Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8](=[O:29])[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:16][C:17]4[C:23]([CH:24]([CH3:26])[CH3:25])=[CH:22][C:21]([C:27]#[N:28])=[CH:20][C:18]=4[N:19]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(O)C.[CH3:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=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>[C:27]([C:21]1[CH:22]=[C:23]([CH:24]([CH3:26])[CH3:25])[C:17]2[O:16][C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][C:5]4[CH:30]=[CH:31][C:2]([C:39]5[CH:40]=[CH:41][C:36]([CH3:35])=[CH:37][CH:38]=5)=[CH:3][CH:4]=4)=[O:29])=[CH:10][CH:11]=3)=[N:19][C:18]=2[CH:20]=1)#[N:28]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCc4ccc(Br)cc4)cc3)oc12
Reactant: Cc1ccc(B(O)O)cc1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2ccc(CNC(=O)c3ccc(-c4nc5cc(C#N)cc(C(C)C)c5o4)cc3)cc2)cc1
Temperature: 150 °C
Yield: 32.6 %

Procedure:
To a solution of N-(4-bromobenzyl)-4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzamide (30 mg, EXAMPLE 1) in toluene (1 ml), water (0.5 ml), and ethanol (0.25 ml) was added (4-methylphenyl)boronic acid (30 mg), 2M aqueous potassium carbonate (1 ml), and tetrakis(triphenylphosphine)palladium(0) (5 mg). The solution was sealed in a microwave tube and heated to 150° C. for 60 min in a microwave reactor. The mixture was then diluted with ethyl acetate (10 ml) and water (10 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (10 ml). The combined organic phases were washed with brine (10 ml), dried (sodium sulfate), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25M column, eluting with 1 column volume of 2% ethyl acetate in hexanes, followed by a linear gradient of ethyl acetate in hexanes from 2 to 100% over 10 column volumes to provide the title compound (10 mg, 33%). Mass spectrum (ESI) 486.1 (M+1). NMR (500 MHz, CDCl3): δ 8.34 (s, 1H), 8.32 (s, 1H), 7.99 (s, 1H), 7.98 (s, 1H), 7.93 (d, J=1.5 Hz, 1H), 7.59 (s, 1H), 7.58 (s, 1H), 7.51 (s, 1H), 7.49 (s, 1H), 7.47 (s, 1H), 7.45 (s, 1H), 7.43 (s, 1H), 7.24 (s, 1H), 6.58-6.56 (app t, J=10.5, 1H), 4.72 (d, J=5.5 Hz, 2H), 3.44-3.50 (m, 1H), 2.40 (s, 3H), 1.45 (d, J=6.5 Hz, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15](Br)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1.[NH2:18][C:19]1[CH:23]=[CH:22][N:21]([CH3:24])[N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(Cl)(Cl)Cl>O1CCOCC1.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]>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:18][C:19]3[CH:23]=[CH:22][N:21]([CH3:24])[N:20]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cn1ccc(N)n1
Reactant: Cc1ccc(Br)c(C(=O)Nc2ccn(C)n2)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Cc1ccc(Nc2ccn(C)n2)c(C(=O)Nc2ccn(C)n2)n1
Temperature: 130 °C
Yield: 17.4 %

Procedure:
In a 10 ml reaction vessel were dissolved 60 mg (0.203 mmol) 3-Bromo-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide and 25 mg (0.254 mmol, 1.5 equiv.) of 3-Amino-1-methyl-pyrazole in 4 ml of dioxane. Cesium carbonate (93 mg, 0.285 mmol, 1.4 equiv.) were added and argon was bubbled through the suspension for 3 min. Then Xanthphos (39 mg, 0.067 mmol, 0.33 equiv.) and Pd2(dba)3.CHCl3 (21 mg, 0.020 mmol, 0.1 equiv.) were added. The vessel was closed and the mixture was heated overnight at 130° C. To the mixture was added silicagel (5 g) and the mixture was evaporated to dryness in vaccuo. The powder was charged onto a silicagel flash chromatography column and eluted (gradient 100% heptane to 100% ethyl acetate) to yield the title compound as a yellow solid (total 11 mg, 17%), MS (ISP): m/e=312.1 (M+H+).
Reaction SMILES: F[C:2]1[C:11]([S:12][CH3:13])=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:18][O-:19].[Na+]>CO>[CH3:18][O:19][C:2]1[C:11]([S:12][CH3:13])=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C(F)(F)F)c(SC)c1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(C(F)(F)F)c(SC)c1OC
Yield: 18.3 %

