Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][C@H:4]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[ClH:48].[F:49][C:50]1[CH:55]=[CH:54][C:53]([CH:56]([C:61]2[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=2)[CH2:57][CH2:58][CH2:59][NH2:60])=[CH:52][CH:51]=1>CN(C=O)C.C(OCC)C>[ClH:48].[F:49][C:50]1[CH:55]=[CH:54][C:53]([CH:56]([C:61]2[CH:62]=[CH:63][C:64]([F:67])=[CH:65][CH:66]=2)[CH2:57][CH2:58][CH2:59][NH:60][C:5](=[O:7])[C@@H:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH2:3][CH:2]([CH3:1])[CH3:14])=[CH:52][CH:51]=1
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C[C@@H](C(=O)O)N1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
(S)-4-Methyl-2-morpholin-4-yl-pentanoic acid (0.300 g, 1.49 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.779 mL, 4.47 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.565 g, 1.49 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 4,4-bis-(4-fluoro-phenyl)butylamine monohydrochloride (0.444 g, 1.49 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 45 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4.The solution was concentrated in vacuo affording an viscous oil. The crude product was further purified by flash chromatography (70% EtOAc in hexane) and treated with ethereal HCl. Subsequent concentration in vacuo and drying under vacuum provided 0.55 g (75%) of the pure titled compound as a white foam; mp 63-78° C. APCI-MS m/z 445.4 (MH+).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([NH2:6])=[S:5].O.[CH2:14](N)[C:15]#[CH:16]>C(O)C>[CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([NH:6][CH2:16][C:15]#[CH:14])=[S:5]
Reactant: C#CCN
Reactant: COC(C(N)=S)c1ccccn1
Solvent: CCO
Solvent: O
Product: C#CCNC(=S)C(OC)c1ccccn1
Reaction time: 8 h

Procedure:
To 4.4 g. (0.026 mole) of 2-methoxy-2-(2-pyridyl)thioacetamide in 20 ml. of water at 0°C. is added 2.9 g. (0.053 mole) of propargylamine with stirring and the resulting suspension is allowed to stand overnight at 5°C. Ethanol (5 ml.) is added and the mixture is stirred for five hours, then extracted with dichloromethane. The extracts are dried and concentrated. The residue is chromatographed on a silica gel "dry-column," using 1:10 ethyl acetate/ether as the eluant. The product fraction is treated with charcoal, filtered, concentrated and the residue is recrystallized from benzene/ligroin to give 2-methoxy-N-propargyl-2-(2-pyridyl)thioacetamide.
Reaction SMILES: O=[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:6]=1)[CH:3]=O.I.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26]([NH:28][NH2:29])=[NH:27]>>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26]1[N:28]=[N:29][CH:3]=[C:2]([C:5]2[CH:6]=[C:7]([N:11]3[CH2:15][CH2:14][CH2:13][C:12]3=[O:16])[CH:8]=[CH:9][CH:10]=2)[N:27]=1
Reactant: N=C(NN)c1ccc(F)cc1F
Reactant: O=CC(=O)c1cccc(N2CCCC2=O)c1
Agent: I
Product: O=C1CCCN1c1cccc(-c2cnnc(-c3ccc(F)cc3F)n2)c1

