Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH:13]=O)[CH:3]=1.C1(P(=[CH:34][C:35]#[N:36])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](/[CH:13]=[CH:34]/[C:35]#[N:36])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)c(Cl)cc1C=O
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)c(Cl)cc1/C=C/C#N
Temperature: 25 °C

Procedure:
A mixture of the product from Example 56C (2.0 g, 8.6 mmol) and (triphenylphosphoranylidene)acetonitrile (2.87 g, 9.5 mmol) in toluene (30 mL) was refluxed for 24 hours. The reaction was cooled to room temperature and filtered through a short plug of silica gel eluting with diethyl ether to remove the triphenyl phosphine oxide. The filtrate was concentrated and the residue was purified via flash chromatography on a silica gel column (5:95 ethyl acetate:hexane) to afford the title compound and the corresponding Z isomer. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.88 (s, 3H) 6.55 (d, J=16.27 Hz, 1H) 8.05 (d, J=16.95 Hz, 1H) 8.09 (s, 1H) 8.13 (s, 1H); MS (DCI+) m/z 273.0 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][CH2:6][N:7]([S:31]([CH3:34])(=[O:33])=[O:32])[C:8]2[C:9]([CH:28]3[CH2:30][CH2:29]3)=[CH:10][C:11]3[C:15]([CH:16]=2)=[N:14][N:13]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:12]=3[C:24]([NH:26][CH3:27])=[O:25])[CH2:2]1.[CH2:35]=O.[BH4-].[Na+].O>CO>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([N:13]2[C:12]([C:24]([NH:26][CH3:27])=[O:25])=[C:11]3[C:15]([CH:16]=[C:8]([N:7]([CH2:6][CH2:5][CH:3]4[CH2:4][N:1]([CH3:35])[CH2:2]4)[S:31]([CH3:34])(=[O:33])=[O:32])[C:9]([CH:28]4[CH2:29][CH2:30]4)=[CH:10]3)=[N:14]2)=[CH:22][CH:21]=1
Reactant: C=O
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCC3CNC3)S(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCC3CN(C)C3)S(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Yield: 124 %

