Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:25])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[NH2:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1.C[O-].[Mg+2].C[O-].CO>>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]([F:22])([F:24])[F:23])[CH:12]=2)[C:3]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=[O:25])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: Nc1nccs1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1C(F)(F)F
Yield: 55.3 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid methyl ester (395 mg, 1.04 mmol) and 2-aminothiazole (209 mg, 1.38 mmol) in a solution of magnesium methoxide in methanol (7.4 wt %, 2.09 mL, 1.38 mmol) was heated at 110° C. for 24 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded the 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide (256.7 mg, 55.1%) as a white solid: mp 95-100° C.; EI-HRMS m/e calcd for C19H21F3N2O3S2 (M+)446.0946, found 446.0944.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=O)[C:5]=2[S:4][CH:3]=1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:10]1[C:5]2[S:4][CH:3]=[C:2]([CH3:1])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: Cc1csc2c(=O)[nH]cnc12
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1csc2c(Cl)ncnc12
Temperature: 110 °C
Reaction time: 2 h

Procedure:
7-Methylthieno[3,2-d]pyrimidine-4(3H)-one (1.5 g) was added to POCl3 (10 mL), and the mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated and diluted with DCM, and sat. NaHCO3 solution was added thereto. The aqueous layer was extracted with DCM to combine organic layers. The organic layer was dried with MgSO4 and filtered to obtain the title compound as a white solid.
Reaction SMILES: O1CCCCC1[O:7][CH:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:9][CH2:10][CH2:11][N:12]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([CH3:28])[C:23]([O:25]CC)=[O:24])[S:13]([CH3:16])(=[O:15])=[O:14].C(O)C.[OH-].[Na+]>Cl.O>[OH:7][CH:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:9][CH2:10][CH2:11][N:12]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([CH3:28])[C:23]([OH:25])=[O:24])[S:13]([CH3:16])(=[O:14])=[O:15]
Reactant: CCCCCC(CCCN(CCCCCC(C)C(=O)OCC)S(C)(=O)=O)OC1CCCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCC(O)CCCN(CCCCCC(C)C(=O)O)S(C)(=O)=O
Reaction time: 4.5 h

Procedure:
A soluton is prepared from ethyl 7-{N-[4-(2-tetrahydropyranyloxy)nonyl]methanesulfonamido}-2-methylheptanoate (4.9 g., 0.01 mole), ethanol (50 ml.), and 4 drops of hydrochloric acid (conc.), and kept at ambient temperature for 4.5 hours. Then to the reaction is added a solution of sodium hydroxide (0.72 g., 0.018 mole) in water (10 ml.) and the reaction is kept at ambient temperature for an additional 20 hours. Most of the ethanol is removed in vacuo and the residue dissolved in water (100 ml.). The solution is extracted once with ether (75 ml.). then acidified with hydrochloric acid (dil.). The oil that separates is extracted into ether, the ether is washed with brine, dried over sodium sulfate, then removed under vacuum to give 7-[N-(4-hydroxynonyl)methanesulfonamido]-2-methylheptanoic acid as a yellow liquid.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:27]=[CH:26][C:21]([CH2:22][CH2:23][C:24]#N)=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.CC[O:31]CC>>[CH2:1]([NH:17][C:18]1[CH:27]=[CH:26][C:21]([CH:22]=[CH:23][CH:24]=[O:31])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCOCC
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CCC#N)cc1
Agent: Cl
Product: CCCCCCCCCCCCCCCCNc1ccc(C=CC=O)cc1
Reaction time: 1 h