Procedure:
Oxo[3-(2-oxopyrrolidin-1-yl)phenyl]acetaldehyde was reacted with 2,4-difluorobenzenecarboximidic hydrazide hydriodide salt (0.74 g, 2.46 mmol) using the method described in Example 1 to give 1-{3-[3-(2,4-difluorophenyl)-[1,2,4]triazin-5-yl]phenyl}pyrrolidin-2-one as a yellow solid (0.5 g): δH H (400 MHz, d6-DMSO) 2.08-2.16 (2H, m), 2.55 (2H, t, J 8.2 Hz), 3.96 (2H, t, J 7.0 Hz), 7.34-7.39 (1H, m), 7.49-7.56 (1H, m), 7.65 (1H, t, J 8.0 Hz), 8.00-8.03 (1H, m), 8.16 (1H, d, J 7.8 Hz), 8.27-8.33 (1H, m), 8.59 (1H, t, J 1.8 Hz), 10.08 (1H, s); m/z (ES+) 353.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]([F:19])[CH:11]=[C:12]2[C:16]=1[NH:15][C:14](=O)[C:13]2=O.O.[OH-].[Na+]>C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([F:19])[CH:11]=[C:12]2[C:16]=1[NH:15][CH:14]=[CH:13]2
Reactant: O=C1Nc2c(Cl)cc(F)cc2C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cc(Cl)c2[nH]ccc2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 37 %

Procedure:
To a stirred solution of lithium aluminium hydride (0.57 g, 15 mmol) in THF (20 mL) at 0° C. under Ar was added portionwise 7-chloro-5-fluoroindole-2,3-dione. The mixture was heated under reflux for 4 h, cooled to 0° C. and water (0.5 mL) was added. The mixture was stirred for 5 min then treated with aqueous sodium hydroxide solution (2 N, 0.5 mL) followed by water (0.5 mL) and filtered through a pad of celite®. The filter-cake was washed with tetrahydrofuran and the filtrate was concentrated in vacuo and purified by column chromatography [SiO2; heptane-ethyl acetate (3:1)] to give the product (0.31 g, 37% yield) as a blue-oil: IR νmax (film)/cm−1 3459, 1575, 1485, 1341, 1120 and 722; NMR δH (400 MHz, CDCl3) 6.55 (1H, t, J 2.5 Hz) 7.01 (1H, dd, J 9,2 Hz) 7.21 (1H, m) 7.29 (1H, t, J 2.5 Hz) 8.33 (1H, brs).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]([OH:13])[C:10]([C:14]#[C:15][Si](C)(C)C)=[CH:9][N:8]=1.Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1.C(N(CC)CC)C.O>CN(C=O)C>[C:14]([C:10]1[C:11]([O:13][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[N:12][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:8][CH:9]=1)#[CH:15]
Reactant: COc1ccc(CCl)cc1
Reactant: C[Si](C)(C)C#Cc1cnc(-c2ccccn2)nc1O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: C#Cc1cnc(-c2ccccn2)nc1OCc1ccc(OC)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 25.6 %

Procedure:
A mixture of compound 37-i (1.0 g, 3.7 mmol), 1-(chloromethyl)-4-methoxybenzene (0.7 g, 4.4 mmol), and triethylamine (1.5 g, 11.1 mmol) in DMF (10 mL) was stirred overnight at 80° C. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (PE:EA=1:3) to afford compound 37-j (300 mg, 25%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.988-8.980 (s, 1H)), 8.775 (s, 1H), 8.581-8.555 (m, 1H), 8.020 (m, 1H), 7.554-7.541 (m, 1H), 7.522-7.493 (d, J=8.7 Hz, 2H), 6.924-6.895 (d, J=8.7 Hz, 2H), 5.741 (s, 2H), 3.807 (s, 1H), 3.509 (s, 1H), LC-MS (ESI): 318 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[N+:11]([O-])([O-:13])=[O:12].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(F)ccc1C#N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(F)c([N+](=O)[O-])cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
4-Fluoro-2-methylbenzonitrile (10 mmol, 1.35 g) was dissolved in concentrated sulphuric acid (10 mL) under argon then treated with potassium nitrate (10 mmol, 1.01 g, 1 eq) at 0° C. portionwise to keep the temperature around 0° C. The mixture was allowed to stir for 2 h while warming up to room temperature. The mixture was then poured onto ice and extracted twice with ether. The organics were combined, dried and concentrated under reduced pressure to give the title compound as a solid (9.4 mmol, 1.7 g, 94% yield).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:14]([O:16][C:17](=[O:36])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=1)[CH3:15]>>[CH2:14]([O:16][C:17](=[O:36])[CH2:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[CH3:15]
Reactant: O=Cc1ccc(C(F)(F)F)cc1Br
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc(C(F)(F)F)ccc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 2-bromo-4-trifluoromethyl-benzaldehyde and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.I[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].N1CCC[C@H]1C(O)=O>[Cu]I.CCOC(C)=O.O.CS(C)=O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(I)cc1
Reactant: Nc1ccc(F)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2ccc(F)cc2)cc1
Temperature: 90 °C
Yield: 77.8 %