Procedure:
A mixture of 19.9 g (74.2 mmol) of methyl 2-fluoro-3-methylthio-4-(trifluoromethyl)benzoate and 40.1 g (30% by weight, 223 mmol) of sodium methoxide in 250 ml of methanol was heated under reflux for 6 h. For work-up, the mixture was concentrated on a rotary evaporator, the residue was taken up in water and the mixture was extracted with dichloromethane. The organic phase was dried and the filtrate was freed from the solvent. This gave 15.9 g of methyl 2-methoxy-3-methylthio-4-(trifluoromethyl)benzoate as residue. The aqueous phase from the extractive work-up was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and the filtrate was freed from the solvent. This gave an additional 3.80 g of methyl 2-methoxy-3-methylthio-4-(trifluoromethyl)benzoate as residue.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Cl[CH:10]([C:16](=O)[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:16]([CH3:17])[N:8]=2)[N:7]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1ccc(Cl)nn1
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2ccc(Cl)nn12
Yield: 32.6 %

Procedure:
A mixture of 6-chloropyridazin-3-amine (5.3 g, 41 mmol), ethyl 2-chloro-3-oxobutanoate (6.7 g, 41 mmol) and ethanol (50 mL) was heated under reflux for 2 days. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the obtained residue, and the insoluble material was filtered off. The filtrate was extracted with ethyl acetate, and the collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate and diisopropyl ether were added to the obtained residue, and the insoluble material was filtered off. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0) and washed with ethyl acetate/diisopropyl ether to give the title compound (3.2 g, 32%) as a colorless solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=O)[C:4](=[CH:8][C:9]2[CH:10]=[C:11]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27]C)=[O:25])[CH2:20][CH2:19]3)[CH:12]=[CH:13][C:14]=2[N+:15]([O-])=O)[NH:3]1.II.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.[Pd]>[O:1]=[C:2]1[NH:6][C:5]2=[N:15][C:14]3[CH:13]=[CH:12][C:11]([N:18]4[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH2:19]4)=[CH:10][C:9]=3[CH:8]=[C:4]2[NH:3]1
Reactant: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])c(C=C3NC(=O)NC3=O)c2)CC1
Agent: [Pd]
Agent: II
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(c2ccc3nc4[nH]c(=O)[nH]c4cc3c2)CC1
Reaction time: 90 h
Yield: 50.4 %

Procedure:
An alternate preparation of the title compound involves hydrogenating ethyl 1-[3-[(2,4-dioxoimidazolidin-5-ylidene)methyl]-4-nitrophenyl]-4-piperidinecarboxylate (5.00 g, 13 mmol) in dimethylformamide (100 mL) over 10% palladium on charcoal (750 mg) at 60 p.s.i. in a low pressure hydrogenation apparatus. After 90 hours, the mixture was filtered through Kieselguhr, the solvent evaporated, and the residue added to ethanol (150 mL) and acetic acid (5 mL). The mixture was heated at refux for 2 hours before addition of 10% sodium carbonate. The resultant gray solid was added to methanol (150 mL), heated to reflux, iodine (1.86 g, 7.3 mmol) added portionwise, and reflux contonued for 2 hours. Upon cooling, 10% sodium thiosulfate and 10% sodium carbonate were added until pH=8. The precipitate was collected added to methanolic hydrochloric acid (120 mL), and heated at reflux for 20 hours. Upon cooling, 10% sodium carbonate was added until pH=8, and the gray solid collected, washed with H2O, methanol, and dried to afford methyl 1-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)-4-piperidinecarboxylate (2.14 g, 50%). An analytical sample of the title product as a partial hydrate, m.p. >310° C., was prepared by crystallization from aqueous dimethylformamide.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([OH:15])=O)([O-:9])=[O:8].ClCCl.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.CN(C)C=O>[CH3:19][C:18]1[CH:17]=[CH:16][C:12]([C:13]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:15])=[CH:11][C:10]=1[N+:7]([O-:9])=[O:8]
Reactant: Nc1ccccc1
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
Oxalyl chloride (3 mL, 35 mmol) was added dropwise to a stirred solution of 3-nitro-4-methylbenzoic acid (5.0 g, 28 mmol) in a mixture of tetrahydro-furan or dichloromethane (125 mL) and dimethylformamide (½ mL) under N2 at ice bath temperature. The mixture was allowed to warm to room temperature. After 1 hour, the solvent was removed by rotary evaporator under reduced pressure. The residue was redissolved in fresh tetrahydro-furan (100 mL) and recooled to ice bath temperature under N2, while a solution of aniline (5.2 g, 56 mmol) in tetrahydro-furan (25 mL) was added dropwise. After 16 hours of stirring at room temperature, the mixture was concentrated to half-volume by rotary evaporator and the residue stirred in water (200 mL). After several hours, the precipitate was filtered off, rinsed three times with water, and dried to afford the product (6.8 g); m.p. 147-148° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([N:24]4[CH2:29][CH2:28][S:27][CH2:26][CH2:25]4)=[O:22])=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: C1CSCCN1
Reactant: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)O)s1
Product: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)N2CCSCC2)s1
Yield: 59 %

