Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:26]=1[CH:27]=[CH:28][C:29](O)=[O:30].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:24][C:25]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:26]=1[CH:27]=[CH:28][C:29]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)=[O:30]
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccc(F)cc1F
Yield: 78.5 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (1.7 mL), 2,4-difluorocinnamic acid (2.2 g), WSC.HCl (2.3 g), and methylene chloride (70 mL), to give the captioned compound (3.0 g, 80%) as crystals.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3].Br[C:20]1[O:24][C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][N:32]3[CH:35]=[CH:36][N:37]=[C:31]3[CH:30]=2)=[O:26])=[CH:22][CH:21]=1.BrC1C=CC(N)=CC=1>>[N:37]1[CH:36]=[CH:35][N:32]2[CH:33]=[CH:34][C:29]([CH2:28][NH:27][C:25]([C:23]3[O:24][C:20]([C:9]4[N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[N:6]=[CH:7][CH:8]=4)=[CH:21][CH:22]=3)=[O:26])=[CH:30][C:31]=12
Reactant: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(Br)o1
Agent: Nc1ccc(Br)cc1
Product: CC(C)Cn1nccc1-c1ccc(C(=O)NCc2ccn3ccnc3c2)o1

Procedure:
The title compound was prepared as described in Example 51A, substituting 1-isobutyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 5-bromo-N-(imidazo[1,2-a]pyridin-7-ylmethyl)furan-2-carboxamide for 4-bromoaniline. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.03 (t, J=6.1 Hz, 1H), 8.49 (dd, J=7.0, 0.7 Hz, 1H), 7.89 (s, 1H), 7.54-7.51 (m, 2H), 7.41 (s, 1H), 7.30 (d, J=3.6 Hz, 1H), 6.96 (d, J=3.6 Hz, 1H), 6.85 (dd, J=7.0, 1.6 Hz, 1H), 6.76 (d, J=1.9 Hz, 1H), 4.50 (d, J=6.0 Hz, 2H), 4.22 (d, J=7.3 Hz, 2H), 2.04 (dp, J=13.8, 6.8 Hz, 1H), 0.81 (d, J=6.7 Hz, 6H); MS (ESI(+)) m/e 364 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:23]=1[CH:24]=O.CO>CS(C)=O>[CH3:20][C:15]1[CH:14]=[C:13]([NH:12][S:9]([C:4]2[CH:5]=[CH:6][C:7]3[N:8]=[C:24]([C:23]4[C:22]([Cl:21])=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:30])[NH:1][C:2]=3[CH:3]=2)(=[O:11])=[O:10])[CH:18]=[CH:17][C:16]=1[CH3:19]
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(N)c(N)c2)cc1C
Reactant: O=Cc1c(Cl)cccc1Cl
Solvent: CS(C)=O
Solvent: CO
Product: Cc1ccc(NS(=O)(=O)c2ccc3nc(-c4c(Cl)cccc4Cl)[nH]c3c2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A freshly prepared solution of 3,4-diamino-N-(3,4-dimethyl-phenyl)-benzenesulfonamide in DMSO (0.2 M, 0.40 mL) was placed in a vial. To it was added 2,6-dichloro-benzaldehyde (0.2 M in toluene, 0.48 mL), followed by FeCl3 (0.02 M in THF, 0.2 mL). The mixture was stirred in open air at ambient temperature overnight. The mixture was then diluted by MeOH and the whole was loaded onto a solid phase extraction (SPE) cartridge that contained strong cation exchange (SCX) (1 g media in 6 mL cartridge, United Chemical Technology). Wash-to-waste (5 mL MeOH) was followed by elute-to-collect (5 mL 20:2:1 ethyl acetate-MeOH-Et3N) and, after evaporation of volatiles, the crude was further purified by silica gel column chromatography to give 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-sulfonic acid (3,4-dimethyl-phenyl)-amide: MS (m/z) 446 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:18]=[CH:17][C:11]([C:12](OCC)=[O:13])=[CH:10][C:9]=1[O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22].[OH-].[Na+]>O1CCCC1>[CH3:7][C:8]1[CH:18]=[CH:17][C:11]([CH2:12][OH:13])=[CH:10][C:9]=1[O:19][C:20]([F:24])([F:25])[CH:21]([F:23])[F:22]
Reactant: CCOC(=O)c1ccc(C)c(OC(F)(F)C(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(CO)cc1OC(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105 %

