Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]([CH2:18][CH3:19])[C:11]2[CH:16]=[CH:15][C:14](O)=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[C:20](=[O:23])([O-])[O-].[Na+].[Na+].[I-].[K+].[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(O)C.O>[CH2:28]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]([CH2:18][CH3:19])[C:11]2[CH:16]=[CH:15][C:14]([O:23][CH2:20][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C([O-])[O-]
Reactant: CCC(C(=O)c1ccc(O)cc1)c1ccc(O)cc1
Reactant: ClCc1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC(C(=O)c1ccc(OCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1

Procedure:
A mixture of 4,4'-dihydroxy-α-ethyldesoxybenzoin (4.26 g.), sodium carbonate (4.8 g.), potassium iodide (0.15 g.) and benzyl chloride (4.57 g.) in ethanol (35 ml.) and water (5 ml.) was stirred and heated under reflux for 8 hours. The mixture was cooled, filtered, and the residue washed with water and recrystallised from petrol (b.p. 100°-120° C.) to give 4,4'-dibenzyloxy-α-ethyldesoxybenzoin, m.p. 84° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:26][C:27]1[S:28][CH:29]=[N:30][N:31]=1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][S:26][C:27]3[S:28][CH:29]=[N:30][N:31]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: Sc1nncs1
Product: O=C(CCCSc1nncs1)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 84 %

Procedure:
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 2-mercapto-1,3,4-thiadiazole as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in an 84% yield.
Reaction SMILES: C1[C:14]2[C:5](=C[C:7]3[C:12]([CH:13]=2)=CC=CC=3)C=CC=1.CI.[Mg].C1[C:31]2[C:22](=C[C:24]3[C:29]([CH:30]=2)=CC=CC=3)C=CC=1.[Mg].C1CC=CC=1.CC(CC(C)=O)=O.CC(CC(C)=O)=O.CC(CC(C)=O)=O.[Co:59]>C1COCC1>[CH-:7]1[CH:12]=[CH:13][CH:14]=[CH:5]1.[CH-:24]1[CH:29]=[CH:30][CH:31]=[CH:22]1.[Co+2:59]
Reactant: [Co]
Reactant: c1ccc2cc3ccccc3cc2c1
Agent: C1=CCC=C1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CC(=O)CC(C)=O
Solvent: CI
Product: [Co+2]
Product: c1cc[cH-]c1
Temperature: 20 °C

Procedure:
1.1 g (6.2 mMoles) of anthracene, 300 ml of THF and 0.1 ml of methyliodide are added to 14.4 g (600 mMoles) of magnesium powder (particle size <0.15 mm) in an inert gas atmosphere. A yellow-green solution is formed with stirring at 20° C., orange-colored magnesium anthracene precipitating therefrom after about 2 hours. The reaction mixture is treated for about 3 hours in an ultrasonic bath (continuous peak HF output 240 watts, 35 kHz) and then heated with stirring to 60° C. After the addition of 19.8 g (300 mMoles) of monomeric cyclopentadiene, the heat source is removed and 35.6 g (100 mMoles) of solid cobalt-(III) acetyl acetonate are added over a period of 20 minutes. The reaction mixture changes color to dark brown with vigorous evolution of heat and begins refluxing (66° C.). After cooling to 20° C., the reaction mixture is filtered off from unreacted magnesium through a G-3-glass frit and the clear dark brown filtrate is concentrated by evaporation to dryness (max. bath temperature 30° C.) in a high vacuum (10-3Torr). The residue is taken up in 500 ml of pentane and any undissolved fractions are isolated by filtration through a G-3-glass frit. The filter cake is washed several times with a total of 500 ml of pentane until the filtrate is substantially colorless. The clear red-brown filtrate is concentrated to approximately 200 ml and the complex is left to crystallize out at -80° C. The supernatant mother liquor is removed under pressure and washed 2 to 3 times with approximately 50 ml of pentane cooled to -80° C. Drying in vacuo (0.1 Torr) gives 12.4 g (63.7 mMoles=63.7% of the theoretical) of pure cobaltocene in the form of black-violet crystals melting at 172.5° C., as measured in an inert gas atmosphere.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11]([O:14]C3C(F)=C(F)C(F)=C(F)C=3F)(=O)=[O:12])[CH:9]=2)[C:4]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=2[C:36]2[N:40]([CH3:41])[N:39]=[CH:38][CH:37]=2)=[CH:3]1.[CH3:42][C:43]1[S:47][C:46]([NH2:48])=[N:45][C:44]=1[C:49]([F:52])([F:51])[F:50].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11]([NH:48][C:46]3[S:47][C:43]([CH3:42])=[C:44]([C:49]([F:52])([F:50])[F:51])[N:45]=3)(=[O:12])=[O:14])[CH:9]=2)[C:4]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:35])[F:34])=[CH:28][C:27]=2[C:36]2[N:40]([CH3:41])[N:39]=[CH:38][CH:37]=2)=[CH:3]1
Reactant: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cn(C)c2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Cc1sc(N)nc1C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1sc(NS(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccnn4C)cn(C)c3c2)nc1C(F)(F)F
Reaction time: 1 h
Yield: 27 %