Procedure:
To a solution of Compound (6) (27 mg, 0.05 mmol) in MeOH (2 mL) was added, simultaneously, paraformaldehyde (30 mg) and sodium borohydride (30 mg). After 16 h at ambient temperature water (25 ml) was added and the aqueous layer was extracted into EtOAc (3×30 mL). The combined organics were washed with brine (25 mL), dried (MgSO4) and concentrated in vacuo to give a colourless oil (32 mg). The crude material was purified by reverse phase preparative LCMS: Acetonitrile/water (0.1% formic acid) to give Compound (7) (7.70 mg, 30%). ESI-MS m/z calculated for [M+H]+: 516.2. found: 516.1. 1H NMR (400 MHz, CD3CN, formate salt) δ 8.30 (s, 1H), 7.79 (s, 1H), 7.62-7.49 (m, 4H), 7.35 (s, 1H), 7.22 (br s, 1H), 3.84-3.70 (m, 2H), 3.70-3.56 (m, 2H), 3.38 (dd, J=16.0, 7.5 Hz, 2H), 3.07 (s, 3H), 2.89 (d, J=4.8 Hz, 3H), 2.75 (dt, J=15.4, 7.8 Hz, 1H), 2.51 (s, 3H), 2.35 (ddd, J=13.6, 8.1, 5.6 Hz, 1H), 1.87 (ddd, J=17.6, 11.0, 5.2 Hz, 2H), 1.11-0.98 (m, 3H), 0.65-0.57 (m, 1H).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([Li])(CC)C.[CH:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)C>[C:1]([N:8]1[CH2:9][CH2:10][CH2:11][CH:12]1[CH:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1
Reactant: O=Cc1ccccc1
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC1C(O)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
N-Boc-pyrrolidine (5.0 g) was dissolved in diethyl ether (60 mL) and the solution was cooled to −78° C. N,N,N′,N″-Tetramethylethylenediamine (TMEDA) (4.4 mL) was added to the mixture followed by sec-butyl lithium (27.0 mL, 1.3 M in cyclohexane) maintaining the temperature below −60° C. After 2 h, benzaldehyde (3.6 mL) was added and the mixture was stirred at −70° C. for an additional 30 min. The reaction mixture was allowed to warm to room temperature and was then quenched with water and poured into EtOAc (200 mL). The separated organic layer was washed with saturated aq. ammonium chloride (3×50 mL) followed by brine (50 mL), dried (MgSO4), and concentrated. The crude product was purified by column chromatography (heptane/EtOAc, 8/1; 6/1) to afford 6.3 g of N-Boc-2-(hydroxy(phenyl)methyl)-pyrrolidine as a mixture of diastereomers. The resulting N-Boc-2-(hydroxy(phenyl)methyl)pyrrolidine (5.6 g) was dissolved in dichloromethane (500 mL) and trifluoroacetic acid (60 mL) was added. The mixture was concentrated, dissolved in dichloromethane (200 mL), and washed with saturated aq. sodium bicarbonate (3×100 mL). The aqueous layers were extracted with dichloromethane (4×50 mL) and the combined organic layers were concentrated. The crude product was distilled in a Kugelrohr apparatus (150-175° C., 0.2 Torr) to afford 2.47 g of the title compound as a mixture of diastereomers. Physical characteristics. MS (ESI+) m/z 178 (M+H)+.
Reaction SMILES: C=O.[CH:3]([C:6]1[S:15][C:14]2[NH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[N:10]=[C:9]([N:20]3[CH2:25][CH2:24][NH:23][C@@H:22]([CH2:26][C@@H:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[OH:28])[CH2:21]3)[C:8]=2[N:7]=1)([CH3:5])[CH3:4].[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(=O)(O)[O-].[Na+]>[CH:3]([C:6]1[S:15][C:14]2[NH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[N:10]=[C:9]([N:20]3[CH2:25][CH2:24][N:23]([CH3:35])[C@@H:22]([CH2:26][C@@H:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[OH:28])[CH2:21]3)[C:8]=2[N:7]=1)([CH3:5])[CH3:4]
Reactant: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](C[C@H](O)c2ccccc2)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](C[C@H](O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.7 %

Procedure:
Add formaldehyde (23 μL, 0.29 mmol, 37% in water) to a solution of (S,S)-2-[4-(2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol (117 mg, 0.26 mmol) in dichloroethane (5 mL). Stir 15 min at ambient temperature. Add sodium triacetoxyborohydride (83 mg, 0.39 mmol) and stir 2 h at ambient temperature. Dilute with saturated sodium bicarbonate solution and extract with methylene chloride. Dry the extracts with sodium sulfate, filter and concentrate the filtrate. Purify by radial silica gel chromatography using a 2 mm plate and 2N ammonia in methanol-methylene chloride (1%–4%) as the eluent to give 68 mg (56%) of the title compound: mass spectrum (ion spray): m/z=462 (M+1), 460 (M−1). HR-MS calculated for C26H32N5OS: 462.2328. Found 462.2322. 1H NMR (DMSO-d6): δ 7.82 (s, 1H), 7.35–7.18 (m, 5H), 6.91–6.76 (m, 3H), 6.69 (br d, 1H), 5.29 (s, 1H), 4.58–4.46 (m, 1H), 4.14–3.77 (m, 2H), 3.02–3.17 (m, 2), 2.90 (dd, 1H), 2.74–2.65 (m, 1H), 2.28–2.11 (m, 1H), 2.14 (s, 3H), 2.03–1.84 (m, 2H) 1.70–1.54 (m, 1H), 1.26 (d, 6H).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:21]=[C:22]([S:26]([NH:29][CH2:30][CH2:31][OH:32])(=[O:28])=[O:27])[CH:23]=[N:24][CH:25]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[CH:25]=[N:24][CH:23]=[C:22]([S:26]([NH:29][CH2:30][CH2:31][OH:32])(=[O:28])=[O:27])[CH:21]=2)[CH:11]=1
Reactant: O=S(=O)(NCCO)c1cncc(Br)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1cncc(S(=O)(=O)NCCO)c1