Procedure:
To a solution of lithium aluminum hydride (1.02 g, 26.8 mmol) in tetrahydrofuran (100 ml) was added a solution of ethyl 4-methyl-3-((1,1,2,2-tetrafluoroethyl)oxy)benzoate (5.0 g, 17.8 mmol) in tetrahydrofuran (20 ml) under ice-cooling. After the reaction solution was stirred at room temperature for 30 min., 1N aqueous sodium hydroxide solution (20 ml) was added, and the mixture was filtered with celite. The filtrate was concentrated and water was added. The mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give (4-methyl-3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methanol (4.45 g, 100%) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3]P(=O)(OC)OC.CC(C)([O-])C.[K+].[CH3:17][C:18]([CH3:25])([CH:23]=O)[C:19]([O:21][CH3:22])=[O:20]>O1CCCC1>[CH3:17][C:18]([CH3:25])(/[CH:23]=[CH:3]/[C:2](=[O:1])[CH3:10])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)C(C)(C)C=O
Reactant: COP(=O)(CC(C)=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)/C=C/C(C)=O
Reaction time: 0.25 h
Yield: 47 %

Procedure:
To a solution of dimethyl (2-oxopropyl)phosphonate (4.09 mL, 30 mmol) in tetrahydrofuran (200 mL) at 0° C. was added potassium tert-butoxide (3.22 g, 28.7 mmol). After 15 minutes, the reaction flask was moved to a 20° C. water bath and then a solution of methyl 2,2-dimethyl-3-oxopropanoate (3.39 g, 26 mmol) in tetrahydrofuran (10 mL) was added. After 20 hours, the opaque reaction mixture was partitioned between diethyl ether (100 mL) and water (100 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (1×100 mL, 1×50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (0-4% methanol/dichloromethane gradient) to afford methyl (3E)-2,2-dimethyl-5-oxohex-3-enoate (2.21 g, 12.21 mmol, 47% yield) as a light yellow oil. 1H NMR (500 MHz, CDCl3) δ 6.95 (d, J=16.3, 1H), 6.09 (d, J=16.3, 1H), 3.71 (s, 3H), 2.29 (s, 3H), 1.37 (d, J=2.3, 614).
Reaction SMILES: C([O:5][C:6](=[O:55])[C:7]([O:10]/[N:11]=[C:12](/[C:42]1[N:43]=[C:44]([NH:47]C(OC(C)(C)C)=O)[S:45][CH:46]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][NH:33]C(OC(C)(C)C)=O)[C:27]1=[O:41])=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:33][CH2:32][CH2:31][N:28]1[CH2:29][CH2:30][N:26]([CH2:25][C@@H:17]2[C@H:16]([NH:15][C:13](=[O:14])/[C:12](=[N:11]\[O:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:55])=[O:5])/[C:42]3[N:43]=[C:44]([NH2:47])[S:45][CH:46]=3)[C:19](=[O:20])[N:18]2[S:21]([OH:24])(=[O:22])=[O:23])[C:27]1=[O:41]
Reactant: CC(C)(C)OC(=O)NCCN1CCN(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN1CCN(CCN)C1=O)c1csc(N)n1)C(=O)O
Yield: 4.2 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((3-(2-((tert-butoxycarbonyl)amino)ethyl)-2-oxoimidazolidin-1-yl)methyl)-4-oxoazetidine-1-sulfonic acid (42 mg, 0.051 mmol), TFA (237 μl, 3.08 mmol) in DCM (500 μL). The crude residue was purified by reverse phase prep HPLC (Xselect CSH, 30×100 mm, 5 μM, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min) to afford the title compound (1.2 mg, 4%). LC/MS: Rt=0.35 min, m/z=563.2 (M+1) Method 2m_acidic; 1H NMR (400 MHz, D2O): δ 1H NMR 6.99 (s, 1H), 5.32 (d, J=5.9 Hz, 1H), 4.56-4.50 (m, 1H), 3.70 (dd, J=15.1, 9.6 Hz, 1H), 3.59-3.49 (m, 1H), 3.46 3.30 (m, 4H), 3.29-3.20 (m, 2H), 3.08-3.02 (m, 2H), 1.40 (s, 3H), 1.38 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]3[C:14]([C:22]4[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=4)=[C:15]4[C:20](=[CH:21][C:12]=3[S:11][C:10]=2[CH:29]=1)[CH:19]=[CH:18][CH:17]=[CH:16]4.O[C@@H:32]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:33]([O:35]C)=[O:34]>>[C:3]([CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]3[C:14]([C:22]4[CH:23]=[CH:24][C:25]([O:28][CH:32]([CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:33]([OH:35])=[O:34])=[CH:26][CH:27]=4)=[C:15]4[C:20](=[CH:21][C:12]=3[S:11][C:10]=2[CH:29]=1)[CH:19]=[CH:18][CH:17]=[CH:16]4)([OH:2])=[O:30]
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: COC(=O)COc1ccc2c(c1)sc1cc3ccccc3c(-c3ccc(O)cc3)c12
Product: O=C(O)COc1ccc2c(c1)sc1cc3ccccc3c(-c3ccc(OC(Cc4ccccc4)C(=O)O)cc3)c12

