Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][C@H:10]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@@H:12]([CH2:13][CH2:14][C:15]3[C:16]4[C@:22]([CH3:30])([CH2:23][CH2:24][C:25]=32)[C:19](=[CH:20][CH3:21])[CH2:18][CH:17]=4)[C:11]1([CH3:32])[CH3:31])(=O)C1C=CC=CC=1.C([O:41][C@H:42]1[CH2:60][CH2:59][C@@:58]2(C)[C@@H:44](CCC3C4[C@](C)(CCC=32)[C@@H](C=C)CC=4)[C:43]1(C)C)(=O)C1C=CC=CC=1>>[CH3:31][C:11]1([CH3:32])[C@@H:10]([OH:9])[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@H:12]1[CH2:13][CH2:14][C:15]1[C:16]3[C@:22]([CH3:30])([CH2:23][CH2:24][C:25]=12)[C@@H:19]([C@H:20]([O:41][C:42]1[CH:60]=[CH:59][CH:58]=[CH:44][CH:43]=1)[CH3:21])[CH2:18][CH:17]=3
Reactant: C=C[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Reactant: CC=C1CC=C2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Product: C[C@@H](Oc1ccccc1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
—1,1′-(Azodicarbonyl)dipiperidine (5.54 g) was added to an ice-cooled solution of compound 13a (2.0 g), triphenylphosphine (5.76 g), and phenol (2.06 g) in dry THF (10 ml). After 5 min. stirring dry THF (60 ml) was added and the reaction mixture was stirred for 2 h at room temperature. Then it was poured into heptane (100 ml); the resulting mixture was filtered and the filtrate was concentrated under reduced pressure. Column chromatography afforded (3β,5α,20R)4,4-dimethyl-20-phenoxypregna-8,14-dien-3-ol benzoate (compound 14b), together with the elimination products (3β,5α)-4,4-dimethylpregna-8,14,17(20)-trien-3-ol benzoate and (3β,5α)-4,4-dimethylpregna-8,14,20-trien-3-ol benzoate (2.80 g totally). The product was used in the following step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][C:10]2=O)=[CH:5][C:4]=1[CH3:16].[C:17]([Mg]Cl)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:10]1[C:11]2[C:6](=[CH:5][C:4]([CH3:16])=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([CH3:15])([CH3:14])[CH2:8][CH:9]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: COc1cc2c(cc1C)C(C)(C)CCC2=O
Reactant: CC(C)(C)[Mg]Cl
Product: COc1cc2c(cc1C)C(C)(C)CC=C2C(C)(C)C
Yield: 35.3 %

Procedure:
Following General Procedure A, 7-methoxy-4,4,6-trimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 6, 1.5 g, 6.9 mmol) was reacted with a solution of 2M tert-butylmagnesium chloride (12 mL, 23 mmol), and the crude product was purified by flash column (hexane:ethyl acetate=4:1) to give 0.63 g (36%) of the title product as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][C:37]([F:41])([F:40])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[F:41][C:37]1([F:40])[CH2:38][CH2:39][N:34]([S:31]([C:26]2[CH:25]=[CH:30][CH:29]=[CH:28][C:27]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:33])=[O:32])[CH2:35][CH2:36]1
Reactant: O=S(=O)(c1ccccc1Br)N1CCC(F)(F)CC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCC(F)(F)CC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)-4,4-difluoropiperidine. MS (ESI): mass calcd. for C21H19F3N4O2S, 448.12; m/z found, 449.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 8.27 (d, J=1.4, 1H), 8.12 (d, J=8.0, 1H), 7.98 (m, 1H), 7.75-7.67 (m, 1H), 7.63 (m, 1H), 7.43 (d, J=7.6, 1H), 7.32 (d, J=10.6, 2H), 3.02-2.93 (m, 4H), 1.90-1.73 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH2:8][CH2:9][C:10]2[S:11][CH:12]=[C:13]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)[CH2:6][O:5][C:4](=[O:7])[NH:3]1>C(O)C.[Pd]>[CH3:1][C:2]1([CH2:8][CH2:9][C:10]2[S:11][CH:12]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:14]=2)[CH2:6][O:5][C:4](=[O:7])[NH:3]1
Reactant: CC1(CCc2cc(C#CCCCc3ccccc3)cs2)COC(=O)N1
Agent: [Pd]
Solvent: CCO
Product: CC1(CCc2cc(CCCCCc3ccccc3)cs2)COC(=O)N1
Reaction time: 4 h
Yield: 93.6 %