Procedure:
A solution of 10.0 g. of 4-hexadecylaminohydrocinnamonitrile in 100 ml. of dry ether is added rapidly to a mixture of 10.2 g. of anhydrous stannous chloride and 80 ml. of ether which has been saturated with dry hydrogen chloride for 2 hours. Dry hydrogen chloride is again bubbled through the reaction mixture which is stirred for 1 hour and allowed to stand for 20 hours. The ethereal solution is decanted from the semi-solid product which is washed again with ether and then treated with water and heated to reflux for 3 hours. Cooling and extraction of the reaction mixture with ether provides 4-(hexadecylamino)cinnamaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[C:17]1([C:23]2[O:27][N:26]=[CH:25][C:24]=2[CH2:28][CH2:29][CH2:30][C:31](O)=[O:32])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][C:24]2[CH:25]=[N:26][O:27][C:23]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: O=C(O)CCCc1cnoc1-c1ccccc1
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccc(NC(=O)CCCc2cnoc2-c2ccccc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (1.74 g), 4-(5-phenyl-4-isoxazolyl)butanoic acid (1.38 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (1.08 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.38 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-diethylphosphonomethylphenyl)-4-(5-phenyl-4-isoxazolyl)butaneamide (2.56 g, yield 94%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 128–129° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:9][CH3:10])=[CH:5][C:6]=1[C:7]#[N:8].F[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].[H-].[Na+]>O1CCCC1>[F:18][C:16]1[CH:15]=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[C:12]([NH:1][C:2]2[S:3][C:4]([CH2:9][CH3:10])=[CH:5][C:6]=2[C:7]#[N:8])[CH:17]=1
Reactant: CCc1cc(C#N)c(N)s1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cc(C#N)c(Nc2cc(F)ccc2[N+](=O)[O-])s1
Reaction time: 18 h

Procedure:
Dissolve 2-amino-5-ethyl-thiophene-3-carbonitrile (8.2 g, 54 mmol) and 2,4-difluoronitrobenzene (8.6 g, 54 mmol) in tetrahydrofuran (20 ml) and add to a stirring solution of sodium hydride (50% dispersion in mineral oil)(4.1 g, 1.4 equiv) in tetrahydrofuran (50 ml) under a nitrogen atmosphere. Maintain the rate of addition to keep the temperature below 45° C. and gas evolution under control. Stir 18 h. Pour the mixture into a mixture of ice and 2NHCl, extract into ethyl acetate, dry (MgSO4) and concentrate under reduced pressure. Dissolve in ethanol (100 ml) and collect 2-(5-fluoro-2-nitro-phenylamino)-5-ethyl-thiophene-3-carbonitrile by filtration as a yellow solid (7.9 g, 50%): mass spectrum (LCMS) 292 (M+1), 314 (M+Na). NMR (1H, 300 MHz, CDCl3): δ 9.7 (1H broad), 8.25 (1H,m), 6.80 (1H, s), 6.75 (1H,dd), 6.65 (1H, s), 2.80 (2H,q), 1.35(3H,t).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH:12]([C:17]([OH:19])=O)[C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.C(Cl)(=O)C([Cl:23])=O.CN(C=O)C>ClCCl>[F:1][CH2:2][CH2:3][N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH:12]([C:17]([Cl:23])=[O:19])[C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: O=C(O)C1CCCc2c1c1ccccc1n2CCF
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1CCCc2c1c1ccccc1n2CCF
Yield: 102 %

Procedure:
9-(2-Fluoro-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid (31) (0.5 g, 1.91 mmol) in dry dichloromethane (6 mL) was stirred under an atmosphere of nitrogen at room temperature with oxalyl chloride (490 mg, 3.8 mmol, 0.34 mL) and a drop of DMF. The reaction was concentrated in vacuo to afford 545 mg (quantitative) of 9-(2-fluoro-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carbonyl chloride (32) which was used in the next step without purification. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 20.2, 21.6, 26.7, 43.1, 43.4, 50.6, 80.9, 83.1, 105.3, 108.8, 118.3, 120.0, 121.6, 126.5, 136.2, 137.5, 176.1.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].Cl[C:6]1[C:11]([O:12][CH3:13])=[CH:10][N:9]=[C:8]([O:14][CH3:15])[N:7]=1.C(O)(=O)C.[Cl-].[Na+]>CN1CCCC1=O>[CH3:15][O:14][C:8]1[N:7]=[C:6]([NH:3][C:2]#[N:1])[C:11]([O:12][CH3:13])=[CH:10][N:9]=1
Reactant: N#CN
Reactant: COc1ncc(OC)c(Cl)n1
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: COc1ncc(OC)c(NC#N)n1
Temperature: 25 °C
Reaction time: 0.27 h
Yield: 98.8 %

