Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH:9]1[CH2:13][C:12](=[O:14])[CH:11]=[CH:10]1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[I-].[Li+].[H-].[Al+3].[Li+].[H-].[H-].[H-].COC(C)(C)C>CCCCCCC>[Si:2]([O:1][C@@H:9]1[CH2:13][C@H:12]([OH:14])[CH:11]=[CH:10]1)([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC1C=CC(=O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [I-]
Solvent: CCCCCCC
Solvent: COC(C)(C)C
Product: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@@H](O)C1
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 73.9 %

Procedure:
A mechanically stirred solution of 4-tert-butyldimethylsiloxy-2-cyclopentenone (50.2 g, 236 mmol) in anhydrous toluene (1L) under an atmosphere of argon is treated with lithium iodide (160 g, 1.20 mol). The mixture is cooled to -20° C. and treated with lithium aluminum hydride (9.0 g, 237 mmol) in one portion. The reaction is then stirred for 5 minutes and anhydrous tert-butyl methyl ether (200 mL) is added at a rate that maintains the temperature of the reaction at or below -15° C. (total addition time is approximately 3 minutes). The reaction is stirred for one hour at -20° C. and then it is quenched by slow addition of aqueous sodium hydroxide (1N, 250 mL) at a rate that maintains the temperature of the reaction below 20° C. The resulting suspension is then filtered through a pad of diatomaceous earth and the pad is subsequently rinsed with toluene (400 mL). The filtrate phases are separated and the aqueous phase is extracted with toluene (300 mL). The organic phase and organic extract are combined, rinsed with aqueous sodium hydroxide (1N, 300 mL), brine (300 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum (40° C., 20 mmHg). The residue is then purified by Kugelrohr distillation (60°-80° C., 1 mmHg) to provide the title compound (37.4 g, 74% yield) as a colorless oil; cis/trans/1-2+1-4 addition, 95.3/2.1/2.6; Rf =0.20, 20% ethyl acetate/hexane, GC retention time for the title compound is 13.95 minutes, while GC retention times for the byproducts corresponding to compounds 3 (trans) and 4 (1-2+1-4 addition) in Scheme I wherein Pg is a TBDMS group are 14.45 min. and 14.06 min. respectively; for the title compound, 1H NMR (CDCl3)δ 5.93 (dt, J=5.5, 1.7 Hz, 1H), 5.84 (dr, J=5.5, 1.6 Hz, 1H), 4.63-4.68 (m, 1H), 4.52-4.62 (m, 1H), 2.76-2.86 (bs, 1H), 2.69 (dr, J=13.8, 7.1 Hz, 1H), 1.52 (dt, J=13.8, 4.7 Hz, 1H), 0.90 (s, 9H), 0.09 (s, 6H); 13C NMR (CDCl3) δ 136.7, 135.6, 75.1, 75.0, 44.5, 25.9, 18.1; IR (neat) νmax 3373, 2957, 2932 cm-1 ; MS (EI) m/e (% relative intensity) 157 (M+ -57).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:7][N:8]=1.[CH2:18]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)/[CH:19]=[C:20](/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])\[CH3:21].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH2:18]([O:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([NH:3][C:4]2[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:7][N:8]=2)=[O:34])=[CH:36][CH:37]=1)/[CH:19]=[C:20](/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])\[CH3:21]
Reactant: Nc1nnc(SCCN2CCCCC2)s1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)Nc2nnc(SCCN3CCCCC3)s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.8 %

