Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])=[C:6]([Cl:18])[CH:5]=[CH:4][N:3]=1.N([O-])=[O:20].[Na+]>OS(O)(=O)=O>[Cl:17][C:15]1[CH:14]=[C:11]([CH:10]=[C:9]([O:8][C:7]2[C:2]([OH:20])=[N:3][CH:4]=[CH:5][C:6]=2[Cl:18])[CH:16]=1)[C:12]#[N:13]
Reactant: O=N[O-]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccnc2N)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccnc2O)c1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 3-[(2-amino-4-chloropyridin-3-yl)oxy]-5-chlorobenzonitrile (590 mg, 2.106 mmol) in 5% aqueous H2SO4 (20 mL) cooled over an ice bath for 5 minutes was added sodium nitrite (247 mg, 3.58 mmol) and stirred 5 minutes. This mixture was then heated to 100° C. for 5 minutes. The mixture was re-cooled over an ice bath and treated with additional sodium nitrite (124 mg, 1.79 mmol), stirred cold for another 5 minutes and then heated to 100° C. for 5 minutes. The reaction mixture was again cooled over an ice bath and the resulting white solid was filtered and washed with water (4×5 mL). This solid was dried under high vacuum to provide the title compound. LRMS (M+1): 280.7.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].CC1C=CC(S(O[CH:21]2[CH2:24][CH2:23][CH2:22]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:21]2[CH2:24][CH2:23][CH2:22]2)=[CH:4][C:3]=1[F:9]
Reactant: Cc1ccc(S(=O)(=O)OC2CCC2)cc1
Reactant: Oc1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1cc(OC2CCC2)ccc1Br
Temperature: 60 °C

Procedure:
4-bromo-3-fluorophenol (315 mg, 1.648 mmol), cyclobutyl 4-methyl-benzenesulfonate (373 mg, 1.648 mmol), and cesium carbonate (1074 mg, 3.30 mmol) were dissolved in DMSO (1648 μl) and heated to 60° C. overnight. The reaction mixture was diluted with water and EtOAc. The aqueous phase was extracted with EtOAc (×2) and the combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on a Biotage™ 50 g column by eluting with 2% to 50% EtOAc:Hexane. 1H NMR δ (ppm) 7.4 (t, 1H), 6.10 (dd, 1H), 6.53 (dd, 1H), 4.60 (quintet, 1H), 2.49-2.43 (m, 2H), 2.21-2.13 (m, 2H), 1.93 (m, 1H), 1.73 (sextet, 1H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=5)[NH:15][C:14]4=[O:24])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]3)=[CH:35][CH:34]=2)O1>>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:24])[C@:13]12[CH2:12][C@H:11]1[C:7]1[CH:6]=[C:5]2[C:10]([C:2]([C:33]3[CH:34]=[CH:35][C:36]([CH:39]4[CH2:40][CH2:41][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:43][CH2:44]4)=[CH:37][CH:38]=3)=[N:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(I)n[nH]c3c1)C(=O)N2
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)n[nH]c3c1)C(=O)N2
Yield: 94.9 %

