was recovered by filtration, washed with hexane and dried. As a result of these operations, the desired title compound having an m.p. of 158°-159° C. was recovered in a yield of about 84%.