Procedure:
As described for example 77c, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-thiazole-5-carboxylic acid (83 mg, 0.25 mmol) was converted, using thiomorpholine instead of 4-aminotetrahydropyran, to the title compound (61 mg, 59%) which was obtained as a yellow solid after purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) and trituration from diethyl ether. MS: m/e=417.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([B:11]([OH:13])[OH:12])[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].O[C:15]([C:18](O)([CH3:20])[CH3:19])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1.CCO>[F:1][C:2]1[CH:3]=[C:4]([B:11]2[O:13][C:18]([CH3:20])([CH3:19])[C:15]([CH3:17])([CH3:16])[O:12]2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1ccc(B(O)O)cc1F
Reactant: CC(C)(O)C(C)(C)O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)OB(c2ccc(C(=O)O)c(F)c2)OC1(C)C

Procedure:
3-Fluoro-4-carboxy-phenylboronic acid (CAS 120153-08-4)(1.0 g, 5.4 mmol) and pinacol (0.645 g, 5.4 mmol) were stirred in Toluene/EtOH (1:1) (30 ml) with heating to give a thick white slurry. The mixture was concentrated under reduced pressure, toluene (30 ml) was added and the mixture was again concentrated under reduced pressure to a white solid. LCMS(-ve ion mode) showed a single peak trace with 265 (M−H RP). The material was dried under high vacuum overnight to give 1.42 g.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16]([O:18][CH3:19])=[O:17])[C:6]2[C:7]([CH3:15])=[CH:8][N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1)#[N:2].[N:20]([Si](C)(C)C)=[N+:21]=[N-:22].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CO.C(Cl)Cl>CCOC(C)=O.CC(O)=O>[CH:12]([N:9]1[C:10]2[CH:11]=[C:3]([C:1]3[NH:22][N:21]=[N:20][N:2]=3)[CH:4]=[C:5]([C:16]([O:18][CH3:19])=[O:17])[C:6]=2[C:7]([CH3:15])=[CH:8]1)([CH3:14])[CH3:13]
Reactant: COC(=O)c1cc(C#N)cc2c1c(C)cn2C(C)C
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(-c2nnn[nH]2)cc2c1c(C)cn2C(C)C
Temperature: 85 °C
Reaction time: 18 h
Yield: 47.9 %

Procedure:
To a stirred suspension of methyl 6-cyano-1-isopropyl-3-methyl-1H-indole-4-carboxylate (0.50 g, 1.951 mmol) in azidotrimethylsilane (1.0 mL, 7.53 mmol) in a small vial was added tetrabutylammonium fluoride trihydrate (300 mg, 0.951 mmol). The reaction was heated to 85° C. and stirred for 18 hr (attached a small reflux condensor). (The reaction became a semi-solid mass.) The reaction was taken up in EtOAc (75 mL), washed with 1 N HCl (75 mL) (stirred till dissolved). The organic phase was removed, dried (Na2SO4), filtered and concentrated under vacuum. Purification by silica gel chromatography (Analogix, SF40-80 g, 0 to 3% MeOH/CH2Cl2 with 0.1% HOAc) gave the product methyl 1-isopropyl-3-methyl-6-(1H-tetrazol-5-yl)-1H-indole-4-carboxylate (0.28 g, 0.935 mmol, 48.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J=1.3 Hz, 1H), 8.15 (d, J=1.5 Hz, 1H), 7.69 (s, 1H), 4.86 (quin, J=6.6 Hz, 1H), 3.94 (s, 3H), 2.33 (s, 3H), 1.50 (d, J=6.6 Hz, 6H). MS(ES)+ m/e 300.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:22]=[C:23]([F:26])[C:24]=1[F:25])[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.ClCCl>[F:26][C:23]1[CH:22]=[C:13]([CH:12]=[C:11]([F:10])[C:24]=1[F:25])[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:2]2[N:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=2)[CH2:17][CH2:16]1
Reactant: N#Cc1ccc(Cl)nn1
Reactant: NC1CCN(Cc2cc(F)c(F)c(F)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NC2CCN(Cc3cc(F)c(F)c(F)c3)CC2)nn1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 74 %