Procedure:
To a 100 mL three-neck round bottom flask were added sequentially 7.8 g (121.53 mmol)) of sodium hydrogen cyanamide and then 34.2 g of N-methyl-2-pyrrolidinone (NMP) in one portion, and the slurry mixture was cooled in an ambient temperature water bath. To this mixture was added 10.0 g (54.99 mmol) of 96% 4-chloro-2,5-dimethoxypyrimidine (1; CDMP) in one portion. The mixture was allowed to stir at ambient temperature (<20° C.). After 48 hours (h), 3.78 g (62.95 mmol) of glacial acetic acid was added in one portion and the internal pot temperature rose from 19° C. to 23° C. This reaction slurry was poured over 85 g of crushed ice and the ice was allowed to melt. To this mixture was added 10 g of sodium chloride. The mixture was allowed to stand for 16 minutes (min). Once melted, the cold slurry was suction filtered and the filter cake was washed with two 20-mL portions of water and a final 10 mL water wash. The wet cake transferred to a drying dish and allowed to air dry for 48 h to give 6.78 g (98.8% pure by NMR assay using benzyl acetate) of 2,5-dimethoxy-4-cyanoaminopyrimidine (2) as a light yellow solid in 68% yield. 1H and 13C NMR spectra were identical to that reported in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([C@H:15]3[C@H:20]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]5[N:35]([CH3:36])[N:34]=[N:33][N:32]=5)[CH:26]=4)=[O:23])[CH2:19][CH2:18][NH:17][CH2:16]3)=[O:14])[CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>ClCCl>[F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([C@H:15]3[C@H:20]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]5[N:35]([CH3:36])[N:34]=[N:33][N:32]=5)[CH:26]=4)=[O:23])[CH2:19][CH2:18][N:17]([S:47]([CH3:46])(=[O:49])=[O:48])[CH2:16]3)=[O:14])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: Cn1nnnc1-c1cccc(NC(=O)N[C@@H]2CCNC[C@H]2C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nnnc1-c1cccc(NC(=O)N[C@@H]2CCN(S(C)(=O)=O)C[C@H]2C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Reaction time: 0.42 h
Yield: 57.7 %