Procedure:
A flask was charged with perfluorophenyl 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)-phenyl)-1H-indole-6-sulfonate (INTERMEDIATE E) (44.48 mg, 0.074 mmol), 5-methyl-4-(trifluoromethyl)thiazol-2-amine (17.51 mg, 0.096 mmol) and THF (0.5 mL). The flask was cooled in an ice bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (185 μl, 0.185 mmol) was added dropwise to give an orange solution. The mixture was stirred for 1 h, then an additional portion of the base solution (0.08 mL) was added. After 20 min, the cooling bath was removed. The mixture was stirred for an additional 20 min, then an additional portion of 5-methyl-4-(trifluoromethyl)thiazol-2-amine (10 mg) was added. The mixture was stirred for 20 min, then was quenched with AcOH (0.1 mL) and concentrated from MeOH/DCM. The crude product was purified by chromatography on silica gel (0 to 5% MeOH/DCM) to give 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(5-methyl-4-(trifluoromethyl)thiazol-2-yl)-1H-indole-6-sulfonamide (12.27 mg, 0.020 mmol, 27.7% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ=8.01 (d, J=1.5 Hz, 1 H), 7.94-7.82 (m, 2 H), 7.77 (d, J=0.9 Hz, 1 H), 7.61 (d, J=8.5 Hz, 1 H), 7.50 (dd, J=1.7, 8.5 Hz, 1 H), 7.37 (d, J=1.9 Hz, 1 H), 7.24 (s, 1 H), 6.34 (d, J=1.9 Hz, 1 H), 3.82 (s, 3 H), 3.24 (s, 3 H), 2.40-2.35 (m, 3 H). m/z (ESI) 600.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH:21]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:24](=[O:35])[NH:23][CH2:22]2)=[C:4]([O:36][CH3:37])[CH:3]=1.[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:38]([N:23]1[CH2:22][CH:21]([C:12]2[CH:13]=[C:14]([C:17]([F:20])([F:18])[F:19])[CH:15]=[CH:16][C:11]=2[C:5]2[CH:6]=[C:7]([CH:8]([CH3:9])[CH3:10])[C:2]([F:1])=[CH:3][C:4]=2[O:36][CH3:37])[N:25]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C:24]1=[O:35])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COc1ccc(CN2C(=O)NCC2c2cc(C(F)(F)F)ccc2-c2cc(C(C)C)c(F)cc2OC)cc1
Reactant: BrCc1ccccc1
Product: COc1ccc(CN2C(=O)N(Cc3ccccc3)CC2c2cc(C(F)(F)F)ccc2-c2cc(C(C)C)c(F)cc2OC)cc1