Procedure:
A mixture of 4-fluoroaniline (78.63 g, 0.708 mol), 4-iodoanisole (138.00 g, 0.590 mol), anhydrous K2CO3 (122.23 g, 0.884 mol), CuI (11.23 g, 58.96 mmol) and L-proline (13.58 g, 0.118 mol) was mixed together in a dry 1 L three-necked round-bottomed flask fitted with a stirring bar, a reflux condenser and an argon inlet. Anhydrous DMSO (300 mL) was added at room temperature. The reaction mixture was stirred and heated to 90° C. for 20 hours under argon. Then, the mixture was cooled to room temperature and hydrolyzed with water (300 mL). EtOAc (200 mL) was added to partition the solution. The EtOAc layer was separated. The aqueous layer was extracted with 100 mL of EtOAc. The EtOAc layers were combined, washed with brine (2×100 mL) and dried over anhydrous MgSO4 (50 g). The solvent was removed under reduced pressure. The brown oil residue was purified by flash column chromatography (silica gel, Hexanes/EtOAc=9/1 v/v) to afford 4-fluoro-N-(4-methoxyphenyl)aniline (1c) as a yellow solid product, 99.70 g, 77.8% yield. M.p. 46-48° C. MS (ESI) m/z 218.1 [M+H]+, 1H NMR (DMSO-d6, 300 MHz) δ 7.77 (bs, 1H), 7.03-6.98 (m, 4H), 6.93-6.82 (m, 4H), 3.70 (s, 3H).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[OH:14][C@@H:15]1[C@@H:34]([N:35]2[CH2:40][CH2:39][O:38][C:37]([CH3:42])([CH3:41])[CH2:36]2)[CH2:33][C@@:32]2([CH3:43])[C@@H:17]([CH2:18][CH2:19][C@@H:20]3[C@@H:31]2[C@@H:30]([OH:44])[CH2:29][C@@:28]2([CH3:45])[C@H:21]3[CH2:22][CH2:23][C@@H:24]2[C:25](=[O:27])[CH3:26])[CH2:16]1>CO>[OH:14][C@@H:15]1[C@@H:34]([N:35]2[CH2:40][CH2:39][O:38][C:37]([CH3:42])([CH3:41])[CH2:36]2)[CH2:33][C@@:32]2([CH3:43])[C@@H:17]([CH2:18][CH2:19][C@@H:20]3[C@@H:31]2[C@@H:30]([OH:44])[CH2:29][C@@:28]2([CH3:45])[C@H:21]3[CH2:22][CH2:23][C@@H:24]2[C:25](=[O:27])[CH3:26])[CH2:16]1.[OH:4][C:3]([C:5]([O-:7])=[O:6])([CH2:8][C:9]([O-:11])=[O:10])[CH2:2][C:1]([O-:13])=[O:12]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCOC(C)(C)C5)C[C@]4(C)[C@H]3[C@@H](O)C[C@]12C
Solvent: CO
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
A solution of citric acid (92 mg) in methanol (3 ml) was added to a suspension of (2β,3α,5α,11β)-3,11-dihydroxy-2-(2,2-dimethyl-4-morpholinyl)pregnan-20-one (213 mg) in methanol (2 ml). The resulting solution was taken to dryness under reduced pressure to give (2β,3α,5α,11β)-3,11-dihydroxy-2-(2,2-dimethyl-4-morpholinyl)pregnan-20-one 2-hydroxy-1,2,3-propanetricarboxylate (1:1) salt. [α]D +119° (c 0.3).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:28][C:15]3[N:16]=[C:17](SC)[N:18]=[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[C:29]1([C:35]2[CH:36]=[N:37][CH:38]=[C:39]([Sn](CCCC)(CCCC)CCCC)[CH:40]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>COCCOC.C(OCC)(=O)C.CSC.[Cu]Br.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][S:2]([N:5]1[CH2:6][CH2:7][N:8]([CH2:11][C:12]2[S:28][C:15]3[N:16]=[C:17]([C:39]4[CH:38]=[N:37][CH:36]=[C:35]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:40]=4)[N:18]=[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]=3[CH:13]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: CSc1nc(N2CCOCC2)c2cc(CN3CCN(S(C)(=O)=O)CC3)sc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(-c2ccccc2)c1
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CSC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cncc(-c5ccccc5)c4)nc3s2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[2,3-d]pyrimidine (135 mg) in 1,2-dimethoxyethane (10 mL) was added 3-phenyl-5-tributylstannanyl-pyridine (270 mg) and copper(I)bromide-dimethyl sulfide (125 mg) and the reaction mixture was stirred at room temperature for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (18 mg) was then added and the reaction mixture was heated at reflux for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (20 mL) and washed with water (2×20 mL) and brine (2×20 mL). The organic phase was dried (MgSO4), reduced in vacuo and purified by column chromatography to give 403. NMR: (CDCl3): 3.17 (3H, s, Me), 3.93-3.95 (4H, m), 4.13-4.16 (4H, m), 5.28 (2H, s, NH), 7.83 (1H, t, J 7.0, Ar), 7.92 (1H, s, Ar), 8.26 (2H, td, J 7.7 and 1.5, Ar), 8.53-8.54 (1H, m, Ar) and 9.30 (2H, s, Ar). MS: (ESI+): MH+497.08
Reaction SMILES: C(N(CC)[C:4](=[O:18])[C:5]([OH:17])([C:8]1[CH:13]=[CH:12][NH:11][C:10](=[O:14])[C:9]=1[CH2:15][OH:16])[CH2:6][CH3:7])C.C(N(CC)C(=O)C(=O)CC)C.Cl>C(COC)OC>[CH2:6]([C:5]1([OH:17])[C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[C:9]=2[CH2:15][O:16][C:4]1=[O:18])[CH3:7]
Reactant: CCN(CC)C(=O)C(O)(CC)c1cc[nH]c(=O)c1CO
Agent: CCC(=O)C(=O)N(CC)CC
Agent: Cl
Solvent: COCCOC
Product: CCC1(O)C(=O)OCc2c1cc[nH]c2=O
Reaction time: 4 h
Yield: 21.4 %