Procedure:
The title compound was synthesized according to the method of Example A43, except reacting a mixture of (1R*,2S*)-2-(3-iodo-1H-indazol-6-yl)-5′-methoxyspiro [cyclopropane-1,3′-indolin]-2′-one (192 mg, 0.446 mmol) with tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (190 mg, 0.49 mmol). The crude reaction mixture was concentrated under reduced pressure to dryness, and purified by flash chromatography using EtOAc/hexanes as eluent (1:4 to 7:3) to give the title compound as a yellow solid (239 mg, 80%). 1H NMR (400 MHz, MeOD) δ 7.93-7.90 (m, 3H), 7.36-7.34 (m, 3H), 7.02 (d, J=8.0 Jz, 1H), 6.80 (d, J=8.0 Hz, 1H), 6.58 (dd, J=8.0, 4.0 Hz, 1H), 5.55 (s, 1H), 4.39-4.20 (m, 2H), 3.35-3.46 (m, 1H), 3.29 (s, 3H), 2.89-2.79 (m, 2H), 2.76-2.67 (m, 1H), 2.08-2.02 (m 2H), 1.91-1.83 (m, 2H), 1.75-1.61 (m, 2H), 1.51 (s, 9H); MS ESI 565.3 [M+H]+, calcd for [C34H36N4O4+H]+ 565.27.
Reaction SMILES: C([O:3][C:4](=[O:7])[CH2:5][SH:6])C.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[O:18][CH2:19]Cl>CN(C=O)C>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[O:18][CH2:19][S:6][CH2:5][C:4]([OH:3])=[O:7]
Reactant: CCOC(=O)CS
Reactant: ClCOc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CSCOc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To a solution of mercapto-acetic acid ethyl ester (2.4 g, 19.86 mmol) in dry DMF (20 mL) was added NaH (556 mg, 23.27 mmol, 60% in mineral oil). The mixture was stirred for 30 min. at room temperature followed by dropwise addition of 2,4-dichloro-1-chloromethoxy-benzene (3.5 g, 16.55 mmol), stirring was continued for 16 hrs at ambient temperature. The reaction was quenched by addition of water (50 mL) and extracted with diethyl ether (2×50 mL). The combined organic phases were washed with saturated aq. ammonium chloride (50 mL), dried (Na2SO4), filtered and evaporated in vacuo. The residue was dissolved in EtOH (20 mL) and to this solution was added aq. 32% NaOH (1 mL) and water (10 mL). Stirring was continued for 16 hrs at room temperature. The volatiles were evaporated in vacuo, water (20 mL) was added followed by washing with diethyl ether (20 mL). The aqueous phase was acidified to pH˜1 with conc. HCl followed by extraction with diethyl ether (2×25 mL). The combined organic phases were dried (Na2SO4), filtered and the solvent evaporated in vacuo affording 2.5 g (57%) of crude (2,4-dichloro-phenoxymethylsulfanyl)-acetic acid as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: ClCc1ccc(Cl)cc1
Product: Cl
Product: Clc1ccc(CN2CCNCC2)cc1
Yield: 65 %

Procedure:
First of all, a mixture of 4-chlorobenzylchlorine and piperazine was treated according to the general preparation 1 to obtain N-(4-chlorobenzyl) piperazine dihydrochloride, yield 65%, mp 278-280° C. Then, a mixture of the above product (5 g, 20 mmol), KHCO3 (70 mmol) and 2-bromo-1-phenylpropan-1-one (3.96 ml, 26 mmol) in 40 ml of ethanol was refluxed for 8 hours, and then treated according to the general preparation 2 to obtain 6.1 g of N1-(4-chlorobenzyl)-N4-(1-benzoylethyl) piperazine dihydrochloride, yield 59.51%, mp 260-262° C. Finally, a mixture of above compound (1.5 g, 3.45 mmol) and KBH4 (0.74 g, 14 mmol) was treated according to the general preparation 3 to obtain the title compound, yield 65%, mp. 240° C.).
Reaction SMILES: C([O:8][C:9]1[C:10]([N+:25]([O-])=O)=[C:11]([CH:22]=[CH:23][CH:24]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1)=[O:13])C1C=CC=CC=1.CC1C(C)=C(C)C(C)=C(C)C=1>FC(F)(F)C(O)=O>[NH2:25][C:10]1[C:9]([OH:8])=[CH:24][CH:23]=[CH:22][C:11]=1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1)=[O:13]
Reactant: O=C(Nc1ccc(Cl)cn1)c1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: Cc1cc(C)c(C)c(C)c1C
Solvent: O=C(O)C(F)(F)F
Product: Nc1c(O)cccc1C(=O)Nc1ccc(Cl)cn1
Temperature: 40 °C
Yield: 89.6 %