Procedure:
In a dry flask 1-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidin-4-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea (67 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL), and then triethylamine (65 •L, 0.47 mmol) and methanesulfonyl chloride (9 μL, 0.11 mmol) were added. The reaction mixture was stirred for 25 minutes. The reaction mixture was concentrated in vacuo then was purified by preparative reverse-phase HPLC (10-80% acetonitrile in water with 0.05% trifluoroacetic acid) to give a white amorphous solid (38 mg, 60%). 1H NMR NMR (400 MHz, DMSO-d6, 140° C.), δ: 8.37 (s, 1H), 7.89 (t, 1H, J=2), 7.54 (d, 1H, J=6), 7.44 (t, 1H, J=8), 7.35 (m, 1H), 7.14 (m, 2H), 6.99 (t, 2H, J=9), 6.05 (d, 1H, J=8), 4.12 (s, 3H), 4.05 (d, 2H, J=14), 3.85 (m, 1H), 3.63 (m, 2H), 3.16 (td, 1H, J=10, J′=4), 2.90 (m, 3H), 2.88 (s, 3H), 2.66 (m, 1H), 2.56 (dd, 1H, J=14, J′=6), 2.44 (dd, 1H, J=14, J′=8), 2.01 (m, 1H), 1.79 (qd, 1H, J=13, J′=4), 1.65 (bs, 3H), 1.40 (m, 1H), 1.20 (m, 1H). HRMS (ESI), C28H36FN8O4S m+/z: calc. 599.2564, found=599.2586.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:12](OC(Cl)(Cl)Cl)=[O:13]>C(Cl)Cl>[C:2]1([C:1]2[S:8][C:12](=[O:13])[NH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=S)c1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=c1[nH]nc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of thiobenzhydrazide (3.7 g, 24.34 mmole) in methylene chloride (50 ml), equipped with magnetic stirrer, nitrogen inlet, and an outlet connected to a trap containing a diluted NAOH solution, was added trichloromethyl chloroformate (4 g, 20.2 mmole). The reaction mixture was stirred at room temperature for one hour. The mixture was diluted with methylene chloride (100 ml) and washed with water (3×50 ml) and brine. The organic layer was dried over MgSO4. After the drying agent was filtered off the filtrate was concentrated to a residue. The residue was triturated with hexane and the solid product was collected by suction-filtration to give 3.7 g as a powder. m.p.=140°-143° C.
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][N:3]=[CH:2]1.[NH:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1>C(O)(=O)CC>[S:1]1[C:5]([C:6]2[C:12]3[NH:8][C:9]([C:6]([C:5]4[S:1][CH:2]=[N:3][CH:4]=4)=[C:9]4[N:8]=[C:12]([C:6]([C:5]5[S:1][CH:2]=[N:3][CH:4]=5)=[C:9]5[NH:8][C:12](=[C:6]([C:5]6[S:1][CH:2]=[N:3][CH:4]=6)[C:9]6[CH:10]=[CH:11][C:12]=2[N:8]=6)[CH:11]=[CH:10]5)[CH:11]=[CH:10]4)=[CH:10][CH:11]=3)=[CH:4][N:3]=[CH:2]1
Reactant: O=Cc1cncs1
Reactant: c1cc[nH]c1
Solvent: CCC(=O)O
Product: C1=Cc2nc1c(-c1cncs1)c1ccc([nH]1)c(-c1cncs1)c1nc(c(-c3cncs3)c3ccc([nH]3)c2-c2cncs2)C=C1
Temperature: 25 °C
Yield: 23.2 %

Procedure:
A 250-mL three-necked flask equipped with a condenser and charged with propionic acid (60 mL) was heated to reflux. 5-Thiazolecarboxaldehyde (1, 373 mg, 3.30 mmol), pyrrole (230 μL, 3.32 mmol), and an additional 5 mL of propionic acid were added. After 3.5 h at reflux, the mixture was cooled to room temperature while exposed to a stream of air. The solvent was removed in vacuo, the residue was redissolved in CHCl3/MeOH/concentrated NH4OH (6:3:1; 100 mL), and the solvent was removed in vacuo. The residue was adsorbed onto silica gel (3 g) and purified by column chromatography (gradient elution, 1-2% MeOH/CH2Cl2) to provide porphyrin 6 (123 mg, 14%) as a solid: 1H NMR (300 MHz, CDCl3) δ −2.70 (s, 2 H), 8.67 (s, 4 H), 9.02 (s, 8 H), 9.38 (s, 4 H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=1)([CH3:10])[CH2:8][OH:9].C([O-])([O-])=O.[K+].[K+]>ClCCl>[Br:17][C:13]1[CH:12]=[C:11]([C:7]([NH:6][C:3](=[O:4])[CH2:2][Cl:1])([CH3:10])[CH2:8][OH:9])[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)CCl
Reactant: CC(N)(CO)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(CO)(NC(=O)CCl)c1cccc(Br)c1
Temperature: 25 °C