Procedure:
4-Methyl-4-{2-[4-(5-phenylpent-1-ynyl)thiophen-2-yl]}ethyloxazolidin-2-one (174 mg, 0.49 mmol) obtained in Example 25(h) was dissolved in ethanol (9 ml), and 5% palladium-charcoal (90 mg) was added thereto followed by stirring for 4 hours under a hydrogen atmosphere. After the catalyst was filtered out through Celite, the filtrate was evaporated to dryness under reduced pressure. The residue was purified by chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=1:1) to give the title compound (164 mg, 93% yield).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5]([Cl:20])=[CH:6][C:7]2[NH:11][C:10](=[O:12])[N:9]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:8]=2[CH:19]=1.[O:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.[BH3-]C#N.[Na+]>CO>[Cl:20][C:5]1[C:4]([O:3][CH3:2])=[CH:19][C:8]2[N:9]([CH:13]3[CH2:14][CH2:15][N:16]([CH:24]4[CH2:25][CH2:26][O:21][CH2:22][CH2:23]4)[CH2:17][CH2:18]3)[C:10](=[O:12])[NH:11][C:7]=2[CH:6]=1
Reactant: O=C1CCOCC1
Reactant: COc1cc2c(cc1Cl)[nH]c(=O)n2C1CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(cc1Cl)[nH]c(=O)n2C1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Methoxy-5-chloro-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (D50) (30 mg, 0.1 mmol), Ti(iPrO)4 (0.15 ml, 0.5 mmol), and tetrahydro-4H-pyran-4-one (50 mg, 0.5 mmol) were stirred together at room temperature for 1 h; dry methanol (1 ml) followed by NaBH3CN (30 mg, 0.5 mmol) were added and the mixture was stirred at room temperature for 2 h. The crude mixture was then quenched with methanol and it was purified first by SCX column chromatography followed by silica gel chromatography (10% methanol-NH3-dichloromethane) to afford 5-chloro-6-methoxy-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one. Conversion to the hydrochloride gave the title compound, 10 mg, MH+=366 and 368.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[CH2:17][NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.OO.C(=O)([O-])[O-:30].[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[CH2:17][NH:18][CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH2:11])=[O:30])=[CH:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Oc2ccc(CNCCc3ccccc3)c(Cl)c2)cc1
Agent: OO
Agent: [K+]
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3ccccc3)c(Cl)c2)cc1

Procedure:
The compound of step 1 above is subject to hydrolysis using hydrogen peroxide and potassium carbonate. The details of the hydrolysis procedure to form the amide form nitrile have been described exhaustively elsewhere in this document. Electrospray MS M+1 ion=381. 1H-NMR (CDCl3, 200 MHz): 7.92-7.85 (m, 2H), 7.39 (d, 1H, J=8.3 Hz), 7.30-7.12 (m, 5H), 7.06-6.91 (m, 4H), 3.84 (s, 2H), 2.83 (s, 4H).
Reaction SMILES: [O:1]=[C:2]([C:12]([F:15])([F:14])[F:13])[C:3]([F:11])([F:10])[S:4]([O:7]CC)(=[O:6])=[O:5].FC(F)(F)C(O)=O>>[O:1]=[C:2]([C:12]([F:15])([F:13])[F:14])[C:3]([F:10])([F:11])[S:4]([OH:7])(=[O:6])=[O:5]
Reactant: CCOS(=O)(=O)C(F)(F)C(=O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: O=C(C(F)(F)F)C(F)(F)S(=O)(=O)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Ethyl 2-oxopentafluoropropanesulfonate (25.6 g, 0.10 mol) was stirred at 25° C. and treated with trifluoroacetic acid (17.1 g, 0.15 mol). The mixture was allowed to stand overnight, and then it was heated to reflux (60° C. ) in a spinning band still. Fractional distillation of the mixture at a pot temperature below 100° C. gave 2-oxopentafluoropropanesulfonic acid (18.4 g, 0.081 mol, 81%) bp 73° C. (2.6 mm Hg).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18](SC)[N:17]=3)=[CH:14][N:13]=[C:12]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:11]=2)=[CH:5][CH:4]=1.[NH3:31]>O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH2:31])[N:17]=3)=[CH:14][N:13]=[C:12]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:11]=2)=[CH:5][CH:4]=1
Reactant: N
Reactant: COc1ccc(Nc2nc(N3CCCCC3)ncc2-c2nc(C)nc(SC)n2)cn1
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(N3CCCCC3)ncc2-c2nc(C)nc(N)n2)cn1
Temperature: 100 °C
Yield: 88 %