Procedure:
To 7.44 g of 3-benzyloxy-N-(5-chloro-2-pyridyl)-2-nitrobenzamide were added 40 ml of trifluoroacetic acid and 3.72 g of pentamethylbenzene and the mixture was stirred at 40° C. for one night. The reaction solution was concentrated in vacuo, a saturated aqueous solution of sodium bicarbonate was added to the resulting residue to such an extent that the residue did not become alkaline and the mixture was extracted with chloroform. The organic layer was extracted with a 1N aqueous solution of sodium hydroxide and the aqueous layer was acidified by adding hydrochloric acid thereto and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo and 200 ml of an ethanolic suspension of Raney nickel was added to the resulting residue. The mixture was stirred in a hydrogen atmosphere for 6 hours, N,N-dimethylformamide was added and the insoluble matters were filtered off. The solvent was evaporated in vacuo and water was added to the resulting residue. The resulting precipitate was filtered and dried in vacuo to give 4.58 g of 2-amino-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2.CN1CCCC1=O.[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:27][O:26][C:22](/[CH:23]=[CH:24]/[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2)=[O:25]
Reactant: C=CC(=O)OC
Reactant: O=C(O)C1CCc2cc(I)ccc2O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)/C=C/c1ccc2c(c1)CCC(C(=O)O)O2
Temperature: 70 °C
Reaction time: 400 h

Procedure:
Palladium (II) acetate (0.15 g, 0.66 mmol) and the compound from Example 28 (2.00 g, 6.58 mmol) were put in a round bottom flask under an argon atmosphere. To the flask was added 1-methyl-2-pyrrolidinone (20 mL), methyl acrylate (0.74 mL, 8.22 mmol), and triethylamine (2.29 mL, 16.5 mmol). The mixture was heated to 70° C. and stirred for 400 h. The reaction was cooled to RT and poured into water (70 mL). The mixture was extracted with ethyl acetate (1×). The aqueous layer was then acidified with 1.0 N aqueous HCl to generate a cloudy mixture. The mixture was extracted with ethyl acetate (3×). The combined organics from the second extraction were dried (MgSO4) and concentrated to a tan solid (1.75 g, 100%). 1H NMR (300 MHz, acetone-d6) δ 11.28 (s, 1H), 7.57 (d, J=16.18 Hz, 1H), 7.43 (m, 1H), 7.40 (m, 1H), 6.86 (m, 1H), 6.37 (d, J=16.18 Hz, 1H), 4.88 (m, 1H), 3.70 (s, 3H), 2.85 (m, 2H), 2.24 (m, 2H); MS (ES) m/z 263 (MH+).
Reaction SMILES: [CH:1](O)=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[O:16]=[C:17]1[N:22]2[C:23]3[C:28]([NH:29][CH2:30][C:21]2=[N:20][CH:19]=[C:18]1[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][CH:26]=[CH:25][CH:24]=3.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:1]([N:29]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]2[C:17](=[O:16])[C:18]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:19][N:20]=[C:21]2[CH2:30]1)=[O:2]
Reactant: CCOC(=O)c1cnc2n(c1=O)-c1ccccc1NC2
Reactant: O=CO
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cnc2n(c1=O)-c1ccccc1N(C=O)C2
Reaction time: 6 h
Yield: 66.5 %

Procedure:
A solution of 700 mg of formic acid (98%) in 70 ml of CH2Cl2 was stirred at room temperature under nitrogen while 100 mg of carbonyldiimidazole were added thereto. After 30, minutes 1.5 g of ethyl 5,6-dihydro-1-oxo-1H-pyrimido [1,2-a] quinoxaline-2-carboxylate were added thereto and the mixture was stirred for another 6 hours. Then, the solution was poured into an aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried over MgSO4, decolorized with charcoal and evaporated to dryness. The residue was crystallized from ethyl acetate to obtain 1.1 g (67% yield) of ethyl 5,6-dihydro-6-formyl-1-oxo-1H-pyrimido [1,2-a] quinoxaline-2-carboxylate melting at 172°-4° C.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][NH2:4].[CH2:5]1[O:7][CH:6]1[CH2:8][Cl:9].Cl.[OH-:11].[Na+].[OH2:13]>>[CH2:1]=[CH:2][CH2:3][NH3+:4].[CH2:5]1[O:7][CH:6]1[CH2:8][Cl:9].[C:5]([O-:7])([OH:13])=[O:11].[C:5](=[O:7])([OH:13])[O-:11]
Reactant: C=CCN
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: ClCC1CO1
Product: C=CC[NH3+]
Product: O=C([O-])O
Temperature: 36 °C
Reaction time: 3 h