Procedure:
To a suspension of 560.0 mg of compound (15) as obtained from example 9 (1.983 mmol) in 11.2 mL dimethoxyethane were added dropwise at 0° C. 1.68 mL concentrated aqueous hydrochloric acid (36.5%) (19.83 mmol, 10.0 eq). The ice bath was removed after 15 min and the triphasic mixture was vigorously stirred. After 4 h, the mixture was evaporated to dryness in a rotary evaporator (27° C., 5 mbar, then 1 mbar). The crude product was obtained as a lightly yellow semisolid (805.4mg, 194% by weight).333.3 mg crude product were purified by trituration with 0.7 mL methanol at room temperature for 18 h furnishing the title compound (168.7 mg, 0.425 mmol, 98% by weight) as white crystals.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][CH:32]([O:35][CH2:36][CH:37]=[CH2:38])[CH2:31][CH2:30]1.I([O-])(=O)(=O)=[O:40].[Na+].C[Mg]Br.[Cl-].[NH4+].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C.O.O1CCCC1.C(#N)C.[Os]=O.CC(C)=O>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:30][CH2:31][CH:32]([O:35][CH2:36][C:37](=[O:40])[CH3:38])[CH2:33][CH2:34]1
Reactant: C=CCOC1CCC(n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc23)CC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os]
Agent: C[Mg]Br
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OCC(C)=O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.2 %