Procedure:
A glass microwave reaction vessel was charged with N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)-2-(piperidin-1-yl)pyrimidin-4-amine (22 mg, 0.052 mmol), ammonia (0.5 mL, 30% in water) and dioxane (2 mL). The reaction mixture was stirred and heated in an oil bath at 100° C. for 23 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with EtOAc to give 4-(4-(6-methoxypyridin-3-ylamino)-2-(piperidin-1-yl)pyrimidin-5-yl)-6-methyl-1,3,5-triazin-2-amine (18 mg, 0.046 mmol, 88% yield). 1H NMR (300 MHz, CDCl3) δ 11.88 (s, 1H); 9.27 (s, 1H); 8.35 (s, 1H); 7.97-8.06 (m, J=8.18, 1.46 Hz, 1H); 6.76 (d, J=8.92 Hz, 1H); 5.21 (s, 2H); 3.95 (s, 3H); 3.83 (s, 4H); 2.48 (s, 3H); 1.57-1.76 (m, 6H). m/z (ESI, +ve ion) 394.1 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[S:18][C:17]3=[CH:19][N:20]=[C:21]([S:22][CH3:23])[N:16]3[CH:15]=2)[CH2:11][C@@H:10]([O:24][Si](C(C)(C)C)(C)C)[CH2:9]1)=[O:7])[CH:3]=[CH2:4].C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(#N)C>[CH2:2]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[S:18][C:17]3=[CH:19][N:20]=[C:21]([S:22][CH3:23])[N:16]3[CH:15]=2)[CH2:11][C@@H:10]([OH:24])[CH2:9]1)=[O:7])[CH:3]=[CH2:4]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1Cc1cn2c(SC)ncc2s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cc1cn2c(SC)ncc2s1
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
Concentrated hydrochloric acid (1.3 ml) is added to a solution of 1.37 g of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-(5-methylthioimidazo[5,1-b]thiazol-2-yl)methylpyrrolidine in 15 ml of acetonitrile under ice cooling, and the mixture is stirred for 30 min. The reaction mixture is neutralized with a saturated sodium hydrogencarbonate solution, and ethyl acetate is added, followed by extraction three times. The extract is washed three times with semi-saturated saline and dried over magnesium sulfate. The solvent is removed by evaporation to give 1.03 g of (3R,5S)-1-allyloxycarbonyl-3-hydroxy-5-(5-methylthioimidazo[5,1-b]thiazol-2-yl)methylpyrrolidine. This compound is dissolved in 18 ml of THF, 1.53 g of triphenylphosphine and 0.92 ml of diethyl azodicarboxylate are added thereto at −17° C., and the mixture is stirred for 30 min. Further, 0.7 ml of thiobenzoic acid is added thereto, and the mixture is stirred at about −20° C. for 40 min. The solvent is removed by evaporation, and the residue is purified by column chromatography on Sephadex LH-20 (dichloromethane:methanol=1:1) to give 1.06 g of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43](Cl)=[O:44])[CH2:39][CH2:38]1.CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[N:17]=[C:16]([NH:18][C:19]4[CH:20]=[C:21]5[C:25](=[CH:26][CH:27]=4)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]5)[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:44])[CH2:39][CH2:38]1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)Nc2cccc(-c3nc(Nc4ccc5c(cnn5C(=O)OC(C)(C)C)c4)c4ccccc4n3)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.22 mmol) and 4-methylpiperazine-1-carbonyl chloride hydrochloride (88 mg, 0.44 mmol) in CH2Cl2 (2 mL) was added Et3N (92 μL, 0.66 mmol) and catalytic amount of DMAP. The reaction mixture was stirred at RT for 2 h after which 2 equivalents each of 4-methylpiperazine-1-carbonyl chloride hydrochloride and 3 equivalents of Et3N were added. Continued to stir at ambient temperature for 16 hours. The reaction was concentrated in vacuo and the residue was purified by flash chromatography on silica (8:1 CH2Cl2:MeOH). The product tert-butyl 5-(2-(3-(1-methylpiperazine-4-carboxamido)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate was isolated. (160 mg, 100%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[CH:5]=[CH:6][CH:7]=1.Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(Br)c2)C(OCc2ccc3ccccc3c2)C1
Agent: Cl
Solvent: CO
Product: Brc1cccc(C2CCNCC2OCc2ccc3ccccc3c2)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 90.8 %