Procedure:
1.4 kg of water is loaded into a 2 liter glass reactor. The temperature is set to 35° C. and 100 g of sevelamer hydrochloride is added in portions, stirring the mixture. A solution of 30% sodium hydroxide is then added until pH 12 is reached (around 71 g). The suspension is maintained at 35-37° C. under stirring for 40 minutes and then filtered, the wet solid is resuspended in 800 ml of distilled water and stirred for two hours at room temperature. The solid is then filtered and washed with distilled water. The solid is loaded into a fluid bed dryer at 50° C. for three hours, after which a carbon dioxide stream is passed through the solid until obtaining an internal pressure of around 40000 Pa. The flow is maintained until the pressure decreases. Finally, the drier is maintained under vacuum and the temperature is raised to 60° C. for 72 hours. Sevelamer carbonate/bicarbonate is thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:21]=4)=[CH:15][N:14](S(C4C=CC(C)=CC=4)(=O)=O)[C:11]3=[N:12][CH:13]=2)=[CH:4][C:3]=1[NH:40][S:41]([CH3:44])(=[O:43])=[O:42].[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][C:3]=1[NH:40][S:41]([CH3:44])(=[O:42])=[O:43]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(F)c(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc(-c2cnc3[nH]cc(-c4cnn(CCc5ccccc5)c4)c3c2)ccc1F
Yield: 37.5 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(2-fluoro-5-(3-(1-phenethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methanesulfonamide (145 mg, 0.230 mmol) was hydrolyzed by lithium hydroxide (48 mg, 1.15 mmol) in THF/methanol/water (15/5/5 ml) to yield 41 mg (37.6% yield) of the titled compound after purification by preparative TLC(Silicagel-1000 micron) using 50% ethyl acetate in hexane as eluent. 1H NMR (CD3OD, 300 MHz): δ 8.44-8.40 (d, 1H), 8.108-8.101 (d, 1H), 7.83-7.74 (m, 2H), 7.58-7.50 (m, 2H), 7.40-7.10 (m, 5H), 4.46-4.42 (t, 2H), 3.20-3.16 (t, 2H), 3.06 (s, 3H). MS: m/z=476.5 (M+1), HPLC: 93.52% in method A.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([N:13]([C:21]1[N:31]=[CH:30][C:29]2[C:28]3[S:32][CH:33]=[CH:34][C:27]=3[CH2:26][CH2:25][O:24][C:23]=2[CH:22]=1)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:12])([CH3:11])[CH3:10]>CN(C)C=O>[Br:1][C:33]1[S:32][C:28]2[C:29]3[CH:30]=[N:31][C:21]([N:13]([C:9]([CH3:10])([CH3:11])[CH3:12])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:22][C:23]=3[O:24][CH2:25][CH2:26][C:27]=2[CH:34]=1
Reactant: CC(C)(C)OC(=O)N(c1cc2c(cn1)-c1sccc1CCO2)C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(c1cc2c(cn1)-c1sc(Br)cc1CCO2)C(C)(C)C
Reaction time: 18 h