Procedure:
2-Chloroacetyl chloride (2.24 g, 19.8 mmol) was added dropwise at 0° C. to a suspension of 2-amino-2-(3-bromo-phenyl)-propan-1-ol (3.8 g, 16.5 mmol), K2CO3 (4.55 g, 33 mmol) and dichloromethane (40 ml). The mixture was allowed to warm to room temperature over a period of approximately 3 h, washed with 1N hydrochloric acid and brine, dried with Na2SO4 and evaporated in vacuo to yield the crude title compound. 1H-NMR (400 MHz, CDCl3): 7.43 (m, 2H), 7.23 (m, 2H), 4.10-4.03 (m, 4H), 1.71 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:10]([CH2:15][CH3:16])[CH2:11][C:12]([OH:14])=O)=[O:9])=[CH:4][CH:3]=1.[NH2:17][CH:18]1[C:36](=[O:37])[N:20]2[C:21]([C:33]([OH:35])=[O:34])=[C:22]([CH2:25][S:26][C:27]3[S:31][C:30]([CH3:32])=[N:29][N:28]=3)[CH2:23][S:24][C@H:19]12>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:10]([CH2:15][CH3:16])[CH2:11][C:12]([NH:17][CH:18]2[C:36](=[O:37])[N:20]3[C:21]([C:33]([OH:35])=[O:34])=[C:22]([CH2:25][S:26][C:27]4[S:31][C:30]([CH3:32])=[N:29][N:28]=4)[CH2:23][S:24][C@H:19]23)=[O:14])=[O:9])=[CH:6][CH:7]=1
Reactant: CCC(CC(=O)O)S(=O)c1ccc(O)cc1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Product: CCC(CC(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12)S(=O)c1ccc(O)cc1

Procedure:
484 mg. of 3-(p-hydroxyphenylsulfinyl)pentanoic acid and 7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 555 mg. of 7-[3-(p-hydroxyphenylsulfinyl)pentanamido]-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:3]=1[C:4]([N:6]1[CH2:12][C:11]2[S:13][CH:14]=[CH:15][C:10]=2[CH2:9][C:8]2[N:16]=[CH:17][CH:18]=[CH:19][C:7]1=2)=[O:5].C(N(CC)CC)C.[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:42])=[C:37]([CH:41]=1)[C:38](Cl)=[O:39]>ClCCl>[N:16]1[C:8]2[CH2:9][C:10]3[CH:15]=[CH:14][S:13][C:11]=3[CH2:12][N:6]([C:4]([C:3]3[CH:20]=[CH:21][C:22]([NH:24][C:38](=[O:39])[C:37]4[CH:41]=[C:33]([F:32])[CH:34]=[CH:35][C:36]=4[CH3:42])=[CH:23][C:2]=3[Cl:1])=[O:5])[C:7]=2[CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccc(C(=O)N2Cc3sccc3Cc3ncccc32)c(Cl)c1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3sccc3Cc3ncccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2 mmol of 5-(2-chloro-4-aminobenzoyl)-6,10-dihydro-5H-pyrido[3,2-b]thieno[3,2-e]azepine and 10 mmol of triethylamine in 25 ml of dichloromethane is added 2.1 mmol of 5-fluoro-2-methylbenzoyl chloride. After stirring at room temperature for 16 hours, the solution is washed with H2O, 1M NaHCO3 and brine. The solution is dried (Na2SO4) and the solvent removed to give the product as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:18]=[CH:17][O:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.[O:20]1CCCC1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:18]=[CH:17][O:16][CH:15]=2)[CH:12]([OH:20])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccoc2)CC1
Agent: B
Product: CC(C)(C)OC(=O)N1CCC(c2ccoc2)C(O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of 4 (2.33 g, 9.358 mmol) in THF (10 mL) at 0° C. borane-tetrahydrofuran, BH3-THF (28.07 mL, 28.07 mmol, 3 eq., 1M sol. in THF) was added dropwise. After stirring the reaction mixture under inert atmosphere at room temperature for 3 h, the unreacted borane was quenched by the addition of methyl alcohol (30 mL). After quenching, 3N NaOH (30 mL) was added slowly to the reaction mixture. This was followed by the addition of 30% H2O2 (15 mL). The reaction mixture was stirred under inert atmosphere at room temperature for 16 h. Solvents were removed under reduced pressure and the crude mixture was dissolved in ethyl acetate (60 mL). The ethyl acetate solution was washed with water (40 mL), bicarbonate solution (40 mL), water (40 mL), and brine (40 mL), dried over anhydrous magnesium sulfate and filtered. Removal of solvent at reduced pressure yielded the pure, white, crystalline solid 5 (2.18 g, 87%). TLC Rf=0.48 (95% CH2Cl2—MeOH); 400 MHz 1H-NMR (CDCl3) δ 1.47 (s, 9H), 1.57-1.69 (m, 1H), 1.82-1.85 (m, 0.5H), 1.86-1.88 (m, 0.5H), 2.50 (ddd, J=12.4, 10.0, 4.0 Hz, 1H), 2.62 (t, J=10.8 Hz, 1H), 2.76 (m, 1H), 3.47 (m, 1H), 4.12 (m, 1H), 4.32 (m, 1H), 6.35 (s, 1H), 7.38 (d, J=18.8 Hz, 2H); 125 MHz 13C-NMR (CDCl3) δ 14.4, 20.2, 28.6, 40.2, 60.1, 70.1, 80.1, 109.5, 126.0, 139.7, 143.6, 154.9. HRMS Calcd. for C14H21NO4Na [M++Na]: 290.1368. Found: 290.1368.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[CH2:12](Br)[CH3:13].[H-].[Na+]>CN(C)C=O>[CH2:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)[CH3:13]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(C=O)c2ccccc21
Yield: 80 %