Procedure:
A solution of 173 mg (0.35 mmol) of tert-butyl (3RS,4RS)-4-(3-bromophenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in 6 ml of methanol was treated with 6 ml of a 2 N solution of hydrogen chloride in MeOH and stirred at 50° C. for 4 hours. Subsequently, the mixture was partitioned between ethyl acetate and a 5% sodium hydrogen carbonate solution, the organic phase was dried over magnesium sulphate and finally the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel with a 10:1:0.1 mixture of methylene chloride, MeOH and 25% ammonia and the eluent. There were obtained 126 mg (91% of theory) of (3RS,4RS)-4-(3-bromophenyl)-3-(naphthalen-2-ylmethoxy)-piperidine as a light yellow oil. MS: 396, 398 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.I[CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:10][CH3:11])=[CH:6][N:7]=1
Reactant: Oc1ccc(Br)nc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(Br)nc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 6-bromopyridin-3-ol (7.58 g), iodoethane (5.23 mL), potassium carbonate (9.03 g), and DMF (80 mL) was stirred at 60° C. for 3 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (7.58 g) as a pale yellow solid.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C@@H:9]([CH2:23][CH2:24][C:25]([NH:27][CH2:28][NH:29][S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])=[NH:26])[C:8]1=[O:40])=[O:5])C.[Li+].[OH-]>C1COCC1>[CH2:16]([O:15][C:13]([N:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:4]([OH:5])=[O:3])[C:8](=[O:40])[C@@H:9]1[CH2:23][CH2:24][C:25]([NH:27][CH2:28][NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)(=[O:32])=[O:31])=[NH:26])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)CN1CCN(C(=O)OCc2ccccc2)[C@@H](CCC(=N)NCNS(=O)(=O)c2ccc(C)cc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NCNC(=N)CC[C@H]2C(=O)N(CC(=O)O)CCN2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 85.3 %

Procedure:
A solution of the compound of Example 11 (185 mg, 0.32 mmol) in THF (2 mL) was treated with 2 N LiOH (0.32 mL, 0.64 mmol). The mixture was stirred at room temperature for two and one-half hours. The organic solvent was evaporated in vacuo. The aqueous layer was extracted with EtOAc to remove organic impurities and acidified to pH 2-3 with 2N aq HCl at 0° C. The acidified aqueous layer was extracted with EtOAc and the organic layer was dried over Na2SO4 and evaporated to give the title compound as a white solid (149 mg).
Reaction SMILES: [NH2:1][CH:2]1[C:16](=[O:17])[N:4]2[C:5]([C:13]([OH:15])=[O:14])=[C:6]([CH2:9][N:10]=[N+:11]=[N-:12])[CH2:7][S:8][C@H:3]12.[C:18](=[O:21])(O)[O-:19].[Na+]>O.C(O)(C)(C)C>[N:10]([CH2:9][C:6]1[CH2:7][S:8][C@@H:3]2[CH:2]([NH:1][C:18]([O:19][C:6]([CH3:9])([CH3:7])[CH3:5])=[O:21])[C:16](=[O:17])[N:4]2[C:5]=1[C:13]([OH:15])=[O:14])=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]12
Temperature: 25 °C
Reaction time: 72 h
Yield: 71 %