Procedure:
Following the procedure described in EXAMPLE 379, Step A, 31 mg of 5-[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1-(4-methoxybenzyl)imidazolidin-2-one (INTERMEDIATE 32) and 9 μL of benzyl bromide gave the title compound. Mass spectrum (ESI) 607.5 (M+1).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[OH:7][C:8]([CH3:41])([CH3:40])[CH2:9][C@@:10]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:24]=[CH:23][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:21][CH:20]=2)[CH3:18])[CH2:12][CH2:11]1.Cl[C:43]1[CH:44]=[C:45]([CH3:51])[C:46](=[O:50])[N:47]([CH3:49])[N:48]=1>CN(C)C=O>[CH3:49][N:47]1[C:46](=[O:50])[C:45]([CH3:51])=[CH:44][C:43]([C:22]2[CH:21]=[CH:20][C:19]([C@@H:17]([N:13]3[CH2:12][CH2:11][C@:10]([CH2:9][C:8]([OH:7])([CH3:40])[CH3:41])([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:15][C:14]3=[O:16])[CH3:18])=[CH:24][CH:23]=2)=[N:48]1
Reactant: Cc1cc(Cl)nn(C)c1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)nn(C)c1=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2 M aqueous Na2CO3 solution (0.31 mL) was added to a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.15 g) and 6-chloro-2,4-dimethyl-2H-pyridazin-3-one (75 mg) in dimethylformamide (1 mL). The resulting mixture was sparged with argon for 10 min, before [1,1-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane complex (15 mg) was added. The mixture was heated to 100° C. and stirred at this temperature overnight. After cooling to ambient temperature, water was added, and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel (CH2Cl2/MeOH 98:2→80:20) to afford the title compound.
Reaction SMILES: Cl[CH:2]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)[CH3:3].[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1>O>[CH:5]1[C:6]2[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[CH:15]=[CH:16][C:4]=1[CH:2]([N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH3:3]
Reactant: c1nc[nH]n1
Reactant: CC(Cl)c1ccc2c(c1)Cc1ccccc1-2
Solvent: O
Product: CC(c1ccc2c(c1)Cc1ccccc1-2)n1cncn1
Temperature: 120 °C

Procedure:
The thus obtained 2-(1-chloroethyl)-9H-fluorene was mixed with 1,2,4-triazole (1.31 g) and heated at 120° C. for 30 minutes without further adding solvent. After cooling, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated and then the resulting residue was subjected to silica gel column chromatography. First, elution was carried out with a mixed solvent of chloroform and methanol (50:1), and the thus obtained crude crystals were recrystallized from a mixed solvent of ether and ethyl acetate to obtain 0.24 g of 1-[1-(9H-fluoren-2-yl) ethyl]-1H-1,2,4-triazole (Example 5). Thereafter, crude crystals obtained from the chloroform-methanol (50:1) eluate were recrystallized from a mixed solvent of ethyl acetate and ether to obtain 0.25 g of 4-[1-(9H-fluoren-2-yl) ethyl]-4H-1,2,4-triazole (Example 6).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:7][C:8]=1[CH3:9])[NH2:2].[CH:16](O)=O>>[CH3:9][C:8]1[C:3]2[N:4]([CH:16]=[N:2][N:1]=2)[N:5]=[C:6]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH:7]=1
Reactant: Cc1cc(N2CCOCC2)nnc1NN
Reactant: O=CO
Product: Cc1cc(N2CCOCC2)nn2cnnc12