Procedure:
A mixture of 4′-({5-oxo-4-[4-(prop-2-en-1-yloxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (1.8 g), osmium oxide (7% immobilized catalyst, 0.92 g), sodium periodate (3.9 g), acetone (20 mL), acetonitrile (20 mL) and water (20 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate and water, and the insoluble material was filtered off through celite. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel chromatography was dissolved in tetrahydrofuran (20 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 1.9 mL) was added at −78° C. The reaction mixture was warmed to 0° C., and stirred for 16 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel chromatography was dissolved in acetonitrile (15 mL), 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-on (0.3 g) was added, and the mixture was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate solution and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.17 g, 68%).
Reaction SMILES: BrC1C=CC(CCC(C)(S(C)(=O)=O)C(O)=O)=CC=1.C([O:21][C:22](=[O:39])[C:23]([S:35]([CH3:38])(=[O:37])=[O:36])([CH3:34])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=1[F:33])C.[OH-].[Li+]>O>[Br:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][C:23]([S:35]([CH3:38])(=[O:36])=[O:37])([CH3:34])[C:22]([OH:39])=[O:21])=[C:27]([F:33])[CH:28]=1
Reactant: CCOC(=O)C(C)(CCc1ccc(Br)cc1F)S(C)(=O)=O
Agent: CC(CCc1ccc(Br)cc1)(C(=O)O)S(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(CCc1ccc(Br)cc1F)(C(=O)O)S(C)(=O)=O

Procedure:
The title compound was synthesized according to the general procedure of Preparation 2, Step 3, for the preparation of (II) except that 4-(4-bromo-2-fluoro-phenyl)-2-methanesulfonyl-2-methyl-butyric acid ethyl ester was used instead of (+/−)-ethyl 4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoate and that lithium hydroxide was dissolve in water prior to addition to yield as a white solid: 1.96 g, (96.2%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.76 (s, 3H) 2.23 (td, 1H) 2.47 (td, J=12.59, 4.88 Hz, 1H) 2.63 (td, J=12.88, 4.68 Hz, 1H) 2.84 (td, J=12.49, 5.07 Hz, 1H) 3.11 (s, 3H) 7.10 (t, J=8.20 Hz, 1H) 7.20-7.23 (m, 1H) 7.25-7.34 (m, 1H)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:14][C:13]([SH:15])=[N:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].CC(O[CH2:25][C:26]1[CH2:35][S:34][C@@H:29]2[C@H:30]([NH2:33])[C:31](=[O:32])[N:28]2[C:27]=1[C:36]([OH:38])=[O:37])=O.Cl>CC(C)=O>[NH2:33][CH:30]1[C:31](=[O:32])[N:28]2[C:27]([C:36]([OH:38])=[O:37])=[C:26]([CH2:25][S:15][C:13]3[S:14][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[N:11][N:12]=3)[CH2:35][S:34][C@H:29]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)NCc1nnc(S)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Reaction time: 2 h
Yield: 56.2 %