Procedure:
7-Amino-3-azidomethylceph-3-em-4-carboxylic acid (170 g.) was suspended by stirring in water (750 ml.) and sodium bicarbonate (60 g.) added carefully, followed by t-butanol (750 ml.). Bis(O-t-butyl)carbonic anhydride (170 ml.) dissolved in t-butanol (375 ml.) was added and the mixture left to stir at ambient temperature; further portions of reagent (20 ml.) in t-butanol (40 ml.) were added after 24 and 48 hours. After 72 hours, t-butanol was removed by evaporation and the aqueous residue, diluted with water to 21°, was cooled in ice. The pH was reduced to 3 with concentrated hydrochloric acid, and the precipitate filtered, and washed free of acid. After drying under vacuum, the crude product was extracted successively with 500 ml. and two 400 ml. portions of acetonitrile. The combined extracts were evaporated to a small volume and filtered to give 3-azidomethyl-7-t-butoxycarbonylaminoceph-3-em-4-carboxylic acid (84 g.), having the following n.m.r. in solvent A: 1.4(s, 9 H); 3.5(d, 2H); 4.2(d, 2H); 5.0(d, 1H); 5.4(d, 1H).
Reaction SMILES: C1(CO[CH:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)=[CH:21][CH:20]=2)[CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)C=CC=CC=1.[C:37]([OH:41])(=[O:40])[CH2:38][SH:39].B(F)(F)F.O(CC)CC>C(Cl)Cl>[C:13]1([CH2:12][O:11][CH2:10][CH:9]([S:39][CH2:38][C:37]([OH:41])=[O:40])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)=[CH:21][CH:20]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(COCC(OCc2ccccc2)c2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Reactant: O=C(O)CS
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)CSC(COCc1ccccc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of the ether (151 mg) (Step 2) and thioglycolic acid (31 μL) in CH2Cl2 at 0° C. was added BF3 /OEt2 (117 μL) dropwise. The mixture was stirred at 0° C. for 1 h and poured onto 25% aqueous NH4OAc, extracted with CH2Cl2 and the organic phase was dried and evaporated. Chromatography on silica gel using ethyl acetate/hexane containing 0.1% AcOH afforded the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[S:12][C:11]([CH2:13][CH3:14])=[N:10][N:6]2[C:7](=[O:9])[CH:8]=1.[I-].[Na+].C(=O)(O)[O-:18].[Na+].O>CS(C)=O>[CH2:13]([C:11]1[S:12][C:5]2=[N:4][C:3]([CH2:2][OH:18])=[CH:8][C:7](=[O:9])[N:6]2[N:10]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: CCc1nn2c(=O)cc(CCl)nc2s1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCc1nn2c(=O)cc(CO)nc2s1
Temperature: 80 °C
Yield: 40.1 %

Procedure:
A mixture of 7-Chloromethyl-2-ethyl-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (11.48 g, 50 mmol), sodium iodide (15 g, 100 mmol, 2 equiv), sodium bicarbonate (12.6 g, 150 mmol, 3 equiv), water (25 mL) and DMSO (250 mL) was stirred and heated at 80° C. for 18 h. The volatiles were mostly removed on the rotary evaporator, then the residue treated with ethyl acetate to precipitate the salts, and the mixture filtered. The filtrate was lyophilized and chromatographed on silica gel using a gradient of ethyl acetate to 3% methanol in ethyl acetate, affording 2-ethyl-7-hydroxymethyl-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (4.24 g, 40%). This alcohol was dissolved in acetone (150 mL) and refluxed for 3 days with a total of 15 equivalents of MnO2, added in 3-equiv portions over this time, affording complete conversion to the corresponding aldehyde. The reaction mixture was filtered through celite, the cake washed with acetone (3×100 mL), and the filtrate concentrated in vacuo, affording the title product (2.84 g, 67%). 1H NMR (300 MHz, CDCl3): δ 1.55 (t, 3H), 3.10 (q, 2H), 6.98 (s, 1H), 9.90 (s, 1H). MS (APCI) calcd for C8H7ClN3O2S: 209.03, found (M+H+): 210.2.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:13]=[CH:14][N:15]=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24][CH2:23]3)[C:17]=2[N+:18]([O-:20])=[O:19])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: CC(C)(C)C(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)CN1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Temperature: 80 °C
Yield: 25.4 %