Procedure:
20 Grams of 3-hydrazino-4-methyl-6morpholinopyridazine are dispersed in 200 milliliters of 99 percent aqueous formic acid. The mixture is heated at the boiling temperature under reflux and then concentrated until an oily residue remains in the reaction vessel. The residue is taken up in aqueous sodium carbonate solution, and the aqueous mixture is extracted with chloroform. The chloroform extract is dried with anhydrous sodium sulfate, then evaporated under reduced pressure to obtain the 8-methyl-6-morpholino-s-triazolo[4,3-b]pyridazine product as the free base. The product is recrystallized twice from isopropanol and found to melt at 177°-178° C.
Reaction SMILES: [OH:1][N:2]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14](OC)[CH:15]=[C:8]3[C:9]=2[C:4](=[CH:5][CH:6]=[CH:7]3)[C:3]1=[O:18].Cl.[NH2:20]O.[N:22]1[CH:27]=[CH:26]C=CC=1>>[OH:1][N:2]1[C:3](=[O:18])[C:4]2[C:9]3[C:8]([CH:7]=[CH:6][CH:5]=2)=[C:15]2[NH:20][C:27]([CH3:26])=[N:22][C:14]2=[CH:13][C:10]=3[C:11]1=[O:12]
Reactant: c1ccncc1
Reactant: COc1cc2c3c(cccc3c1)C(=O)N(O)C2=O
Reactant: NO
Agent: Cl
Product: Cc1nc2cc3c4c(cccc4c2[nH]1)C(=O)N(O)C3=O
Temperature: 80 °C

Procedure:
A mixture of 4-acetylamino-3-amino-1,8-naphthalic anhydride (0.10 g, 0.37 mmol, from Example 13) and hydroxylamine hydrochloride (0.10 g, 1.4 mmol) in pyridine (3 mL) was heated at 80° C. for 5 hours and poured into ice water. The solid was filtered, washed with ether, and recrystallized from ethanol to give 0.09 g of the title compound, mp >330° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH3:33])=[CH:15][N:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24](=[O:32])[C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)[C:10]=2[N:9]=[CH:8]1)(=O)C.[OH-].[Na+].COCCOC.Cl>CO>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([C:21]2[CH:22]=[CH:23][C:18]([CH2:17][N:16]3[C:10]4[N:9]=[CH:8][N:7]([CH2:6][CH2:5][OH:4])[C:12](=[O:13])[C:11]=4[C:14]([CH3:33])=[CH:15]3)=[CH:19][CH:20]=2)=[O:32])=[CH:30][CH:29]=1
Reactant: CC(=O)OCCn1cnc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: COCCOC
Product: Cc1cn(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c2ncn(CCO)c(=O)c12
Reaction time: 4 h
Yield: 95.3 %

Procedure:
3-Acetoxyethyl-7-[4-(4-chlorobenzoyl)benzyl]-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-one (464 mg) was dissolved in methanol (12 ml) followed by addition of 1N-sodium hydroxide (2 ml). To this mixture was added DME (6 ml) to prepare a homogeneous solution. After 4 hours of stirring, 1N-HCl (2 ml) was added and the solvent was distilled off under reduced pressure. The residue was diluted with water and triturated and the resulting powder was rinsed with water and methanol and dried to provide the title compound as crystalline powder (402 mg).
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][CH2:10]Cl)=[CH:6][CH:5]=1)=[O:3].[NH2:14][C:15]1[S:16][C:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][C:23]=2[N:24]=1.CCOCC>C(Cl)(Cl)Cl>[OH2:3].[NH2:14][C:15]1[S:16][C:17]2[CH2:18][CH2:19][N:20]([CH2:10][CH:9]=[CH:8][C:7]3[CH:12]=[CH:13][C:4]([S:2]([CH3:1])=[O:3])=[CH:5][CH:6]=3)[CH2:21][CH2:22][C:23]=2[N:24]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: CS(=O)c1ccc(C=CCCl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CS(=O)c1ccc(C=CCN2CCc3nc(N)sc3CC2)cc1
Product: O
Yield: 48 %

