Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:26]=[CH:25][C:3]=1[O:4][C@H:5]1[C@@H:9]([OH:10])[CH2:8][N:7]([CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[C:6]1=[O:24].[ClH:33]>C(Cl)Cl.O1CCOCC1>[ClH:33].[F:1][C:2]1[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:26]=[CH:25][C:3]=1[O:4][C@H:5]1[C@@H:9]([OH:10])[CH2:8][N:7]([CH:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[C:6]1=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(N2C[C@H](O)[C@H](Oc3ccc(S(C)(=O)=O)cc3F)C2=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(O[C@@H]2C(=O)N(C3CCNCC3)C[C@@H]2O)c(F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
tert-butyl 4-((3S,4S)-3-(2-fluoro-4-(methylsulfonyl)phenoxy)-4-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (80 mg, 0.169 mmol) was dissolved in CH2Cl2 (1 mL) and 4N HCl in dioxane (1 mL) was added and stirred at ambient temperature for 6 hours. The reaction was concentrated to afford crude (3S,4S)-3-(2-fluoro-4-(methylsulfonyl)phenoxy)-4-hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride (80 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH:17]1([CH2:20][C:21]([NH2:29])([CH3:28])[C:22]2[N:26]=[C:25]([CH3:27])[O:24][N:23]=2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][C:21]([NH:29][C:8]([C:5]2[CH:4]=[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:2]([Br:1])=[CH:7][N:6]=2)=[O:10])([CH3:28])[C:22]2[N:26]=[C:25]([CH3:27])[O:24][N:23]=2)[CH2:19][CH2:18]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(Br)cn1
Reactant: Cc1nc(C(C)(N)CC2CC2)no1
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(OCC(F)(F)F)c(Br)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 78e, using 5-Bromo-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 78d) and 2-Cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 66e) as starting materials and isolated (89 mg, 58%) as colorless oil; MS (ESI, m/z): 463.4 (M+H+).
Reaction SMILES: [C:1]1([N:7]([CH2:28][CH2:29][CH3:30])[C@H:8]([C:13]([NH:15][N:16]=[CH:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH3-]C#N.[Na+].C(O)(=O)C>C1COCC1>[C:1]1([N:7]([CH2:28][CH2:29][CH3:30])[C@H:8]([C:13]([NH:15][NH:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCN(c1ccccc1)[C@@H](CC(C)C)C(=O)NN=CCCNC(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCN(c1ccccc1)[C@@H](CC(C)C)C(=O)NNCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
This procedure is based on the method used by Gallina et al. to synthesize a series of Z-hydrazines [Calbretta et al, Eur. J. Med. Chem. 30, 931 -941 (1995); incorporated herein by reference]. PhPr-Leu-NH—N═CH(CH2)2—NH-Boc (1.928 g, 4.46 mmol) and NaBH3CN (5 eq, 1.400 g, 22.3 mmol) were dissolved in anhydrous THF (23 mL). Glacial acetic acid (104 eq, 27.85 g, 464 mmol, 26.5 mL) was added dropwise to the solution, and the reaction mixture was allowed to stir at rt overnight. The solvents were evaporated and the crude oil dissolved in ethyl acetate (20 mL). Distilled water (20 mL) was added to the solution, which was vigorously stirred while enough solid NaHCO3 was added to turn the pH of the aqueous layer basic. The organic layer was isolated and washed with a saturated NaCl solution (2×15 mL), a saturated NaHCO3 solution (10 mL), and again with a saturated NaCl solution (10 mL). The organic layer was dried over MgSO4, filtered, and evaporated. The crude solid was purified by silica gel chromatography using 1/1 ethyl acetate/hexanes as the eluent. The solvent was evaporated, leaving a white, foamy solid that was used without further purification: yield 59%; product spot on TLC, Rf=0.43 (10% CH3OH in CH2Cl2). 1H NMR (CDCl3) δ 9.80 (s, 1H), 9.54 (s, 1H), 7.30-7.13 (m, 5H), 6.94 (s, 1H), 6.60 (s, 1H), 4.60-4.47 (m, 1H), 3.25-3.06 (m, 2H), 3.04-2.93 (m, 4H), 2.60-2.51 (m, 2H), 2.87-1.72 (m, 3H), 1.70-1.60 (m, 2H), 1.42 (s, 9H), 0.98-0.82 (m, 6H). MS (ESI+) m/z 435 (M+1).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH2:13]([C@@H:16]1[CH2:20][O:19][C:18](=[O:21])[NH:17]1)[CH2:14][CH3:15]>>[CH2:13]([C@@H:16]1[CH2:20][O:19][C:18](=[O:21])[N:17]1[C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)[CH2:14][CH3:15]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CCC[C@@H]1COC(=O)N1
Product: CCC[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1