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-chloro-2-ethynyl phenoxy)acetate (Intermediate 3) and 5-bromo-N-(2-hydroxyethyl)pyridine-3-sulfonamide (Intermediate 31), the title compound was obtained as an off-white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20]C(=O)C(C)(C)C)[C:10]([C:27]#[N:28])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+]>C(O)C>[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]2[C:10]([C:27]([NH2:28])=[N:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=32)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(-c2ccccc2NC(=O)C(C)(C)C)c(C#N)nn1Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c2c(nn1Cc1ccccc1)c(N)nc1ccccc12
Temperature: 25 °C
Yield: 71.6 %

Procedure:
A solution of N-[2-(1-benzyl-3-cyano-5-methyl-1H-pyrazol-4-yl)phenyl]-2,2-dimethylpropanamide (2.40 g, 6.44 mmol) and sodium tert-butoxide (0.743 g, 7.73 mmol) in ethanol (28 mL) was heated at reflux for 1 day, then was allowed to cool to ambient temperature. A precipitate formed that was isolated by filtration and washed with water followed by water/ethanol (8:1) to provide 1.33 g of 2-benzyl-1-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine as a white powder, mp>250° C.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH3:29][NH:30][CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][O:33]1>>[CH3:29][N:30]([CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][O:33]1)[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2
Reactant: CNCC1CCCO1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN(C)CC3CCCO3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with N-methyl-1-(tetrahydrofuran-2-yl)methanamine via General Procedure E to give 10.7 mg of 290 following reverse phase purification. MS (Q1) 477.2 (M)+
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:8]2=[N:7]1)[C:3]#[N:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[S:25])=[CH:22][CH:21]=1>>[C:3]([C:2]([NH:1][C:24](=[S:25])[C:23]1[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:28][CH:27]=1)([CH3:17])[CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:8]2=[N:7]1)#[N:4]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: COc1ccc2nn(CC(C)(N)C#N)nc2c1
Product: COc1ccc2nn(CC(C)(C#N)NC(=S)c3ccc(C(F)(F)F)cc3)nc2c1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5-methoxy-2H-benzotriazol-2-yl)-2-methylpropionitrile (120 mg, described in Example 44) and 4-trifluoromethylthiobenzoyl chloride (0.16 mL), the title compound was isolated as a white solid (150 mg, 66%). Rf=0.3 (1:1 EA/heptane). MS (ES): M/Z [M+H]=436. 1H NMR: (400 MHz, DMSO-d6): 1.73 (s, 3H), 3.84 (s, 3H), 5.32 (d, J=13.4 Hz, 1H), 5.38 (d, J=13.4 Hz, 1H), 7.10 (dd, J=9.3, 2.3 Hz, 1H), 7.24 (d, J=2.1 Hz, 1H), 7.82 (dd, J=9.2, 0.4 Hz, 1H), 7.87 (d, J=8.6 Hz, 2H), 7.92 (d, J=8.6 Hz, 2H) and 9.00 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −41.9 (s, 3F).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[C:6](=O)([O:15]N1C(=O)CCC1=O)[O:7][N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]1=[O:14].C(N(CC)CC)C>C(#N)C>[C:6](=[O:15])([O:7][N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]1=[O:14])[O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(OCC1CC1)ON1C(=O)CCC1=O
Reaction time: 8 h
Yield: 108.8 %