Procedure:
Compound A2 (0.12 mmol, 50 mg), and 1-bromo-3,3-dimethyl-butan-2-one (0.12 mmol, 16 μL) were dissolved in DMF (1 mL) and triethylamine (0.36 mmol, 50 μL). The reaction was heated in a microwave at 80° C. for 4 minutes. The mixture was quenched with water and extracted with ethyl acetate. Removal of organic solvent in vacuo and purification by HPLC provided Compound A11 as a yellow solid (15 mg, 25%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.11 (s, 1H), 8.32 (s, 1H), 7.89 (d, 2H), 7.78 (d, 2H), 5.49 (s broad, 1H), 3.53 (s broad, 2H), 3.01 (s, 3H), 2.78 (m, 4H), 2.18 (m, 2H), 1.96 (m, 2H), 1.20 (s, 9H). LCMS (ESI), m/z 492.3 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([C:21](=[O:23])[CH3:22])[C:5]([OH:20])=[C:6]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]=1[O:8][CH3:9].[Br:25][CH2:26][CH2:27]Br>>[Br:25][CH2:26][CH2:27][O:20][C:5]1[C:6]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]([O:8][CH3:9])[C:2]([Cl:1])=[C:3]([CH3:24])[C:4]=1[C:21](=[O:23])[CH3:22]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(O)c1OCCCc1ccccc1
Reactant: BrCCBr
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCCc1ccccc1
Yield: 100 %

Procedure:
Example 34a (4.3 g, 17 mmol) was reacted with 1,2-dibromoethane (40 mL) as described under General Procedure F to afford the title compound (5.5 g, 100%) as a red oil. 1H NMR (300 MHz, CDCl3) δ 7.33-7.18 (m, 5H), 4.30 (t, J=6.3 Hz, 2H), 4.09 (t, J=6.3 Hz, 2H), 3.89 (s, 3H), 3.51 (t, J=6.0 Hz, 2H), 2.83 (t, J=8.1 Hz, 2H), 2.52 (s, 3H), 2.20 (s, 3H), 2.14-2.05 (m, 2H). MS (ES+) m/z 457 (M+H+).
Reaction SMILES: C(O[C:4](=[O:10])[NH:5][C:6](=[O:9])[CH2:7]Cl)C.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=1[CH3:19].CN(C)C1C=CC=CC=1>>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:7][C:6](=[O:9])[NH:5][C:4]2=[O:10])=[CH:14][C:13]=1[CH3:19]
Reactant: Cc1cc(N)ccc1Br
Reactant: CCOC(=O)NC(=O)CCl
Solvent: CN(C)c1ccccc1
Product: Cc1cc(N2CC(=O)NC2=O)ccc1Br
Temperature: 130 °C
Reaction time: 5 h
Yield: 54.3 %

Procedure:
(2-Chloro-acetyl)-carbamic acid ethyl ester (356 mg, 2.15 mmol) was added to 4-bromo-3-methyl-phenylamine (400 mg, 2.15 mmol) and dimethylphenylamine (273 μL, 2.15 mmol) at room temperature. The mixture was stirred at 130° C. for five hours, and the reaction solution was then cooled. The precipitate was collected by filtration and washed with CH3CN to give 1-(4-bromo-3-methyl-phenyl)-imidazolidine-2,4-dione as a colorless solid (314 mg, 54%).