Procedure:
Sodium hydride (0.4 g) and 2-amino-5-piperidinoethylthio-1,3,4-thiadiazole (1.5 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 4-Geranyloxybenzoic acid (1.6 g) and carbonyldiimidazole (1.1 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 2.3 g of the aimed compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]2[C:14]3[N:15]=[CH:16][CH:17]=[C:18](O)[C:13]=3[CH:12]=[N:11]2)=[CH:7][CH:6]=1.FC(F)(F)S(N(C1C=CC=CC=1)S(C(F)(F)F)(=O)=O)(=O)=O.[N:43]1([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.[NH4+].[Cl-]>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]2[C:14]3=[N:15][CH:16]=[CH:17][C:18]([N:46]4[CH2:45][CH2:44][N:43]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:48][CH2:47]4)=[C:13]3[CH:12]=[N:11]2)=[CH:7][CH:6]=1
Reactant: COc1ccc(Cn2ncc3c(O)ccnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)ccnc32)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
NaH (0.188 g, 4.70 mmol) in DMF (5 mL) was added dropwise to 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (1.00 g, 3.92 mmol, prepared as described in WO 2007/103308) in DMF (10 mL). The reaction mixture was then warmed to 40° C. and stirred for 30 minutes. After cooling to room temperature, 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (1.68 g, 4.70 mmol) was added and stirred at room temperature for 1 hour. Then tert-butyl piperazine-1-carboxylate (1.61 g, 8.62 mmol) was added. The mixture was warmed to 80° C. and stirred for 3 hours. The reaction was then cooled to room temperature, and a saturated solution of NH4Cl (30 mL) was added. The mixture was extracted with ethyl acetate (2×30 mL) and dried over sodium sulfate. After removal of solvent, the resulting residue was purified by column chromatography (hexane:ethyl acetate, 5:1) to give tert-butyl 4-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (1.64 g, 99% yield) as a solid. MS APCI (+) m/z 424.1 detected. 1H NMR (400 Hz, DMSO-d6) δ 8.24 (s, 1H), 8.13 (d, J=5.2 Hz, 1H), 7.18 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 6.42 (d, J=5.2 Hz, 1H), 5.49 (s, 2H), 3.69 (s, 3H), 3.64 (m, 4H), 3.53 (m, 4H).
Reaction SMILES: [Na].C([O-])(C)C.[Na+:6].[CH3:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([OH:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(O)(C)C>[CH3:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]([O-:30])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7].[Na+:6]
Reactant: CCCCCCCCCCCC(O)CCCCCCCCCCC
Agent: CC(C)[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)O
Product: CCCCCCCCCCCC([O-])CCCCCCCCCCC
Temperature: 175 °C

Procedure:
3.1 g (0.135 mole) sodium metal was dissolved in 40 ml isopropanol under reflux conditions for 4 hrs to make a solution of sodium isopropanolate in isopropanol. 47 g (0.138 mole) 12-tricosanol was added and the resulting isopropanol was subsequently evaporated by heating to 170-180° C. for 2 hrs to yield the sodium 12-tricosanolate for further reaction.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH2:24][CH2:25][CH:26]([OH:28])[CH3:27])C1C=CC=CC=1.C(=O)(O)[O-].[Na+].[H][H]>[Pd].C(O)C>[CH3:23][C:15]([C:13]1[CH:12]=[CH:11][C:10]([CH2:24][CH2:25][CH:26]([OH:28])[CH3:27])=[C:9]([OH:8])[CH:14]=1)([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: [H][H]
Reactant: CCCCCCC(C)(C)c1ccc(CCC(C)O)c(OCc2ccccc2)c1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCCCCC(C)(C)c1ccc(CCC(C)O)c(O)c1

Procedure:
A mixture of 390 mg. (1.02 mmols.) of 4-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-butanol, 360 mg. of solid sodium bicarbonate, 100 mg. of 10% palladium-on-carbon and 10 ml. of ethanol is stirred under one atmosphere of hydrogen for 20 minutes. The reaction mixture is filtered through diatomaceous earth with ethyl acetate and evaporated to an oil. The oil is purified via rapid column chromatography on silica gel eluted with ether to give a quantitative yield of the title compound as an oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1[C:12]([F:23])=[C:13]([CH2:20][CH2:21][OH:22])[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1.[C:24](Cl)(=[O:26])[CH3:25]>C1COCC1>[C:24]([O:22][CH2:21][CH2:20][C:13]1[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=[C:11]([NH2:10])[C:12]=1[F:23])(=[O:26])[CH3:25]
Reactant: Nc1ccc([N+](=O)[O-])c(CCO)c1F
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)OCCc1c([N+](=O)[O-])ccc(N)c1F
Reaction time: 1.5 h
Yield: 68.5 %

Procedure:
To a solution of DIEA (1.80 mL, 10.6 mmol) and 2-(3-amino-2-fluoro-6-nitrophenyl)ethanol (0.88 g, 4.40 mmol), as prepared in the preceding step, in THF (10 mL) in an ice-bath was added a solution of acetyl chloride (319 μL, 4.49 mmol) in THF (5 mL). After stirring for 1.5 hour, the ice-bath was removed and the mixture was continued to stir at ambient temperature overnight. Additional acetyl chloride (63 μL, 0.88 mmol) was added, and the mixture was stirred for another 16 hours. The solvents were removed, and the mixture was partitioned between DCM and H2O. The organic layer was separated, and the aqueous layer was back-extracted with DCM. The organic layers were combined, washed with H2O (twice), dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with EtOAc/DCM (0, 1, 2, and 5%) to give the title compound (0.73 g, 69% yield) as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ 7.85 (dd, J=9.0, 1.5 Hz, 1H), 6.68 (t, J=8.9 Hz, 1H), 4.38-4.35 (m, 4H), 3.38 (dt, J=6.6, 2.8 Hz, 2H), 2.03 (s, 3H).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:12][CH:13]([OH:16])[C:14]#[CH:15]>CN(C=O)C.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.[Cu]I>[OH:16][CH:13]([CH3:12])[C:14]#[C:15][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccccc1I
Reactant: C#CC(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1C#CC(C)O
Temperature: 60 °C
Reaction time: 6 h