Procedure:
To a stirred solution of cyclopropylmethanol (1.0 g, 13.8 mmol) in acetonitrile (15 mL) was added bis(2,5-dioxopyrrolidin-1-yl) carbonate (7.1 g, 27.7 mmol) and triethylamine (5.8 mL, 41.6 mmol). The reaction was stirred overnight, then quenched with saturated NaHCO3 solution (aq.) and extracted with ethyl acetate (3×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound (3.2 g, quant.) as an amber oil: 1H NMR (300 MHz, CDCl3) δ 4.16 (d, J=7.5 Hz, 2H), 2.84 (s, 4H), 1.26 (m, 1H), 0.70-0.64 (m, 2H), 0.40-0.35 (m, 2H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[CH:8]=1.CN(C)[CH:19]=[O:20].[OH-].[Na+]>>[F:6][C:7]1[CH:8]=[C:9]([O:15][CH3:16])[C:10]([CH:19]=[O:20])=[C:11]([O:13][CH3:14])[CH:12]=1
Reactant: COc1cc(F)cc(OC)c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(F)cc(OC)c1C=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
Phosphorous oxychloride (1.8 mL, 19.3 mmol) was added slowly to a well-stirred mixture of 1-fluoro-3,5-dimethoxy benzene (2.6 mL, 19.25 mmol) and N,N-dimethylformamide (2.5 mL, 20 mmol) while temperature was kept below −5° C. Stirring was continued at room temperature for 1.5 h and at 60° C. for another 2 h. Reaction completion was monitored by TLC. The reaction mixture was cooled and hydrolyzed with ice-water (60 mL). The resulting suspension was neutralized by addition of 5N NaOH, extracted with ethyl acetate (2×30 mL), the aqueous phase was adjusted to pH 10 by 5N NaOH and re-extracted with ethyl acetate (2×30 mL). The combined organic phases were washed with saturated aqueous NaHCO3 solution (30 mL) and brine (30 mL) and dried over anhydrous sodium sulfate. The dried solution was concentrated to get the crude product which on purification by column chromatography afforded a colorless pure product. Yield: 75%; white solid mp 79-81° C. 1H NMR: δ 3.85 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 6.25 (S, 2H, Ar—H), 10.24 (s, 1H, CHO). Anal. Calcd for C18H19FO5S: C, 58.70, H, 4.92. Found: C, 58.64, H, 4.91.
Reaction SMILES: CC(C)([O-])C.[K+].CS(C)=O.Br[CH:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)[CH2:13]Br>C(O)(C)(C)C>[CH:13]#[C:12][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1
Reactant: BrCC(Br)c1ccc(-c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CS(C)=O
Product: C#Cc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90.5 %

Procedure:
To a solution of 26 g of potassium t-butoxide in 400 ml of a 1:1 mixture (v/v) of dimethyl sulfoxide and t-butanol at 10°-15° was added with stirring a solution of 39 g of 4-(1,2-dibromoethyl)biphenyl in 400 ml of the same solvent mixture. After stirring for 20 minutes, the reaction mixture was poured into ice-water. The resulting mixture was extracted with diethyl ether. The diethyl ether then was washed successively with water, five percent aqueous sodium bicarbonate, and water, and dried over anhydrous sodium sulfate. The diethyl ether was distilled under reduced pressure and the solid residue crystallized from aqueous ethanol to give 18.5 g of crude 4-biphenylacetylene, mp 79°-81°. Two recrystallizations from hexane gave pure 4-biphenylacetylene, mp 82°-85°. The following elemental analysis was obtained:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[C:4]([F:10])[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([F:10])[CH:3]=1
Reactant: COc1cc(F)cc(Br)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc(F)cc(Br)c1
Temperature: -30 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
To a solution of 1-bromo-3-fluoro-5-methoxybenzene (3.0 g, 0.015 mol) in dry CH2Cl2 (80 mL) under an inert atmosphere and cooled to −30° C. was added 1 M BBr3 (4.27 mL, 0.045 mol) in 21 mL of CH2Cl2 dropwise while maintaining temperature at −30° C. The reaction was stirred for 3 h at 0-5° C. and then the reaction mixture was quenched with aqueous saturated NaHCO3. Water was added and the mixture was extracted with CH2CO2 three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness to give the title compound (2.54 g, 91%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH:7]([S:33]([OH:36])(=[O:35])=[O:34])[C:8]([NH:10][C@@H:11]2[C:14](=[O:15])[N:13]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH2:20][N+:21]4[CH:22]=[CH:23][C:24]([C:27]([NH2:29])=[O:28])=[CH:25][CH:26]=4)[CH2:18][S:19][C@H:12]23)=[O:9])=[CH:5][CH:6]=1.C([O-])(=O)C.[Na+:41]>CN(C=O)C.O>[CH:1]1[CH:2]=[CH:3][C:4]([CH:7]([S:33]([O-:36])(=[O:34])=[O:35])[C:8]([NH:10][C@@H:11]2[C:14](=[O:15])[N:13]3[C:16]([C:30]([O-:32])=[O:31])=[C:17]([CH2:20][N+:21]4[CH:26]=[CH:25][C:24]([C:27]([NH2:29])=[O:28])=[CH:23][CH:22]=4)[CH2:18][S:19][C@H:12]23)=[O:9])=[CH:5][CH:6]=1.[Na+:41]
Reactant: NC(=O)c1cc[n+](CC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(c4ccccc4)S(=O)(=O)O)[C@H]3SC2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc[n+](CC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)C(c4ccccc4)S(=O)(=O)[O-])[C@H]3SC2)cc1