Procedure:
Prepared from 4-methylsulphinyl-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 48% of theory, Melting point: 171°-176° C. (ether).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[CH:17]([OH:19])[CH3:18].Cl[C:21]1[CH:22]=[CH:23][C:24]2[N:25]([C:27]([CH2:30][NH:31][C:32]3[C:41]4[C:36](=[CH:37][C:38]([O:42][CH3:43])=[CH:39][N:40]=4)[N:35]=[CH:34][CH:33]=3)=[N:28][N:29]=2)[N:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([CH2:30][NH:31][C:32]4[C:41]5[C:36](=[CH:37][C:38]([O:42][CH3:43])=[CH:39][N:40]=5)[N:35]=[CH:34][CH:33]=4)=[N:28][N:29]=3)[N:26]=2)[CH:5]=[CH:4][C:3]=1[CH:17]([OH:19])[CH3:18]
Reactant: CC(O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: COc1cnc2c(NCc3nnc4ccc(Cl)nn34)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cnc2c(NCc3nnc4ccc(-c5ccc(C(C)O)c(Cl)c5)nn34)ccnc2c1
Temperature: 100 °C

Procedure:
A suspension of 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanol (228 mg, 807 μmol), N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine (197 mg, 576 μmol), dichloro[1,1 bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (127 mg, 173 μmol), cesium carbonate (751 mg, 2306 μmol) in dioxane (3 mL) and water (0.6 mL) was sparged with argon for 5 min then heated to 100° C. for 6 h. Reaction cooled then partitioned between 9:1 CHCl3/IPA (20 mL) and 1M NaOH (15 mL). Aqueous further extracted with 9:1 CHCl3/IPA (2×10 mL). The combined organics dried over MgSO4. concentrated, then purified on 40 g silica eluting with an isocratic 7% 2M NH3 in MeOH/DCM. Product further purified prep HPLC eluting with water/ACN (0.1% TFA). After collected fractions were reduced to a clear the residue was dissolved in 1:1 ACN/water and pH adjusted to 9 with 1M NaOH (3-4 drops). Resulting solid collected by filtration and solid washed with water (2 mL). MS (ESI pos. ion) m/z: 462 (MH+). Calc'd exact mass for C23H20ClN7O2: 461.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([CH:10]=O)[N:4]2[N:3]=1.C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].N1CCCCC1>N1C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]2=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([CH:10]=[CH:19][C:20]([OH:22])=[O:21])[N:4]2[N:3]=1
Reactant: Cc1nn2c(C=O)c(-c3ccccc3)nc2s1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: Cc1nn2c(C=CC(=O)O)c(-c3ccccc3)nc2s1
Temperature: 5 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
90 g of 2-methyl-6-phenyl-imidazo[2,1-b]-1,3,4-thiadiazole-5-carbaldehyde, 60 g of malonic acid and 3 ml of piperidine in 95 ml of pyridine were boiled under reflux for 10 hours. The mixture was cooled to 5° C., stirred at this temperature for 2 hours and filtered. The residue was washed with water and dried. 92 g (84% of theory) of β-(2-methyl-6-phenyl-imidazo[2,1-b]-1,3,4-thiadiazol-5-yl)-propenoic acid of melting point 278°-280° C. (decomposition) were obtained.
Reaction SMILES: O.O.[NH2:3][CH:4]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([OH:22])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[CH2:13][S:14][C@H:9]12)=[O:6].[O:31]=[C:32]1[N:36]([C:37](Cl)=[O:38])[C:35]2[CH:40]=[CH:41][CH:42]=[CH:43][C:34]=2[NH:33]1.Cl>C(#N)C>[O:31]=[C:32]1[N:36]([C:37]([NH:3][CH:4]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:5]([NH:7][CH:8]2[C:23](=[O:24])[N:10]3[C:11]([C:20]([OH:22])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[CH2:13][S:14][C@H:9]23)=[O:6])=[O:38])[C:35]2[CH:40]=[CH:41][CH:42]=[CH:43][C:34]=2[NH:33]1
Reactant: O=C(Cl)n1c(=O)[nH]c2ccccc21
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3ccccc3)[C@H]2SC1
Agent: Cl
Solvent: CC#N
Solvent: O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(NC(=O)n3c(=O)[nH]c4ccccc43)c3ccccc3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 102.6 %