Procedure:
Pd(PPh3)4 (1.9 g, 0.006 eq) and CuI (2.6 g, 0.05 eq) were suspended in DMF (350 ml). Methyl 2-iodobenzoate (70.8 g, 1 eq), but-3-yn-2-ol (32 ml, 1.5 eq), TEA (75 ml, 2 eq) were added under nitrogen atmosphere and the mixture was stirred at 60° C. for 6 hrs and at RT. overnight. The precipitated solid was filtered off, the mother liquors was diluted with a saturated solution of NaClaqueous and extracted with EtOAc (twice). The collected organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound, as a brownish thick oil (47.7 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:46][O:47][CH3:48])[C:8]([NH:10][CH:11]2[C:44](=[O:45])[N:13]3[C:14]([C:28]([O:30]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:29])=[C:15]([CH2:18][S:19]/[CH:20]=[CH:21]\[C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:46][O:47][CH3:48])[C:8]([NH:10][CH:11]2[C:44](=[O:45])[N:13]3[C:14]([C:28]([OH:30])=[O:29])=[C:15]([CH2:18][S:19]/[CH:20]=[CH:21]\[C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CS/C=C\c3cccnc3)CS[C@H]12)c1csc(N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CS/C=C\c3cccnc3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 43.3 %

Procedure:
To a suspension of benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylate (syn isomer) (1 g) in anisole (2.5 ml) was added trifluoroacetic acid (6 ml) under ice-cooling. The mixture was stirred for 40 minutes at ambient temperature, concentrated in vacuo to about a half volume and poured into diisopropyl ether (120 ml). The resulting precipitate was collected, dissolved in an aqueous solution (150 ml) of sodium bicarbonate (320 mg). The aqueous solution was washed with ethyl acetate and adjusted to pH 4-5 with 1N hydrochloric acid to give a precipitate. The precipitate was collected, washed with water and dried over phosphorus pentoxide to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer) (330 mg).
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:15][CH:16]=2)[O:11][C:10]=1[C:38]1[CH:43]=[C:42]([O:44]C)[C:41]([O:46]CC2C=CC=CC=2)=[C:40]([O:54]C)[CH:39]=1)C1C=CC=CC=1.B(Br)(Br)Br.CO.O>ClCCl>[OH:8][C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:15][CH:16]=2)[O:11][C:10]=1[C:38]1[CH:43]=[C:42]([OH:44])[C:41]([OH:46])=[C:40]([OH:54])[CH:39]=1
Reactant: CCCCCCCCCCCCCCCCCCc1ccc2c(=O)c(OCc3ccccc3)c(-c3cc(OC)c(OCc4ccccc4)c(OC)c3)oc2c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCc1ccc2c(=O)c(O)c(-c3cc(O)c(O)c(O)c3)oc2c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a stirring solution of 40j (0.455 g, 0.6 mmol) in dichloromethane (25 ml) under Ar at 0° C. was added boron tribromide in dichloromethane (1.0M, 6 ml, 6 mmol, 9.8 equ). The mixture was warmed to room temperature and then stirred for 22 hours. The reaction was then cooled to 0° C. and methanol (25 ml) added. The reaction was heated to reflux for 2 hours, then concentrated in vacuo to give a yellow solid. Water (50 ml) was added and sonicated then left to stand overnight then 9j (0.325 g, 99%) was collected as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10]Cl.[BH4-].[Na+]>O1CCOCC1.O>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[NH:1][CH:10]=[CH:9]2