Procedure:
Prepared from of [11 -(4-hydroxy-phenyl)-benzo[b]naphtho[2,3-d]thiophen-3-yloxy ]-acetic acid methyl ester (Example 72) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 96). White solid: mp: 191-201° C.: NMR (DMSO-d6); δ13.1 (broad s, 2 H), 8.45 (s, 1 H), 8.01 (d, J=8 Hz, 1 H), 7.55-7.25 (m, 11H), 7.16 (d, J =9 Hz, 2 H), 6.67 (dd, J=9, 2Hz, 1 H), 6.49 (d, J=9 Hz, 1 H), 5.18 (dd, J=7,4Hz, 1 H), 4.74 (s, 2 H), 3.28 (dd, J=7, 4 Hz, 1 H), 3.21 (dd, J=14, 7 Hz, 1 H); MS (EI): 458 (80%, M+); Anal. Calc. for C33H24O6S: C, 72.25, H, 4.41, N, 0.00. Found: C, 69.57, H, 4.15, N, 0.32; Analytical HPLC :92% purity.
Reaction SMILES: [Si]([O:8][C:9]1([CH2:13][C@H:14]([NH:28][S:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])[C:15]2[C:16](F)=[N:17][C:18]([F:26])=[C:19]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:20]=2)[CH2:12]C[CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[H-].[Na+]>C1COCC1>[F:26][C:18]1[N:17]=[C:16]2[O:8][C:9]([CH3:12])([CH3:10])[CH2:13][C@H:14]([NH:28][S:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])[C:15]2=[CH:20][C:19]=1[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)Cc1cc([C@H](CC2(O[Si](C)(C)C(C)(C)C)CCC2)NS(=O)C(C)(C)C)c(F)nc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)Cc1cc2c(nc1F)OC(C)(C)C[C@@H]2NS(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a 150 mL RBF was added N—((S)-2-(1-(tert-butyldimethylsilyloxy)cyclobutyl)-1-(2,6-difluoro-5-neopentylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (0.070 g, 0.14 mmol), THF (3 mL), and TBAF, 1M in THF (0.14 ml, 0.14 mmol). The reaction was stirred at RT. After 20 minutes, the reaction was eluted through a plug of silica gel with THF. The resulting filtrate was concentrated in vacuo and taken up in THF (20 mL) and treated with NaH (0.035 g, 0.88 mmol, 60% in mineral oil). The reaction was stirred at 40° C. for 16 hours. The reaction was allowed to cool to RT and quenched with sat'd NH4Cl, and extracted with EtOAc (25 mL). The combined organic layers were concentrated in vacuo to give N—((S)-7-fluoro-2,2-dimethyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)-2-methylpropane-2-sulfinamide. This material was carried forward without further purification. MS m/z: 383 (M+1).
Reaction SMILES: [ClH:1].[CH2:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:5]=1[NH:12][C:13]([NH:15][C:16](=[NH:19])[NH:17][CH3:18])=[O:14])[CH3:3].[CH3:20]N(C(OC)OC)C.Cl.CO>CC#N>[ClH:1].[CH2:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:2][CH3:3])[C:5]=1[N:12]1[CH:18]=[N:17][C:16]([NH:19][CH3:20])=[N:15][C:13]1=[O:14])[CH3:11]
Reactant: CCc1cccc(CC)c1NC(=O)NC(=N)NC
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: CC#N
Solvent: CO
Product: CCc1cccc(CC)c1-n1cnc(NC)nc1=O
Yield: 47 %