Procedure:
1-ethylindole-3-carboxaldehyde was prepared from alkylation reaction of indole-3-carboxaldehyde. Indole-3-carboxaldehyde (900 mg, 6.2 mmol) was dissolved in 5 ml dimethylformamide, ethyl bromide (918 μl, 12 mmol) and sodium hydride (282.8 mg, 12 mmol) were added to the reaction mixture. Solution was stirred and refluxed for three hours. The reaction mixture was then evaporated to dryness and washed with water. Pale brown crystals were obtained with 80% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:19])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.[CH3:20][O:21][CH2:22][CH2:23][CH2:24][C:25]#[CH:26]>>[OH:19][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:26]#[C:25][CH2:24][CH2:23][CH2:22][O:21][CH3:20])[CH:3]=1)[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(Br)c1
Reactant: C#CCCCOC
Product: COCCCC#Cc1cccc(C(O)CCNC(=O)OC(C)(C)C)c1

Procedure:
Sonogashira reaction of 39 with 5-methoxypent-1-yne gave tert-butyl 3-hydroxy-3-(3-(5-methoxypent-1-ynyl)phenyl)propylcarbamate as brown oil. Yield (0.347 g, 66%): 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 1H), 7.27-7.37 (m, 3H), 4.83-4.85 (bs, 1H), 4.69-4.71 (m, 1H), 3.66-3.71 (m, 1H), 3.52 (t, J=6.4 Hz, 2H), 3.48 (m, 1H), 3.36 (s, 3H), 3.29 (bs, 1H), 2.49 (t, J=6.4 Hz, 2H), 1.80-2.02 (m, 4H), 1.45 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:32]1([O:38][C:39](Cl)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl.N1C=CC=CC=1.C(Cl)Cl>[CH3:24][N:21]1[C:22]([CH3:23])=[C:18]([C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:39](=[O:40])[O:38][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:7]=3)=[CH:14][CH:13]=2)=[O:17])[C:19](=[O:31])[N:20]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cc2)c(=O)n(-c2ccccc2)n1C
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.4 %

Procedure:
A suspension of N-(4-((2-aminopyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (600 mg, 1.44 mmol) in DCM/pyridine (30 mL/20 mL) was cooled to 0° C., then a solution of phenylcarbonochloridate (565 mg, 3.61 mmol) in DCM (10 mL) was added to the mixture slowly over 1 hour. The reaction was stirred at rt for 2 hours, then diluted with DCM (200 mL). The mixture was washed with water (140 mL×4), followed by washing with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/EtOAc (v/v)=2/1) to give the title compound as a white solid (327 mg, 42%).