Procedure:
By reaction and treatment in the same manner as in Preparation Example 18 and using ethyl 4-iodobenzoate (3.2 mL) and (R)-4-propyloxazolidin-2-one (2.5 g) described in Preparation Example 29, the title compound (5.7 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[NH:4][CH2:5][CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8].[C:16](OCC)(=[O:22])[C:17](OCC)=[O:18]>>[Cl:15][C:13]1[CH:14]=[C:2]2[C:3](=[CH:11][CH:12]=1)[N:4]([CH2:5][CH:6]([CH2:7][CH3:8])[CH2:9][CH3:10])[C:17](=[O:18])[C:16](=[O:22])[NH:1]2
Reactant: CCC(CC)CNc1ccc(Cl)cc1N
Reactant: CCOC(=O)C(=O)OCC
Product: CCC(CC)Cn1c(=O)c(=O)[nH]c2cc(Cl)ccc21
Yield: 76 %

Procedure:
35 g (0.124 mol) of 2-amino-4-chloro-N-(2-ethylbutyl)aniline were refluxed in 350 ml of diethyl oxalate for 2.5 h. After cooling, the precipitate was filtered off with suction and dried to yield 33 g (76%) of the product. Melting point 253°-255°C.
Reaction SMILES: [C:1]([S:5]([C:8]#[C:9][S:10]([C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:12])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[N:17]([CH2:20][N:21]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][C:27]([O:36][CH3:37])=[CH:28][C:29]=2[CH:33]([CH3:35])[CH3:34])[S:22]1(=[O:24])=[O:23])=[N+:18]=[N-:19]>C1C=CC=CC=1>[C:1]([S:5]([C:8]1[N:19]=[N:18][N:17]([CH2:20][N:21]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][C:27]([O:36][CH3:37])=[CH:28][C:29]=3[CH:33]([CH3:35])[CH3:34])[S:22]2(=[O:23])=[O:24])[C:9]=1[S:10]([C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:12])=[O:11])(=[O:6])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)S(=O)(=O)C#CS(=O)(=O)C(C)(C)C
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CN=[N+]=[N-])C2=O
Solvent: c1ccccc1
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(Cn1nnc(S(=O)(=O)C(C)(C)C)c1S(=O)(=O)C(C)(C)C)C2=O

Procedure:
Di(t-butylsulfonyl)acetylene (1.50 g.) was added to part (75 mL) of the above-described solution of 2-azidomethyl-4-isopropyl-6-methoxysaccharin in benzene. The resulting solution was heated under reflux for 65 hours, then chromatographed on silica gel (Kieselgel 60, 68 g) using first benzene and then cyclohexane-ethyl acetate (90:10, then 85:15, then 75:25) as eluant. The fractions containing the product, which were identified by thin layer chromatography, were combined and recrystallized from benzene-cyclohexane. Pan (0.5 g) of the resulting product (1.5 g, m.r. 204°-205° C., 26% yield for both steps) was recrystallized twice from ethyl acetate affording 2-[4,5-di(t-butylsulfonyl)-1,2,3-triazol-1-yl]methyl-4-isopropyl-6-methoxysaccharin as pale yellow elongated prisms (0.15 g, m.r. 207.5°-209° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:29])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[C@H:26]([CH3:27])[CH2:25][O:24][C:23]4=[O:28])=[CH:18][CH:17]=3)=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:27][C@@H:26]1[CH2:25][O:24][C:23](=[O:28])[N:22]1[C:19]1[CH:20]=[CH:21][C:16]([C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[C:4]([CH3:29])=[CH:3][C:2]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:7][N:6]=3)[CH2:9][CH2:10]2)=[O:15])=[CH:17][CH:18]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(Br)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C)cc2)CC1
Product: Cc1cc(-c2ccccc2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C)cc2)CC1