Procedure:
To a suspension of 22.8 g. (80.0 mmol) of 1-(2',6'-diethylphenyl)-3-methylamidinourea hydrochloride in CH3CN (100 ml.) are added 19.1 g. (160.0 mmol) of DMF-DMA and the reaction mixture is heated at reflux for 3 hours. The CH3CN is removed under reduced pressure and the residue partitioned between CHCl3 and H2O. The layers are separated and the aqueous layer extracted with CHCl3 (1×100). The combined CHCl3 extracts are washed with H2O (1×100 ml.), dried (MgSO4) and concentrated under reduced pressure to give an off-white solid, which by NMR confirms the desired free base. The solution is dissolved in H2OH and acidified with HCl/MeOH and the MeOH removed under reduced pressure to give an off-white solid which is crystallized from CH3CN to give after vacuum drying over the weekend (105° C., house vacuum) 16.7 g. (71%) of crude product. The material is recrystallized from CH3CN (a hot filtration is necessary to remove some undissolved solid) to give 11.0 g. (47%) of desired product as a white crystalline solid.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[O:9][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:7]1)=O)C.[BH4-].[K+].Cl.O>CO>[CH3:20][S:17]([C:14]1[CH:13]=[CH:12][C:11]([C@H:10]2[O:9][C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:7][C@@H:6]2[CH2:4][OH:3])=[CH:16][CH:15]=1)(=[O:18])=[O:19]
Reactant: CCOC(=O)[C@H]1N=C(c2ccccc2)O[C@@H]1c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc([C@H]2OC(c3ccccc3)=N[C@@H]2CO)cc1
Temperature: 25 °C

Procedure:
(4S-trans)-4,5-Dihydro-5-[4-(methylsulfonyl)phenyl]-2-phenyl-4-oxazolecarboxylic acid ethyl ester (Compound IIIk) (about 5 g, 0.0134 moles) in methanol (about 50 mL) is reacted in a reaction vessel with potassium borohydride (about 1.1 g, 0.0201 moles) over about 6 hours while maintaining the temperature below about 60° C. The reaction is cooled to ambient room temperature and about 1N HCl (about 10 mL) and water (about 50 mL) are added. The resulting solids are filtered, washed with water, then dried to yield (4R,5R)-4,5-Dihydro-5-[4-(methylsulfonyl)phenyl]-2-phenyl-4-oxazolemethanol (Compound II wherein R1 is methylsulfonyl, R2 is phenyl and R3 is ethyl).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[C:18]([O:20]CC)=[O:19])[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1.[OH-].[Na+].Cl>CO.O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[C:18]([OH:20])=[O:19])[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1
Reactant: CCOC(=O)c1cnn2cc(-c3cnn(C)c3)cc(OC)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C(=O)O)c12
Temperature: 55 °C
Reaction time: 2 h