Procedure:
A mixture of 6-chloro-pyridazine-3-carbonitrile (D4) (1.32 g, 9.46 mmol), 1-(3,4,5-trifluoro-benzyl)-piperidin-4-ylamine (D8) (2.10 g, 8.6 mmol) and diisopropylethylamine (2.25 ml, 12.9 mmol) in acetonitrile (12 ml) was stirred at 120° C. for 20 min., under microwave irradiation (Milestone MW-oven). Dichloromethane, water and a saturated solution of sodium carbonate were then added. The organic layers were filtered over cotton, evaporated in vacuo and the residue was purified by column chromatography (silica gel; 0-2% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo. The residue was precipitated from diisopropyl ether to yield E18 (2.210 g, 74%) as a solid. C17H16F3N5 requires 347. Found 348 (MH+); mp: 185° C.
Reaction SMILES: [CH:1]1([C:4]2(O)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][CH2:7][C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]2=3)[CH2:3][CH2:2]1.C(O)(=O)C.[BrH:24]>C(Cl)Cl>[Br:24][CH2:3][CH2:2][CH:1]=[C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2
Reactant: Br
Reactant: OC1(C2CC2)c2ccccc2CCc2ccccc21
Solvent: CC(=O)O
Solvent: ClCCl
Product: BrCCC=C1c2ccccc2CCc2ccccc21
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
In a 100-mL round bottom flask, 5-cyclopropyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ol (0.130 g, 0.0006 mol) was added with 1 mL acetic acid. The solid was allowed to dissolve at which point the reaction mixture was chilled to 10° C. Then a solution of 33% hydrobromic acid (0.5 mL hydrobromic acid and 0.5 mL acetic acid; total 1 mL) was added to the flask. The reaction was allowed to stir for an additional 30 min. while reaction progress was monitored by HPLC. Then the reaction mixture was transferred to a separatory funnel and DCM (100 mL) added. The organic layer collected and washed with H2O (1×100 mL) and dried over Na2SO4 for 2 hrs. The resulting product was purified by flash column chromatography on silica gel using MeOH/DCM (Biotage 25M column). The product was confirmed by 1H NMR and LC/MS. (Yield ˜62%)
Reaction SMILES: [O:1]=[C:2]1N2C(CCOC2(C)C)[CH2:3]1.[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[N:18]1[CH:21]([CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH2:20][C:19]1=[O:31]>>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[N:18]1[C@@H:21]([CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C@H:20]([CH:2]([OH:1])[CH3:3])[C:19]1=[O:31]
Reactant: CC1(C)OCCC2CC(=O)N21
Reactant: O=C1CC(CCOC2CCCCO2)N1C1CCCCO1
Product: CC(O)[C@@H]1C(=O)N(C2CCCCO2)[C@H]1CCOC1CCCCO1

Procedure:
Following the procedure described for the preparation of 8-oxo-2,2-dimethyl-7α and β-(1-hydroxyethyl)-3-oxa-1-azabicyclo[4.2.0]octane from 8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane and using 1-(2-tetrahydropyranyl)-4-[2-(2-tetrahydropyranyl)oxyethyl]-2-azetidinone one obtains a diastereomeric mixture of both cis and trans-1-(2-tetrahydropyranyl)-3-(1-hydroxyethyl)-4-[2-(2-tetrahydropyranyl)-oxyethyl]-2-azetidinone.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[CH:16]=[N:17][C:18]([C:21]#[N:22])=[N:19][CH:20]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:23]O.[OH-].[Na+]>C(O)C.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[CH:16]=[N:17][C:18]([C:21]([NH2:22])=[O:23])=[N:19][CH:20]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(-c2cnc(C#N)nc2)cc1OC1CCCC1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cnc(C(N)=O)nc2)cc1OC1CCCC1
Reaction time: 0.25 h