Procedure:
Cefsulodin (5.0762 g) was dissolved in 10 mL of DMF and cooled in an ice bath. To this cold, yellow, syrupy solution was added 1.1 eq. of sodium acetate in 15 mL of water with stirring. The mixture was stirred at ice temperature for 10 more minutes. The mixture was then placed in a refrigerator overnight. The crystallized cefsulodin sodium was filtered, dried using heat under reduced pressure to a water content of about 3.18% by weight. 2.82 g of cefsulodin sodium were obtained (63%). Microscopic analysis of the resulting crystals showed that the cefsulodin sodium was spherical-type crystals.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)=[O:19])[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C[Si]([Cl:38])(C)C.CCOCC>CC(CC)=O>[ClH:38].[CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)=[O:19])[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Agent: O=C(c1ccco1)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1
Solvent: O
Solvent: CCC(C)=O
Solvent: CCOCC
Product: Cl
Reaction time: 8 h

Procedure:
1,3-(S)-dibenzyl-8-(furan-2-carbonyl)-1,4,8-triazaspiro[4,5]decan-2-one (365 mg, 0.9 mmol) was dissolved in ethyl methyl ketone (2.9 mL), water (8 μL), TMSCl (118 μL), and ether (20 mL) were added and the mixture was stirred overnight. The solid matter was isolated by filtration, washed with ether, and dried in vacuo. The product 1,3-(S)-dibenzyl-8-(furan-2-carbonyl)-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 338 mg (85%).
Reaction SMILES: [CH2:1]([C@@H:4]1[C:9](=[O:10])[O:8][C@H:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:2]=[CH2:3].C1OCCOCCOCCOCCOC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:55](I)[CH:56]([CH3:58])[CH3:57].[Cl-].[NH4+]>C1COCC1>[CH2:1]([C@:4]1([CH2:55][CH:56]([CH3:58])[CH3:57])[C:9](=[O:10])[O:8][C@H:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1C(=O)O[C@H](c2ccccc2)[C@H](c2ccccc2)N1C(=O)OC(C)(C)C
Reactant: CC(C)CI
Agent: C1COCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=CC[C@]1(CC(C)C)C(=O)O[C@H](c2ccccc2)[C@H](c2ccccc2)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
1 g of tert-butyl (3R,5S,6R)-3-allyl-2-oxo-5,6-diphenylmorpholine-4-carboxylate was dissolved in 20 ml of THF. 3 ml of 15-crown-5 were added, and the mixture was cooled to −78° C. Then 1.4 ml of a 2 M solution of NaHMDS in THF were added dropwise. The mixture was stirred for 10 min and then 300 μl of isobutyl iodide were added dropwise. The temperature was allowed to rise to 0° C. over the course of 6 h, and then the reaction was stopped by adding 50 ml of saturated ammonium chloride solution. The aqueous phase was extracted 3 times with 50 ml of ethyl acetate each time, and the combined organic phases were dried with MgSO4. The solvents were removed in vacuo and the residue was chromatographed on silica gel with heptane/ethyl acetate 10:1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]3[S:16][N:15]=[CH:14][C:13]=3[CH:12]=[CH:11][C:10]=2[C:18]([OH:20])=O)=[C:4]([F:21])[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH:31]([O:33][CH2:34][CH2:35][O:36][NH2:37])=[CH2:32].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[CH:31]([O:33][CH2:34][CH2:35][O:36][NH:37][C:18]([C:10]1[CH:11]=[CH:12][C:13]2[CH:14]=[N:15][S:16][C:17]=2[C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:21])=[O:20])=[CH2:32]
Reactant: C=COCCON
Reactant: O=C(O)c1ccc2cnsc2c1Nc1ccc(Br)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=COCCONC(=O)c1ccc2cnsc2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.8 %