Procedure:
Ethyl 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (532 mg, 1.77 mmol) was dissolved in methanol (2 ml)/1,4-dioxane (2 ml)/Water (2 ml), then 1 N aqueous sodium hydroxide (1.77 ml, 1.77 mmol) was added and the mixture was heated to 55° C. After 2 h, LCMS analysis indicated incomplete conversion. Additional 1 N aqueous sodium hydroxide (0.18 ml, 0.18 mmol) was added and the reaction mixture was stirred for 1 h. LCMS analysis indicated incomplete conversion, so additional 1 N aqueous sodium hydroxide (0.18 ml, 0.18 mmol) was added and the reaction mixture was stirred overnight at 55° C. The reaction mixture was cooled to ambient temperature and 1N HCl (2.12 ml, 2.12 mmol) was added. The mixture was concentrated to give a tan solid that was suspended in 10 mL of water, filtered, and washed with water. The solid was transferred to a flask as a slurry in methanol and concentrated to give 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6](=[O:31])[CH2:7][CH2:8][NH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[N:12](C(OC(C)(C)C)=O)[C:11]=2[C:27]([O:29][CH3:30])=[O:28])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:31])[CH2:7][CH2:8][NH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[NH:12][C:11]=2[C:27]([O:29][CH3:30])=[O:28])=[CH:32][CH:33]=1
Reactant: COC(=O)c1c(NCCC(=O)c2ccc(F)cc2)c2ccc(Cl)cc2n1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1[nH]c2cc(Cl)ccc2c1NCCC(=O)c1ccc(F)cc1
Yield: 62 %

Procedure:
Dissolve 3-[(p-fluorophenacyl)methylamino]-2-carbmethoxy-6-chloro-1-(tert-butyloxycarbonyl)-indole from above in methylene chloride (5 mL). Add trifluoracetic acid (5 mL) and stir for 4 hours at room temperture. Dilute with ethyl acetate (50 mL) and rinse with 1N sodium hydroxide, saturated sodium chloride, dry over magnesium sulfate, filter and concentrate in vacuo. Purify the residue by flash chromatography (30% ethyl acetate/hexane) and recrystallize from ethyl acetate/hexane to yield the title compound (1.0 g, 62%).
Reaction SMILES: [CH3:1][Mg]Cl.[CH2:4]1[C:13]2[C:12]3[CH:14]=[CH:15][C:16]([C:18]([C:20]4[N:21]=[CH:22][NH:23][CH:24]=4)=[O:19])=[CH:17][C:11]=3[CH:10]=[CH:9][C:8]=2[O:7][CH2:6][CH2:5]1.[Cl-].[NH4+]>C(OCC)C.C1COCC1>[CH2:4]1[C:13]2[C:12]3[CH:14]=[CH:15][C:16]([C:18]([C:20]4[N:21]=[CH:22][NH:23][CH:24]=4)([OH:19])[CH3:1])=[CH:17][C:11]=3[CH:10]=[CH:9][C:8]=2[O:7][CH2:6][CH2:5]1
Reactant: O=C(c1ccc2c3c(ccc2c1)OCCC3)c1c[nH]cn1
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)(c1ccc2c3c(ccc2c1)OCCC3)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of methylmagnesium chloride in diethyl ether (3M; 3 mL) was added to a solution of (2,3-dihydro-1H-benzo[f]chromen-8-yl)(1H-imidazol-4-yl)ketone (0.50 g) in THF (20 ml) at 0° C. The mixture was stirred at room temperature for 3 h. Aqueous ammonium chloride solution was added to the mixture and extracted with ethyl acetate. The extract was dried and concentrated. The residue was washed with ethyl acetate to give the titled compound (0.49 g) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:37][O:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])[C:8]([NH:10][CH:11]2[C:35](=[O:36])[N:13]3[C:14]([C:19]([O:21]C(C4C=CC=CC=4)C4C=CC=CC=4)=[S:20])=[C:15]([CH3:18])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>ClCCl>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:37][O:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])[C:8]([NH:10][CH:11]2[C:35](=[O:36])[N:13]3[C:14]([C:19]([OH:21])=[S:20])=[C:15]([CH3:18])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: COC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(C)CS[C@H]12)c1csc(N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Product: COC(=O)CON=C(C(=O)NC1C(=O)N2C(C(O)=S)=C(C)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
To a suspension of benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-(methoxycarbonylmethoxyimino)acetamido]-3-methylthio-3-cephem-4-carboxylate (syn isomer) (11.6 g) and anisole (8.5 g) in dichloromethane (30 ml) was added trifluoroacetic acid (36.5 g) under ice-cooling and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was dropwise added to isopropyl ether (200 ml) under stirring and the precipitates were collected by filtration. The precipitates were dissolved in ethyl acetate and saturated sodium bicarbonate solution and aqueous layer was separated. The aqueous layer was adjusted to pH 4.5 with 10% hydrochloric acid. After removing the solvent in reduced pressure, the solution was acidified to pH 2.5 with 10% hydrochloric acid under ice-cooling. The precipitates were filtered and dried to give 7-[2-(2-aminothiazol-4-yl)-2-(methoxycarbonylmethoxyimino)acetamido]-3-methylthio-3-cephem-4-carboxylic acid (syn isomer) (6.1 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:19]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.C(OCC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1OCc1ccccc1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1ccccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 65.2 %