Procedure:
To 15 ml. of dry acetonitrile were added 883 mg. (2 mmoles) of 7-(α-aminophenylacetamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid dihydrate. The mixture was cooled, and 3.13 grams (14.4 mmoles) of N,O-bis-trimethylsilylacetamide were added. Solution was complete within two minutes. The resulting mixture then was stirred at room temperature, and 452 mg. (2.3 mmoles) of 2,3-dihydro-2-oxo-1H-benzimidazol-1-ylcarbonyl chloride were added, the temperature of the mixture rising from 25° C. to 28° C. Analysis of a sample of the reaction mixture after 30 minutes by thin-layer chromatography (TLC) indicated that reaction was complete. After two hours, the reaction mixture was slowly dropped into rapidly stirred ice water, the pH of the resulting suspension being 1.9. The pH was adjusted to 1.7 by addition of hydrochloric acid. The mixture was filtered, and the solid which was collected was washed with dilute hydrochloric acid and air-dried to give 1.16 grams of the title compound as a buff-colored powder.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=O)[CH:5]=[CH:6][CH:7]=1.Cl.[CH:20]1([NH:26][NH2:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:26]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[N:27]=[C:8]2[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1
Reactant: NNC1CCCCC1
Reactant: COc1ccc(C(=O)c2cccc(Cl)c2F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: COc1ccc(-c2nn(C3CCCCC3)c3c(Cl)cccc23)cc1
Yield: 92 %

Procedure:
Prepared according to Method C step A (3-chloro-2-fluorophenyl)-(4-methoxyphenyl)-methanone (0.55 g, 1.85 mmol), cyclohexylhydrazine hydrochloride (0.42 g, 2.7 mmol) and DMAP (0.225 g, 1.85 mmol) to give the product (0.58 g) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH:19][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: Cc1cccc(CC(=O)O)c1
Product: Cc1cccc(CC(=O)N[C@@H](C)C(=O)OCC(C)C)c1

Procedure:
Following General Procedure I′ above, and using 3-methylphenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure J′ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [CH:1]1([Li])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][S:2]1.[Mg+2:12].[Br-:13].[Br-]>O(CC)CC>[CH:1]1([Mg:12][Br:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][S:2]1
Reactant: [Mg+2]
Reactant: [Li]C1SC=Cc2ccccc21
Reactant: [Br-]
Solvent: CCOCC
Product: Br[Mg]C1SC=Cc2ccccc21

Procedure:
2-Thianaphthylmagnesium bromide is prepared from 2-thianaphthyllithium and MgBr2.OEt2. Using a procedure similar to that of Example 2, 3.85 g crude silylate product is isolated. Usual flash chromatography work-up results in an unidentified, insoluble purple solid. The desired product is isolated by adding 1M ethanolic HCl (95% of theoretical) to an ethereal solution of the free base. The product is a pale yellow solid (1.7 g, 72%); mp 235° C. (dec) (EtOH).
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[N+:6]([C:9]1[CH:10]=[N:11][NH:12][CH:13]=1)([O-:8])=[O:7].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[N+:6]([C:9]1[CH:10]=[N:11][N:12]([CH2:2][C:3]([OH:5])=[O:4])[CH:13]=1)([O-:8])=[O:7]
Reactant: O=C(O)CBr
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)Cn1cc([N+](=O)[O-])cn1
Yield: 77.9 %

Procedure:
Bromo-acetic acid (1.23 g, 8.84 mmol, 2.0 eq) is added at room temperature to a stirred solution of 4-nitro-1H-pyrazole (500 mg, 4.42 mmol, 1.0 eq) in tetrahydrofuran (50 mL), followed by potassium carbonate (6.15 g, 44.2 mmol, 10.0 eq). The reaction mixture is heated under reflux for 2 hours, solvent is then evaporated, the residue is extracted with ethyl acetate (3×40 mL) and water (40 mL), and the pH is adjusted to 4 by the addition of a 0.1N hydrochloric acid aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford (4-nitro-pyrazol-1-yl)-acetic acid as a light yellow solid (589 mg, 78% yield).