Procedure:
A solution of N-bromosuccinimide (59 mg, 0.33 mmol) in 1 ml of dimethylformamide was added dropwise to a solution of tert-butyl tert-butyl(4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepin-8-yl)carbamate (120 mg, 0.32 mmol) in 2 ml of dimethylformamide (DMF). The reaction mixture was stirred for 18 hours, concentrated in vacuum and partitioned between water and ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated in vacuum to give tert-butyl 2-bromo-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepin-8-yl(tert-butyl)carbamate which was used in the next step without further purification. MS: (ESI+) 453.2
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([F:21])=[CH:18][C:19]=2[F:20])=[CH:12][C:11]([C:22]([OH:24])=[O:23])=[C:10]([OH:25])[CH:9]=1.[C:26](=[O:34])([O:31][CH2:32][CH3:33])[O:27][CH:28](Cl)[CH3:29]>CO>[F:20][C:19]1[CH:18]=[C:17]([F:21])[CH:16]=[CH:15][C:14]=1[C:13]1[CH:12]=[C:11]([C:22]([O:24][CH:28]([O:27][C:26]([O:31][CH2:32][CH3:33])=[O:34])[CH3:29])=[O:23])[C:10]([OH:25])=[CH:9][CH:8]=1
Reactant: CCOC(=O)OC(C)Cl
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)OC(C)OC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
A mixture of 1.76 g of the triethylamine salt of diflunisal and 1.0 g of 1-chloroethyl ethyl carbonate are heated in an oil bath at 100°-110° with magnetic stirring for 3 hours. The reaction mixture is then cooled to room temperature and 5 ml of methanol are added. After cooling to 0°-5°, the resulting precipitate is collected by filtration, washed with 3 ml of cold methanol then with 5 ml of 10% ethyl ether in hexane. After air drying there is obtained 1.38 g (75%) of 1-(ethoxycarbonyloxy)ethyl 5-(2,4-difluorophenyl)salicylate, m.p. 76°-78°.
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([OH:19])=[C:10]([CH:18]=1)[C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])(=[O:4])[CH3:3].[CH:20](Cl)(Cl)Cl>CO>[C:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([OH:19])=[C:10]([CH:18]=1)[C:11]([CH2:13][CH2:14][C:15]([O:17][CH3:20])=[O:16])=[O:12])(=[O:4])[CH3:3]
Reactant: ClC(Cl)Cl
Reactant: CC(=O)Nc1ccc(O)c(C(=O)CCC(=O)O)c1
Agent: Cl
Solvent: CO
Product: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1O
Temperature: 0 °C

Procedure:
Hydrogen chloride gas was passed through a gently boiling solution of 3-(5-acetamido-2-hydroxybenzoyl) propionic acid (1.2 g) in dry methanol (20 ml) until esterification was complete. The reaction mixture was then poured into ice-water and chloroform added. The chloroform extract was washed with sodium bicarbonate solution then water, and finally dried and evaporated to leave methyl 3-(5-acetamido-2-hydroxybenzoyl)propionate as a solid (0.75 g, 59%; m.p. 145°-147°C; M+, 265, M 265).
Reaction SMILES: B(Br)(Br)Br.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2C[CH:14]2[CH2:16][C:17]([O:19]CC)=[O:18])=[CH:9][CH:8]=1>ClCCl.C(OCC)(=O)C>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]=[CH:14][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC1CC1c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C=CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 106.2 %

Procedure:
Boron tribromide (246 mL, 1 M) in dichloromethane was added slowly to a solution of ethyl 1-(p-methoxyphenyl)cyclopropane-2-acetate (60 g, 246 mmol) in dichloromethane (1L) at 0° C. and the reaction mixture was stirred at room temperature for 18 h. It was cooled to 0° C. and was quenched with excess ethanol. The reaction mixture was concentrated and the residue in ethyl acetate (1 L) was washed with saturated sodium bicarbonate (500 mL), washed with brine (500 mL), dried and was concentrated. The residue was purified by passing through a thick pad of silica and eluting with 20% ethyl acetate in hexane to afford 50.2 g (89%) of the desired product. 1H NMR (CD3OD) δ 6.93 (d, 2H, J=8.6 Hz), 6.71 (d, 2H, J=8.6 Hz), 4.15(q, 2H, J=7.1 Hz), 2.37 (d, 2H, J=7.2 Hz), 1.66-1.71 (m,1H), 1.23-1.28 (m, 4H), 0.87-0.91 (m, 1H), 0.75-0.79 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:4]=2[N:3]=1.C(O)C.O.[NH2:27]N>C(O)(=O)C>[NH:1]([C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:5]2[CH:15]=[C:16]([C:19]([F:22])([F:20])[F:21])[CH:17]=[CH:18][C:4]=2[N:3]=1)[NH2:27]
Reactant: NC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2)=NC1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2)=NC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 9.1 parts of 2-amino-5-phenyl-7-trifluoromethyl-3H-1,4-benzodiazepine, 150 parts by volume of ethanol and 3.6 parts by volume of glacial acetic acid is added 4.5 parts by volume of 100% hydrazine hydrate. The whole mixture is stirred for 30 minutes at room temperature and treated in a similar manner to Example 1, whereby 2-hydrazino-5-phenyl-7-trifluoromethyl-3H-1,4-benzodiazepine is yielded as a crystalline powder. Melting point: 127° C (sintering), 133° C to 135° C (effervescence).
Reaction SMILES: Cl[CH2:2][CH2:3][OH:4].[CH2:5]([NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[CH3:6].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:5]([N:7]([CH2:2][CH2:3][OH:4])[CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[CH3:6]
Reactant: OCCCl
Reactant: CCNCCOc1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCN(CCO)CCOc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Add 0.90 g (011 mol) 2-chloroethanol to a solution of 2.0 g (0.11 mol) N-ethyl-N-[2-(4-methylphenoxy)ethyl]amine and 1.7 g (012 mol) potassium carbonate in 50 mL methanol. Stir at room temperature for 24 hr. After this time, remove the solvents in vacuo and dissolve the residue in 25 mL water. Adjust the aqueous to pH=8 with 5% sodium bicarbonate solution and extract 3×50 mL methylene chloride. Dry the combined organics over sodium sulfate and evaporate the solvent to obtain the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[N:15])=NC=2)=[CH:4][CH:3]=1.Br[C:17]1C=CC(C#N)=C[N:18]=1.BrC1C=CC(B(O)O)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:17][N:18]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(-c2ccc(Br)cc2)cn1
Reactant: N#Cc1ccc(Br)nc1
Agent: OB(O)c1ccc(Br)cc1
Product: N#Cc1ccc(-c2ccc(Br)cc2)nc1
Yield: 78 %