Procedure:
A mixture of 2-benzyloxyphenylboronic acid (20.2 g, 88.6 mmol), methyl 2-bromo-5-nitrobenzoate (25.4 g, 97.5 mmol), cesium carbonate (57.7 g, 177 mmol) and bis(triphenylphosphine)palladium(II)dichloride (1.16 g, 1.65 mmol) was suspended in anhydrous N,N-dimethylformamide (300 mL), and then was stirred under argon atmosphere at 80° C. for 3 days. After cooling down, ethyl acetate (500 mL), diethylether (300 mL) and water (500 mL) were added thereto, and then separated. The aqueous layer was extracted with a mixture of ethyl acetate (200 mL) and diethylether (200 mL). The combined organic layer was washed with water (500 mL, twice) and saturated brine (300 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (21.0 g) as a pale yellow oil. (Yield 65%)
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[C:13](=O)[C:12](=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][S:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][N:23]([CH3:29])[CH2:24][CH2:25][CH2:26][NH:27][NH2:28]>CO>[CH3:22][N:23]([CH3:29])[CH2:24][CH2:25][CH2:26][N:27]1[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]2[CH2:9][S:10][CH2:11][C:12](=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]2=[N:28]1
Reactant: CN(C)CCCNN
Reactant: O=C1C(=Cc2ccccc2)CSCC1=Cc1ccccc1
Solvent: CO
Product: CN(C)CCCN1N=C2C(=Cc3ccccc3)CSCC2C1c1ccccc1

Procedure:
Tetrahydro-3,5-bis-(phenylmethylene)-4H-thiopyran-4-one (5g) is refluxed with 2.1g of 3-dimethylaminopropylhydrazine in 50ml of methanol for 4 hours. The solvent is evaporated off and the residue is crystallized from 30ml of acetonitrile to yield 3.9g of the title compound, melting point 83°-85°C.
Reaction SMILES: [F:1][CH:2]([F:33])[O:3][C:4]1[C:13]2[C:8](=[C:9]([F:20])[CH:10]=[CH:11][C:12]=2[O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:7]=[C:6]([CH2:21][CH3:22])[C:5]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.Br[C:35]1[CH:36]=[N:37][O:38][C:39]=1[CH:40]1[CH2:42][CH2:41]1.C(=O)([O-])O.[Na+].Cl>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[CH3:19][O:18][C:16](=[O:17])[CH2:15][O:14][C:12]1[CH:11]=[CH:10][C:9]([F:20])=[C:8]2[C:13]=1[C:4]([O:3][CH:2]([F:33])[F:1])=[C:5]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:35]3[CH:36]=[N:37][O:38][C:39]=3[CH:40]3[CH2:42][CH2:41]3)=[CH:26][CH:25]=1)[C:6]([CH2:21][CH3:22])=[N:7]2
Reactant: Brc1cnoc1C1CC1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: O
Solvent: COCCOC
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-c2cnoc2C2CC2)cc1
Temperature: 85 °C
Yield: 17.6 %

Procedure:
A mixture of (4-{[4-difluoromethoxy-2-ethyl-8-fluoro-5-(2-methoxy-2-oxoethoxy)quinolin-3-yl]methyl}phenyl)boronic acid (0.15 g), 4-bromo-5-cyclopropylisoxazole (0.24 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.027 g), sodium hydrogen carbonate (0.082 g), 1,2-dimethoxyethane (1.0 mL) and water (0.4 mL) was heated at 85° C. for 2 hours. The mixture was cooled to room temperature, diluted with water (5 mL), neutralised by the addition of 1.0 M aqueous hydrochloric acid solution (1.0 mL) and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 7:3 by volume) gave title compound as a colourless oil (0.03 g).