Reactant: Nc1c(Cl)cccc1C(=O)CCl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Clc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dissolve 1-(2-amino-3-chlorophenyl)-2-chloroethanone (7.0 g, 34.30 mmol) in 10% aqueous 1,4-dioxane (75 mL). Carefully add NaBH4 (2.6 g, 68.6 mmol, 2 eq.) as a solid. Heat to reflux. After 4 hours, cool to room temperature, dilute with water (300 mL), and extract with dichloromethane (2×200 mL). Combine the organic layers, dry over MgSO4, filter, and remove the solvent in vacuo leaving a light brown oil in the flask. Purify the oil by HPLC (silica gel mobile phase: 100% hexane to 50% EtOAc in hexanes over 50 minutes), to give the title compound as a brown oil: 1H NMR (300 MHz, d6-DMSO-d6): 5.16 (m, 1H), 5.39 (d, 1H), 5.70 (bs, 1H), 6.59 (t, 1H), 7.09 (m, 2H); MS (ES+): m/z 154, 152 (M+H)+.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:33]([C:34]#[C:35][CH2:36][NH:37][C:38](=[O:43])[C:39]([F:42])([F:41])[F:40])=[CH:32][N:13]([C@@H:14]2[O:31][C@H:21]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C@@H:16]([O:17][CH2:18]SC)[CH2:15]2)[C:12](=[O:44])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCCCC=1.[N-:51]=[N+:52]=[N-:53].[Na+]>C(Cl)Cl.CN(C=O)C>[C:1]([NH:9][C:10]1[C:33]([C:34]#[C:35][CH2:36][NH:37][C:38](=[O:43])[C:39]([F:42])([F:41])[F:40])=[CH:32][N:13]([C@@H:14]2[O:31][C@H:21]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C@@H:16]([O:17][CH2:18][N:51]=[N+:52]=[N-:53])[CH2:15]2)[C:12](=[O:44])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CSCO[C@H]1C[C@H](n2cc(C#CCNC(=O)C(F)(F)F)c(NC(=O)c3ccccc3)nc2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C#CCNC(=O)C(F)(F)F)c(NC(=O)c3ccccc3)nc2=O)C[C@@H]1OCN=[N+]=[N-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
The starting material (14) (1.65 g, 2.99 mmol) was dissolved in DCM (18 ml) and cooled to 0° C. Cyclohexene (1.5 ml, 14.95 mmol) and SO2Cl2 (0.72 ml, 8.97 mmol) were added and stirred 1 h in ice bath. TLC indicated starting material still to be present whereupon a further aliquot of SO2Cl2 (0.24 ml) was added and the mixture stirred for 1 h at 0° C. Volatiles were removed by evaporation to yield a light brown solid that was redissolved in 18 ml of dry DMF (18 ml) under N2. Sodium azide (0.97 g, 14.95 mmol) was then added to the solution and stirred for 2.5 h at room temperature. The reaction mixture was passed through a pad of silica and eluted with EtOAc and the volatiles removed by high vacuum evaporation. The resulting brown gel was purified by flash chromatography (petroleum ether:EtOAc 4:1 to 2:1) to yield the desired product as a white crystalline solid (15) (0.9 g, 55%). 1H NMR (d6 DMSO): δ 0.00 (s, 6H, CH3), 0.78 (s, 9H, tBu), 2.16 (m, 1H, H-2′), 2.22 (m, 1H, H-2′), 3.70 (d, 1H, J=11.5 Hz, H-5′), 3.75 (d, 1H, J=11.3 Hz, H-5′), 4.01 (m, 1H, H-4′), 4.10 (m, 1H, CH2NH), 4.23 (m, 1H, H-3′), 4.76 (s, 2H, CH2S), 5.99 (m, 1H, H-1′), 7.37 (m, 2H, Ph), 7.50 (m, 2H, Ph), 7.81 (d, 1H, J=7.4 Hz, Ph), 7.95 (s, 1H, H-6), 9.78 (br s, 1H, NHCH2), 12.64 (br s, 1H, NH). Mass (−ve electrospray) calcd for C28H34F3N7O6Si 649.71. Found 648.2
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[CH:4][C:3]=1[F:10].CC(C)([O-])C.[Na+].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:8]([C:6]1[CH:5]=[CH:4][C:3]([F:10])=[C:2]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:7]=1)[CH3:9]
Reactant: CCc1ccc(F)c(Br)c1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCc1ccc(F)c(N2CCOCC2)c1
Temperature: 85 °C
Reaction time: 15 h
Yield: 88.4 %