Procedure:
5-Tert-butoxycarbonylaminomethyl-1,3,4-thiadiazole-2-thiol (1.24 g.) was dissolved in acetone (10 ml.). The solution was added to the aqueous solution (40 ml.) containing sodium bicarbonate (0.84 g.). The mixed solution was warmed on water bath heating at 70°-75° C. To the solution was added all at once 7-aminocephalosporanic acid (1.35 g.) at 55° C. The mixture was stirred at 65°-70° C. for 2 hrs. and then cooled to 0°-5° C. with ice. The reaction mixture was adjusted to pH 5.0-5.2 with 10% hydrochloric acid. The precipitating pale yellow substance was separated out by filtration, washed with water and acetone, and then dried to give 7-amino-3-(5-tert-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.28 g.). m.p. over than 220° C.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(B(O)O)C=CC=CC=1.IC1[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=1>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].[Pd].[Pd].[Pd].O>[C:1]1([C:7]2[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1
Reactant: Nc1ccc(I)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccccc1
Solvent: O
Product: Nc1ccc(-c2ccccc2)cn1
Yield: 28 %

Procedure:
A mixture of toluene (15 mL) and water (5 mL) was degassed with argon gas for 5 minutes. Sodium carbonate (481 mg, 4.5 mmol) was added and the resulting mixture was again degassed with argon gas for 5 minutes. Phenyl boronic acid (353 mg, 2.7 mmol) and 5-iodo-pyridin-2-ylamine (500 mg, 2.27 mmol) were added and the mixture was again degassed with argon gas for 5 minutes. Tetrakis palladium triphenyl phosphine (525 mg, 4.5 mmol) was then added and the mixture was again degassed with argon gas for 5 minutes. The resulting mixture was heated to reflux for 3 hours. The mixture was then diluted with ethyl acetate and washed with water followed by brine solution. The ethyl acetate layer was collected, dried over sodium sulphate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (35% ethyl acetate in hexane) to afford 10 mg (28%) of 5-phenyl-pyridin-2-ylamine. LCMS: 171.09 (M+1)+, 60.5%.
Reaction SMILES: [OH:1][C:2]1([C:31](O)=[O:32])[CH2:7][CH2:6][CH:5]([N:8]2[C:16]([NH:17][C:18]3[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=3[F:26])=[N:15][C:14]3[C:9]2=[N:10][C:11]([NH:27][CH:28]([CH3:30])[CH3:29])=[N:12][CH:13]=3)[CH2:4][CH2:3]1.[CH:34]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35]1.C(NC(C)C)(C)C>C1COCC1>[CH:34]1([NH:39][C:31]([C:2]2([OH:1])[CH2:7][CH2:6][CH:5]([N:8]3[C:16]([NH:17][C:18]4[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=4[F:26])=[N:15][C:14]4[C:9]3=[N:10][C:11]([NH:27][CH:28]([CH3:30])[CH3:29])=[N:12][CH:13]=4)[CH2:4][CH2:3]2)=[O:32])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CC(C)Nc1ncc2nc(Nc3c(F)cc(F)cc3F)n(C3CCC(O)(C(=O)O)CC3)c2n1
Reactant: NC1CCCC1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)Nc1ncc2nc(Nc3c(F)cc(F)cc3F)n(C3CCC(O)(C(=O)NC4CCCC4)CC3)c2n1
Reaction time: 0.17 h
Yield: 66 %

Procedure:
1-Hydroxy-4-{2-[(methylethyl)amino]-8-[(2,4,6-trifluorophenyl)amino]purin-9-yl}cyclohexanecarboxylic acid (0.200 g, 0.4 mmol) was dissolved in 4 mL of dry THF. Cyclopentyl amine (0.079 mL, 0.8 mmol) was added neat followed by di-isopropyl amine (0.105 mL, 0.6 mmol). Benzotriazol-1-yloxytris(dimethylamino)phosphponium hexafluorophosphate (BOP) was added last, as a solid in one portion at room temperature (0.177 g, 0.4 mmol). The reaction was complete within 10 min as confirmed by LC-MS. DMF was removed under reduced pressure. The residue was triturated in saturated aqueous sodium bicarbonate. The resulting beige solid was collected by filtration and washed with water. The crude product was re-crystallized from hot methanol-water. The crystals were dried in vacuum oven. (141 mg, 66% yield) M+1: 532.