Procedure:
To a stirred mixture of the compound of Example 14 (1.3 g) in ethanol (8 ml) was added hydrogen peroxide (40 vols, 15 ml) and 6M aqueous NaOH (6 ml). After 15 min, the reaction mixture was diluted with water (75 ml) andthe white solid filtered off. Recrystallisation from acetonitrile furnishedthe title compound (200 g) as small white plates (mp235°-238°C.). Found C, 65.06; H, 6.09; N, 13.44. C17H19N3O3 requires C, 65.16; H, 6.11; N, 13.41%.
Reaction SMILES: [CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H:6]([NH2:9])[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13].[C:15]([CH2:17][S:18]([CH2:21][C:22](O)=[O:23])(=[O:20])=[O:19])#[N:16]>>[C:15]([CH2:17][S:18]([CH2:21][C:22]([NH:9][CH:6]1[C:7](=[O:8])[N:4]2[C:3]([C:12]([OH:14])=[O:13])=[C:2]([CH3:1])[CH2:11][S:10][C@H:5]12)=[O:23])(=[O:20])=[O:19])#[N:16]
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: N#CCS(=O)(=O)CC(=O)O
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)(=O)CC#N)[C@H]2SC1

Procedure:
When the t-butyl ester of 7-ADCA is acylated with cyanomethylsulfonylacetic acid by the procedure of Example 5, 7-cyanomethylsulfonylacetamido-3-methyl-3-cephem-4-carboxylic acid is obtained.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH3:21])[CH:16]=[CH:15]2.C(N(CC)CC)C>O1CCCC1>[CH3:21][N:17]1[C:18]2[C:14](=[CH:13][C:12]([NH:11][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:20][CH:19]=2)[CH:15]=[CH:16]1
Reactant: Cn1ccc2cc(N)ccc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1ccc2cc(NC(=O)Oc3ccccc3)ccc21
Temperature: -20 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
To a solution of phenyl chloroformate (2.21 ml; 17.4 mM) in dry tetrahydrofuran (30 ml), cooled in a carbon tetrachloride/solid carbon dioxide bath, was added 5-amino-1-methylindole (D3) (2.31 g; 15.8 mM) followed by triethylamine (2.40 ml; 17.4 mM). The mixture was stirred for 45 min at -20° C. (bath temp.), then evaporated and the residue was dissolved in ethyl acetate, washed with brine, dried and evaporated to give the title compound (4.29 g; 100%), m.p. 103°-107° C. (EtOAc/petrol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[OH-].[Na+].[CH2:14](Br)[C:15]#[CH:16]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH2:16][C:15]#[CH:14])=[O:6]
Reactant: C#CCBr
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: C#CCOC(=O)c1ccc(O)c(Cl)c1
Yield: 64.3 %

Procedure:
Using the above procedure, 3-chloro-4-hydroxybenzoic acid (0.0826 mole) and sodium hydroxide (0.0826 mole) were dissolved in 50% isopropyl alcohol (200 ml). Propargyl bromide (0.0826 mole) was added and the solution was heated to reflux for 6 hours. The solution was then cooled and the isopropyl alcohol was removed under vacuum. The residue was taken up in methylene chloride (200 ml), washed with water (200 ml), saturated sodium bicarbonate, saline and dried over magnesium sulfate. Removal of the solvent yielded crude product, which was recrystallized, from CCI4 to give the pure product. (64.3% yield) m.p. 144-145° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:13][C@@H:14]([C@@H:16]2[CH2:20][C:19](=[O:21])[N:18]([C@@H:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH3:23])[CH2:17]2)[CH3:15])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]#[N:12])[CH:7]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:45]2[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>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.O>[C:11]([C:10]1[CH:9]=[N:8][N:6]2[CH:7]=[C:2]([C:48]3[CH:47]=[CH:46][C:45]([N:42]4[CH2:41][CH2:40][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:44][CH2:43]4)=[CH:50][CH:49]=3)[CH:3]=[C:4]([O:13][C@@H:14]([C@@H:16]3[CH2:20][C:19](=[O:21])[N:18]([C@@H:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[CH3:23])[CH2:17]3)[CH3:15])[C:5]=12)#[N:12]
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Br)cn4ncc(C#N)c34)CC2=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cn4ncc(C#N)c34)CC2=O)cc1
Temperature: 100 °C

Procedure:
To an appropriate sized microwave vial, 6-bromo-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (91.0 mg, 0.188 mmol), (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid (86.5 mg, 0.282 mmol), cesium carbonate (184 mg, 0.565 mmol), dioxane (2.0 mL) and water (0.5 mL) were added. The mixture was degassed with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) catalyst (21.8 mg, 0.0188 mmol) was added and the solution was heated at 100° C. for 45 minutes. After cooling to room temperature, the reaction was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (100% EtOAc) to afford tert-butyl 4-(4-(3-cyano-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)phenyl)piperazine-1-carboxylate.