Procedure:
To a solution of 7-(4-bromo-2-fluoro-phenylamino)-benzo[d]isothiazole-6-carboxylic acid (210 mg, 0.57 mmol) and diisopropylethylamine (0.29 mL, 1.71 mmol) in DMF (2 mL) were added O-(2-vinyloxy-ethyl)-hydroxylamine (117 mg, 1.14 mmol), EDCI (220 mg, 1.14 mmol) and HOBt (154 mg, 1.14 mmol). The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate and washed with water, a saturated aqueous solution of sodium hydrogen carbonate then brine before being dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0% to 100%, TBME in cyclohexane) to afford the title compound as a yellow oil (95 mg, 37%). LCMS (method B): RT=3.90 min, [M+H]+=452/454.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([OH:20])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].O>CN(C=O)C>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][O:20][CH:16]1[C:17]2[C:12](=[CH:11][C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])=[CH:19][CH:18]=2)[CH2:13][CH2:14][CH2:15]1)[CH3:29]
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)CCCC2O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48 %

Procedure:
6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ol (1.2 g, 4.16 mmol) was dissolved in 60 mL of dry DMF, and the reaction mixture was cooled in an ice bath. Sodium hydride (0.2 g of 60% solid in oil, washed with hexanes) was added, and the reaction mixture was stirred under nitrogen for 20 minutes. Ethyl bromoacetate (0.55 mL) was added dropwise, and stirring was continued for three hours, during which time the reaction mixture was allowed to warm to room temperature. Water (250 mL) was added to the reaction mixture, and the aqueous mixture was extracted twice with 150 mL of EtOAc. The combined organic layers were washed with water, brine, dried over MgSO4, and the solvent was removed under reduced pressure to yield an oil which was eluted through silica gel under medium pressure with 4:1 EtOAc/hexanes. Removal of solvent under reduced pressure afforded 0.75 g (2.0 mmol, 48%) of (6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yloxy)-acetic acid ethyl ester as an oil. MS: 375 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:9]3[CH2:18][CH2:19][CH2:20][C@H:8]3[C:7]=12>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[O:17]=[C:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:6]2[CH:5]=[N:4][C:3]([CH:2]=[O:1])=[C:7]2[C@@H:8]2[CH2:20][CH2:19][CH2:18][N:9]12
Reactant: O=C1c2ccccc2-n2cnc(CO)c2[C@@H]2CCCN12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2
Temperature: 25 °C

Procedure:
A suspension of 12.1 g (45 mmol) of (S)-11,12,13,13a-tetrahydro-1-(hydroxymethyl)-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in 300 ml of methylene chloride is treated with 70 g of manganese dioxide and stirred at room temperature for ca 0.75 hour. After filtration over Dicalit, the filtrate is evaporated in vacuo and the residue is washed with ca 100 ml of boiling ethyl acetate. There is obtained (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxaldehyde of melting point 206°-208° C.