Procedure:
By reaction and treatment in the same manner as in Preparation Example 186 and using the obtained (R)-3-{4-[4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-4-methyloxazolidin-2-one (535 mg) and phenylboronic acid (183 mg), (R)-4-methyl-3-{4-[4-(3-methyl-5-phenylpyridin-2-yl)piperazine-1-carbonyl]phenyl}oxazolidin-2-one was obtained. The obtained compound was dissolved in ethyl acetate (10 mL), 4N hydrogen chloride/ethyl acetate (0.3 mL) was added, and the precipitate was collected by filtration to give the title compound (475 mg).
Reaction SMILES: [CH3:1][S:2]([C:4]1[N:5]=[C:6]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[C:10]2=[O:26])[S:7][CH:8]=1)=[O:3].C(Cl)Cl>C(C(O)=O)(F)(F)F>[CH3:1][S:2]([C:4]1[N:5]=[C:6]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][C:19]([OH:21])=[O:20])[C:10]2=[O:26])[S:7][CH:8]=1)=[O:3]
Reactant: CS(=O)c1csc(-n2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)c1csc(-n2c(=O)n(CC(=O)O)c3ccccc32)n1

Procedure:
(±)-tert-Butyl {3-[4-(methylsulfinyl)-1,3-thiazol-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetate from Step D (100 mg, 0.254 mmol) was dissolved in CF3CO2H (3 mL) and CH2Cl2 (3 mL) and the mixture was stirred at ambient temperature for 3 h, then concentrated in vacuo to give the title compound. MS: m/z=338 (M+1).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[CH3:17][NH:18][CH2:19][CH3:20]>CCO>[CH3:17][N:18]([CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1)[CH2:19][CH3:20]
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Reactant: CCNC
Solvent: CCO
Product: CCN(C)CC1OCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 22 using 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (30 mg, 0.10 mmol), N-methylethanamine (0.50 ml, 5.8 mmol) and EtOH (1.0 ml). MS m/z (rel. intensity, 70 eV) 285 (M+, 1), 77 (4), 73 (5), 72 (bp), 51 (3).
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[S:15][CH2:14][C@H:13]([OH:16])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:21](Cl)=[O:22]>ClCCl.N1C=CC=CC=1>[C:1]([O:9][CH2:10][C@H:11]1[S:15][CH2:14][C@H:13]([O:16][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:26]([Cl:27])=[C:18]([Cl:17])[CH:19]=2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC[C@@H]1O[C@@H](O)CS1)c1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OC[C@@H]1O[C@@H](OC(=O)c2ccc(Cl)c(Cl)c2)CS1)c1ccccc1
Yield: 29.7 %

Procedure:
A mixture of cis and trans 2-benzoyloxymethyl-5-hydroxy-1,3-oxathiolane (as prepared in example 1) (8.99 g, 39.8 mmol) was reacted with 8.3 g (39.6 mmol) of 3,4-dichlorobenzoylchloride in dichloromethane (30 mL) and pyridine (9.6 mL) as described in Example 2 to yield 4.86 g of the desired compounds in 1:1 ratio.
Reaction SMILES: [OH:1][C:2]1[C:12]2[N:11]=[CH:10][CH:9]3[CH2:13][CH2:14][CH2:15][N:8]3[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:17].[OH2:18]>C(#N)C>[OH:1][C:2]1[C:12]2[NH:11][CH:10]([OH:18])[CH:9]3[CH2:13][CH2:14][CH2:15][N:8]3[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1ccc2c(c1O)N=CC1CCCN1C2=O
Reactant: O
Solvent: CC#N
Product: Cc1ccc2c(c1O)NC(O)C1CCCN1C2=O
Reaction time: 2 h

Procedure:
64.4 mg of 2,3,5,11a-tetrahydro-9-hydroxy-8-methyl-1H-pyrrolo(2,1-C)(1,4)benzodiazepin-5-one was dissolved in 2.5 ml of hot acetonitrile, 0.5 ml of water was added thereto, and the mixture was allowed to stand first at room temperature for 2 hours and then at -20° C. for 1 day. Thus, 51.1 mg of 2,3,5,10,11,11a-hexahydro-9,11-dihydroxy-8-methyl-1H-pyrrolo(2,1-C)(1,4)benzodiazepin-5-one was obtained as a yellow-colored crystal. Recrystallization of the resulting product from aqueous acetonitrile gave a yellow-colored prismatic crystal having a melting point of 154° to 156° C.
Reaction SMILES: [CH:1]1([CH2:4][C:5]#[N:6])[CH2:3][CH2:2]1.[CH3:7][N:8]([CH:10](N(C)C)OC(C)(C)C)[CH3:9]>>[CH:1]1([C:4](=[CH:7][N:8]([CH3:10])[CH3:9])[C:5]#[N:6])[CH2:3][CH2:2]1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: N#CCC1CC1
Product: CN(C)C=C(C#N)C1CC1

Procedure:
At 100° C., 25 g (292.8 mmol) of cyclopropylacetonitrile (obtainable by the process described in U.S. Pat. No. 3,454,575) and 25.5 g (30.2 ml, 146.4 mmol) of bis(dimethylamino)-tert-butyloxymethane are stirred under a riser pipe for 46 hours. Volatile components are evaporated under reduced pressure and the residue is subsequently distilled at 0.1 Torr and 60-65° C.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:20])[CH3:19])=[CH:13][C:12]=1[C:21](=[O:23])[CH3:22]>C(O)C>[CH3:6][N:4]([CH3:5])[CH:3]=[CH:22][C:21]([C:12]1[CH:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[CH:15]=[CH:16][C:11]=1[O:10][CH3:9])=[O:23]
Reactant: COC(OC)N(C)C
Reactant: COc1ccc(NC(C)=O)cc1C(C)=O
Solvent: CCO
Product: COc1ccc(NC(C)=O)cc1C(=O)C=CN(C)C
Temperature: 22 °C
Reaction time: 30 h
Yield: 101.4 %

Procedure:
Dimethylformamide dimethyl acetal (693.3 g) was added to a suspension of 2′-methoxy-5′-acetamidoacetophenone (3, 1215.1 g) in ethanol (12.15 L) stirred under nitrogen at 22° C. After the resulting suspension had been stirred and refluxed under nitrogen for 18 hours, all solids had dissolved, and additional dimethylformamide dimethyl acetal (346.2 g) was added to the homogeneous reaction mixture. Stirring and refluxing under nitrogen were continued for an additional 30 hours, after which additional dimethylformamide dimethyl acetal (346.2 g) was added. The reaction mixture was then stirred and refluxed under nitrogen for a final 17.5 hours, after which the reaction mixture was rotary evaporated at <45° C. and <50 mm HgA to a solid residue that was dried further overnight at <45° C. and <1 mm HgA to provide brown solid 4 (1547.9 g, 100.6% yield). LC/MS analyses revealed 98.3% and 100% conversion of 3 to 4 before and after evaporation of solvent, respectively.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]#[C:16][C:17](=O)[CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:27][NH2:28]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]2[NH:28][N:27]=[C:17]([CH3:18])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(=O)C#CC(=C1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2)[nH]n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
A mixture of 4-[1-phenyl-1-(3-oxo-1-butyn-1-yl)methylene]-piperidine-1-carboxylic acid tert-butyl ester(0.365 g, 1.069 mmol) and hydrazine hydrate (0.065 mL, 1.14 mmol) in EtOH (5 mL) was allowed to stir at rt for 2 h and then it was heated at 80° C. for 14 h. The solvent was subsequently removed under reduced pressure and the residue was purified by preparative HPLC affording the title compound (0.151 g, 40%) as a colorless solid
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:8][CH2:7][C@@H:6]([N:9]2[C:13]3=[C:14]4[S:20][CH:19]=[CH:18][C:15]4=[N:16][CH:17]=[C:12]3[N:11]=[C:10]2[C@H:21]([OH:23])[CH3:22])[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>CO>[OH:23][C@@H:21]([C:10]1[N:9]([C@@H:6]2[CH2:7][O:8][C@@H:3]([CH2:2][NH:1][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:4][CH2:5]2)[C:13]2=[C:14]3[S:20][CH:19]=[CH:18][C:15]3=[N:16][CH:17]=[C:12]2[N:11]=1)[CH3:22]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)OC1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CNS(C)(=O)=O)OC1
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
To a solution of (1R)-1-{1-[(3S,6R)-6-(aminomethyl)tetrahydro-2H-pyran-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol (11 mg, 0.033 mmol) in methanol (0.5 mL) was added N,N-diisopropylethylamine (17 μL, 0.099 mmol) and methanesulfonyl chloride (2.8 μL, 0.036 mmol). After stirring for 0.5 h, another equivalent of methanesulfonyl chloride was added. After stirring for 20 min, The reaction solution was diluted with methanol and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (5 mg, 37%). LCMS calculated for C17H23N4O4S2 (M+H)+: m/z=411.1. Found: 411.1.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])([O:5][CH3:6])=[O:4].[H-].[Na+].[CH3:15][O:16][C:17]1[C:25]([CH3:26])=[C:24]2[C:20]([C:21](=[O:27])[O:22][CH2:23]2)=[C:19]([O:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34])[C:18]=1[CH2:35][CH2:36][CH:37]([CH3:52])[CH2:38][C@H](C)C(N1[C@H](C(C)C)COC1=O)=O>CN(C=O)C>[CH3:34][O:33][CH2:32][CH2:31][O:30][CH2:29][O:28][C:19]1[C:18]([CH2:35]/[CH:36]=[C:37](\[CH3:52])/[CH2:38][CH:7]([P:3]([O:5][CH3:6])([O:2][CH3:1])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:17]([O:16][CH3:15])[C:25]([CH3:26])=[C:24]2[C:20]=1[C:21](=[O:27])[O:22][CH2:23]2
Reactant: COCCOCOc1c(CCC(C)C[C@H](C)C(=O)N2C(=O)OC[C@H]2C(C)C)c(OC)c(C)c2c1C(=O)OC2
Reactant: CCOC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C/C(C)=C/Cc1c(OC)c(C)c2c(c1OCOCCOC)C(=O)OC2)P(=O)(OC)OC
Reaction time: 0.17 h

Procedure:
To a solution of ethyl dimethylphosphonoacetate (135 mg) in DMF (5 ml) at 0° was added 50% NaH/oil (33 mg), and the mixture stirred for 10 minutes. (E) 4-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2-methylbut-2-enyl bromide (600 mg) was added at the same temperature and allowed to reach room temperature in 30 minutes. The reaction was poured onto water and extracted with EtOAc. The organic layers were washed with water, dried over sodium sulfate, and evaporated to give the crude product which was purified by flash chromatography (CH2Cl2 followed by BtOAc) to obtain ethyl (E) 6-(4-methoxyethoxymethoxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2-(dimethylphosphono)-4-methyl-4-hexenoate as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].C(N(CC)CC)C.C1C(=O)N([O:28][C:29]([CH2:31][CH2:32][S:33][S:34][C:35]2[N:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=O)C(=O)C1>C1(C)C=CC=CC=1>[N:40]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:34][S:33][CH2:32][CH2:31][C:29]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:28]
Reactant: O=C(CCSSc1ccccn1)ON1C(=O)CCC1=O
Reactant: NCCOCCOCCCC(=O)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(O)CCCOCCOCCNC(=O)CCSSc1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(2-(2-aminoethoxy)ethoxy)butanoic acid (Compound 4) (F.W. 312.37, 100 mg, 0.377 mmole) in 20 mL of anhydrous toluene was azetropically distilled under reduced pressure at 60° C. on a rotary evaporator. The azeotropic distillation was repeated with 20 mL of anhydrous toluene. Then, the resulting residue was dissolved in anhydrous DCM (20 ml). To the above solution was added N-succinimidyl-3-(2-pyridithio) propionate (Compound 5) (SDPD, F.W.265.3, 100 mg, 0.32 mmole) and triethylamine (105 μl, 0.75 mmole). The mixture was allowed to stand for overnight under stirring at room temperature. TLC showed the disappearance of SPDP. The reaction solution was washed with diluted phosphoric acid (pH4, 5 ml×2). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was subject to flash chromatography on a Biotage system, giving 140 mg of Compound 6, purity>95% (HPLC).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]3([CH2:20][NH2:21])[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[N:12]=2)=[CH:4][CH:3]=1.[F:22][C:23]([F:39])([F:38])[C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32](O)=[O:33])[N:25]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]3([CH2:20][NH:21][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][CH:37]=[C:29]([C:26]5[N:25]=[C:24]([C:23]([F:39])([F:38])[F:22])[O:28][N:27]=5)[CH:30]=4)[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: CN1CCC(CN)(c2coc(-c3ccc(F)cc3)n2)CC1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: CN1CCC(CNC(=O)c2cccc(-c3noc(C(F)(F)F)n3)c2)(c2coc(-c3ccc(F)cc3)n2)CC1
Yield: 24 %

Procedure:
This compound was synthesized from (4-(2-(4-fluorophenyl)oxazol-4-yl)-1-methylpiperidin-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (50 mg, yield 24%). 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.29-8.27 (m, 1H), 8.13-8.05 (m, 3H), 7.67-7.62 (m, 2H), 7.17-7.13 (t, J=8.7 Hz, 2H), 3.85-3.84 (m, 2H), 3.14-3.00 (m, 4H), 2.67 (m, 3H), 2.43-2.42 (m, 2H), 2.24-2.23 (m, 2H). MS (ESI) m/z: Calculated for C26H23F4N5O3: 529.17. found: 530.2 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([S:6]([CH:8]([CH3:13])[CH2:9][C:10]([OH:12])=O)=[O:7])=[CH:2]1.[NH2:14][CH:15]1[C:34](=[O:35])[N:17]2[C:18]([C:31]([OH:33])=[O:32])=[C:19]([C:22]([S:24][C:25]3[N:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[O:23])[CH2:20][S:21][C@H:16]12>>[S:1]1[CH:5]=[CH:4][C:3]([S:6]([CH:8]([CH3:13])[CH2:9][C:10]([NH:14][CH:15]2[C:34](=[O:35])[N:17]3[C:18]([C:31]([OH:33])=[O:32])=[C:19]([C:22]([S:24][C:25]4[N:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=[O:23])[CH2:20][S:21][C@H:16]23)=[O:12])=[O:7])=[CH:2]1
Reactant: CC(CC(=O)O)S(=O)c1ccsc1
Reactant: NC1C(=O)N2C(C(=O)O)=C(C(=O)Sc3cccnn3)CS[C@H]12
Product: CC(CC(=O)NC1C(=O)N2C(C(=O)O)=C(C(=O)Sc3cccnn3)CS[C@H]12)S(=O)c1ccsc1

Procedure:
436 mg. of 3-(3-thienylsulfinyl)butyric acid and 7-amino-3-(1-oxopyridazine-3-ylthiomethyl)-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 432 mg. of 7-[3-(3-thienylsulfinyl)butyramido]-3-(1-oxopyridazine-3-ylthiomethyl)-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]2[C:13]3[N:22]=[C:21]([Cl:23])[N:20]=[C:19](Cl)[C:14]=3[N:15]=[C:16]([Cl:18])[N:17]=2)[CH:7]=[CH:8][C:9]=1[F:10]>O.[OH-].[Na+].C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]2[C:13]3[N:22]=[C:21]([Cl:23])[NH:20][CH2:19][C:14]=3[N:15]=[C:16]([Cl:18])[N:17]=2)[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: Fc1ccc(Nc2nc(Cl)nc3c(Cl)nc(Cl)nc23)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1ccc(Nc2nc(Cl)nc3c2N=C(Cl)NC3)cc1Cl
Temperature: 10 °C
Reaction time: 2 h

Procedure:
At 2° C. a solution of 191.99 g (5.079 mol) of sodium borohydride in 520 ml of water and 22 ml of 2N sodium hydroxide solution is added dropwise to a suspension of 1100 g (2.902 mol) of (1) in 22 l of ethyl acetate. The mixture is stirred for 2 hours at 10° C. and then heated to 71° C. The suspension is filtered through Celite and cooled to 0° C. The product that crystallises out is filtered off and dried at 40° C. until a constant weight is attained.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]=[C:7]2[C:3]=1[N:4]([CH2:19][C:20]([N:22]([CH2:29][CH3:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21])[C:5](=[O:18])[N:6]2[CH3:17].Cl.[CH3:32][NH:33][CH3:34].C(N(CC)CC)C>CN(C)C=O>[CH2:29]([N:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](=[O:21])[CH2:19][N:4]1[C:3]2[C:7](=[N:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:2]=2[N:33]([CH3:34])[CH3:32])[N:6]([CH3:17])[C:5]1=[O:18])[CH3:30]
Reactant: CNC
Reactant: CCN(C(=O)Cn1c(=O)n(C)c2nc(-c3ccccc3)nc(Cl)c21)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(C(=O)Cn1c(=O)n(C)c2nc(-c3ccccc3)nc(N(C)C)c21)c1ccccc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
A mixture of 6-chloro-N-ethyl-8,9-dihydro-9-methyl-8-oxo-2-phenyl-N-phenyl-7H-purin-7-acetamide obtained in Example 45 (0.6 g), dimethylamine hydrochloride (0.2 g), triethylamine (0.4 g) and dimethylformamide (20 ml) is stirred at 100° C. for four hours. The reaction mixture is concentrated under reduced pressure, and to the residue are added water and chloroform. The chloroform layer is separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from diisopropyl ether to give the desired compound (0.34 g).