Procedure:
The same procedure described for 5-(4′-bromophenyl)-2-pyridinecarbonitrile was used by employing 2-bromo-5-cyanopyridine and 4-bromophenylboronic acid to furnish 81 in 78% yield; mp 157-159° C. 1H NMR (DMSO-d6): δ 7.74 (d, J=8.8 Hz, 2H), 8.12 (d, J=8.8 Hz, 2H), 8.22 (d, J=8.4 Hz, 1H), 8.40 (dd, J=2.4, 8.4 Hz, 1H), 9.09 (d, J=2.4 Hz, 1H).
Reaction SMILES: N[CH:2]1[C:12](=[O:13])[N:4]2[C:5]([C:9]([OH:11])=[O:10])=[CH:6][CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.P(Cl)(Cl)(Cl)=O.CN(C)C=O>C(OCC)(=O)C>[S:8]1[C@@H:3]2[CH2:2][C:12](=[O:13])[N:4]2[C:5]([C:9]([OH:11])=[O:10])=[CH:6][CH2:7]1
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)C1=CCS[C@@H]2CC(=O)N12
Yield: 248.6 %

Procedure:
A solution of 7-amino-3-cephem-4-carboxylic acid (1.0 g.) and trimethylsilylacetamide (3.8 g.) in ethyl acetate (10 ml.) and a solution of 2-[2-(2,2,2-trifluoroacetamidothiazol-4-yl)]-2-(2,4-dichlorobenzyloxyimino)acetic acid (syn isomer, 2.0 g.), phosphoryl chloride (0.9 g.) and N,N-dimethylformamide (0.43 g.) in ethyl acetate (16 ml.) were treated in a similar manner to that of Example 1-(1) to give 7-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]-2-(2,4-dichlorobenzyloxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.3 g.).
Reaction SMILES: C(C1N=[C:7]([N:22]2C[CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2N=NN(CC3C=CC=CC=3Cl)[C:9]=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].COC[C@H]1CCCN1>>[C:28]([C:32]1[N:33]=[C:34]([N:22]2[CH2:7][CH2:8][CH2:9][C@@H:23]2[CH2:24][O:25][CH3:26])[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: COC[C@H]1CCCN1
Product: COC[C@H]1CCCN1c1nc(C(C)(C)C)nc2c1nnn2Cc1ccccc1Cl

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (R)-2-(methoxymethyl)pyrrolidine and isolated as colorless gum (12.4 mg, 64%). MS (m/e): 415.4 (MH+).