Procedure:
To Intermediate 228.1 (203 mg, 1.00 mmol), BINAP (39.8 mg, 0.06 mmol), sodium tert-butoxide (115.3 mg, 1.20 mmol), morpholine (105 μL, 1.2 mmol) and Pd2(dba)3 (27.5 mg, 0.03 mmol), was added 5 mL toluene. The reaction vial was sealed and stirred at 85° C. for 15 h. The mixture was filtered through a 1″ pad of silica gel, eluting with 20% EtOAc/hexanes. The crude product was purified by flash chromatography (0 to 20% EtOAc/hexanes gradient) to afford 185 mg of intermediate 230.1. LCMS (2 min gradient) RT=1.66 min, 210.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH:13]=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:19]1(C)[CH:24]=CC=[CH:21][CH:20]=1.CC(O)C=C.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:15]([C:12]([CH2:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])([CH2:24][CH:19]=[CH:20][CH3:21])[CH:13]=[O:14])[CH2:16][CH2:17][CH3:18]
Reactant: Cc1ccccc1
Reactant: CCCCC(C=O)CS(=O)(=O)c1ccc(C)cc1
Agent: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC=CCC(C=O)(CCCC)CS(=O)(=O)c1ccc(C)cc1

Procedure:
Advantageously, the conversion of 18a to 47 and the conversion of 47 to 31 can be carried out sequentially or simultaneously in a single reaction vessel or in a single reaction mixture without isolation. To further advantage, the preparation of the acetal 18 from aldehyde 19, the conversion of 18 to the corresponding enol ether intermediate, and the conversion of the enol ether intermediate to 31 can all be carried out in a single reaction vessel or reaction mixture. For example, 2-(((4-methylphenyl)sulfonyl)methyl)hexanal can be heated in a solvent such as toluene in the presence of 3-buten-2-ol and p-toluenesulfonic acid with removal of water (e.g., with a Dean-Stark trap) to produce 2-butyl-2-(((4-methylphenyl)sulfonyl)methyl)hex-4-enal.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.C(N(CC)CC)C.[Cl:18][C:19]([Cl:23])([Cl:22])[S:20]Cl>C1C=CC=CC=1>[Cl:18][C:19]([Cl:23])([Cl:22])[S:20][NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Reactant: ClSC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: ClC(Cl)(Cl)SNc1nc(C(Cl)(Cl)Cl)ns1
Yield: 23.9 %

Procedure:
To a 3-neck flask equipped with condenser, thermometer, and stirring bar was added 11.7 g (0.05 mole) 5-amino-3trichloromethyl-1,2,4-thiadiazole, 5.1 g (0.05 mole) triethylamine and 150 milliliters of benzene. After 9.3 g (0.05 mole) trichloromethane-sulfenyl chloride was added, the reaction mixture was heated at reflux for 16 hours and filtered hot. The filtrate was evaporatd under vacuum to give an orange paste which was triturated with acetonitrile, filered and washed with petroleum ether to obtain 4.4 g (24% yield) of product; mp=180° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[NH:28]1[CH2:31][CH2:30][C:29]1=[O:32]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:28]4[CH2:31][CH2:30][C:29]4=[O:32])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=C1CCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCC4=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 35 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (420 mg) described in Preparation Example 112 and 2-azetidinone (70 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (144 mg) was obtained.
Reaction SMILES: Br[C:2]1[S:11][C:10]2[C:9]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:8]=3[O:7][CH2:6][CH2:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:24](#[N:26])[CH3:25]>CCOC(C)=O.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>[CH3:25][C:24]1[CH:10]=[C:4]([C:2]2[S:11][C:10]3[C:9]4[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:8]=4[O:7][CH2:6][CH2:5][C:4]=3[CH:3]=2)[CH:3]=[CH:2][N:26]=1
Reactant: N#Cc1ccc2c(c1)OCCc1cc(Br)sc1-2
Reactant: CC#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(-c2cc3c(s2)-c2ccc(C#N)cc2OCC3)ccn1
Yield: 17 %

Procedure:
A 2 ml microwave vial was loaded with a slurry of 2-Bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-8-carbonitrile (170 mg, 0.55 mmol) and pyridine-2-amino boronic acid pinacolester (130 mg, 0.61 mmol) in 0.800 ml of aqueous 2M Sodium carbonate and 1.2 ml of ACN. The reaction mixture was degassed by bubbling nitrogen through the solution for several minutes. Next palladium tetrakis (51 mg, 2 mmol) was added to the reaction mixture and the vial was tightly capped and flash heated a Biotage microwave at 180 C for 10 minutes. The cooled reaction mixture was diluted with a large volume of EtOAc and the organic was washed with water and saline and concentrated in vacuo. The resulting residue was taken into DMF and purified by preparative RP-HPLC to give 32 mg (17%) of 2-(2-methylpyridin-4-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonitrile