Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[CH:4]=[O:5].C1(O)C=CC=CC=1.[CH3:21][O:22][C:23](=[O:27])[CH:24](Br)[CH3:25]>>[F:1][C:2]1[C:3]([CH:4]=[O:5])=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8]([CH:9]=1)[O:10][CH:24]([CH3:25])[C:23]([O:22][CH3:21])=[O:27]
Reactant: COC(=O)C(C)Br
Reactant: O=Cc1cc([N+](=O)[O-])c(O)cc1F
Solvent: Oc1ccccc1
Product: COC(=O)C(C)Oc1cc(F)c(C=O)cc1[N+](=O)[O-]

Procedure:
Using 2-fluoro-4-hydroxy-5-nitrobenzaldehyde as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure for alkylation of substituted-2-nitrophenols gives the title compound as a white solid: ESI-MS: m/z 272.1 (M+H)+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][C:8]([OH:10])=[C:7]([C:11]3[C:19](=O)[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[N:12]=3)[C:5]=2[CH:6]=1.[Cl-].[OH:22][NH3+:23].O>N1C=CC=CC=1>[CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][C:8]([OH:10])=[C:7]([C:11]3[NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19]=3[N:23]=[O:22])[C:5]=2[CH:6]=1
Reactant: O=C1C(c2c(O)[nH]c3ccccc23)=Nc2ccccc21
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: O
Product: O=Nc1c(-c2c(O)[nH]c3ccccc23)[nH]c2ccccc12
Temperature: 25 °C
Yield: 90.2 %

Procedure:
Indirubin (0.64 g, 2.4 mmol) was dissolved in anhydrous pyridine (25 mL), and hydroxylammonium chloride (1.67 g, 24 mmol) was added to the solution. The reaction liquid was heated and refluxed for 2.5 hours and then cooled to room temperature. The reaction liquid was poured into water (100 mL), and the precipitated crude crystals were collected by suction filtration. The resulting crude crystals were recrystallized from methanol/water to give red needle-shaped crystals of indirubin-3′-oxime (0.60 g, 89%).
Reaction SMILES: [C:1]([C:5]1[CH:18]=[C:17]2[C:19]3=[C:20]4[C:10]([CH:11]=[CH:12][CH:13]=[C:14]4[CH:15]=[CH:16]2)=[CH:9][CH:8]=[C:7]3[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.[Br-:23].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.O>ClCCl.[Br-].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>[Br:23][C:13]1[C:14]2[C:20]3=[C:19]4[C:17](=[CH:16][CH:15]=2)[CH:18]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[C:7]4[CH:8]=[CH:9][C:10]3=[CH:11][CH:12]=1
Reactant: [Br-]
Reactant: CC(C)(C)c1cc2ccc3cccc4ccc(c1)c2c34
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc2ccc3ccc(Br)c4ccc(c1)c2c34
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 161.5 %

Procedure:
Next, a mixed solution of 45.0 g (content: 83%) of 2-t-butylpyrene, 660 ml of dichloromethane and 220 ml of methanol was cooled to 0° C. under an argon gas stream and then 56.4 g of benzyltrimethylammonium tribromide dissolved in 100 ml of dichloromethane was added dropwise. This mixed solution was stirred at room temperature for 2.5 hours and 5.64 g of benzyltrimethylammonium tribromide was added, followed by stirring for 1.5 hours. After the organic layer was isolated by pouring 250 ml of water into this mixed solution, the aqueous layer was extracted twice with 250 ml of dichloromethane. The combined organic layer was washed with 300 ml of water, dried over magnesium sulfate and then evaporated. To the resulting solid, 300 ml of methanol was added, followed by stirring and further filtration. To the resulting solid, 200 ml of hexane was added, and then the resulting solution was stirred, filtered and vacuum-dried to obtain 44.5 g of 1-bromo-7-t-butylpyrene.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([CH3:12])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]#[CH:27])=[N:24][CH:25]=2)=[CH:16][CH:15]=1>N1CCCCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]#[C:27][C:2]3[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([CH3:12])[CH:3]=3)=[N:24][CH:25]=2)=[CH:18][CH:19]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Cc1cc(I)ccc1OCCO
Solvent: C1CCNCC1
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCO

Procedure:
Prepared analogously to Example 4b from 380 mg (1.37 mmol) 2-(4-iodo-2-methyl-phenoxy)-ethanol and 292 mg (1.37 mmol) 5-(4-chloro-phenyl)-2-ethynyl-pyridine in 38 mL piperidine.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[N:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:24]1([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[C:10]([NH:12][CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)=[N:11][C:2]([C:34]2[CH:35]=[N:30][CH:31]=[N:32][CH:33]=2)=[N:3]3)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(CNc2nc(Cl)nc3cccc(-c4ccccc4)c23)cc1
Reactant: CC1(C)OB(c2cncnc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CNc2nc(-c3cncnc3)nc3cccc(-c4ccccc4)c23)cc1
Temperature: 110 °C
Reaction time: 12 h
Yield: 65.7 %

Procedure:
To a solution of methyl 4-((2-chloro-5-phenylquinazolin-4-ylamino)methyl)benzoate (550 mg, 1.36 mmol) in DMF (16 mL) and H2O (0.5 mL) under nitrogen were added pyrimidine-5-ylboronic acid pinacol ester (422 mg, 2.04 mmol) and potassium carbonate (377 mg, 2.72 mmol). The resulting mixture was degassed with nitrogen for 15 min and then (1,1′-bis(diphenylphosphino)ferrocene)-palladium (II) chloride dichloromethane complex (50 mg, 0.068 mmol) was added. Upon completion of addition, the reaction mixture was again degassed for 10 min. with nitrogen. The reaction mixture was then heated to 110° C. where it stirred for 12 h. After this time, the reaction mixture was allowed to cool to room temperature. Once at the prescribed temperature, the reaction mixture was quenched by the addition of water and then extracted with ethyl acetate. The organic layer was washed successively with water and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting concentrate was purified by flash column chromatography using 0.5% MeOH in CH2Cl2 to afford methyl 4-((5-phenyl-2-(pyrimidin-5-yl)quinazolin-4-ylamino)methyl)benzoate (400 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.62 (s, 2H), 9.31 (s, 1H), 7.93-7.86 (m, 4H), 7.54-7.49 (m, 5H), 7.37 (d, J=6.8 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 5.94 (t, J=4.8 Hz, 1H), 4.71 (d, J=5.2 Hz, 1H), 3.85 (s, 3H). LCMS Method C: retention time 2.15 min, [M+1]=448.2. HPLC Method B: purity 98.5%, retention time 9.81 min.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([NH2:11])[CH:10]=1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:29](OCCC(C)C)=O>C1C=CC=CC=1>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[C:9]2[C:8]([CH:12]=[N:29][NH:11]2)=[CH:7][CH:6]=1
Reactant: CC(C)CCON=O
Reactant: Cc1ccc(Oc2ccccc2F)cc1N
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: Fc1ccccc1Oc1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a suspension of 5-(2-fluoro-phenoxy)-2-methyl-phenylamine (2.4 g, 11.04 mmol), acetic anhydride (3.36 g, 33.12 mmol) and potassium acetate anhydrous (1.10 g, 11.16 mmol) in benzene (36 mL) at 80° C. was added dropwise over 30 minutes isoamyl nitrite (2.22 mL, 16.56 mmol) and the reaction mixture was stirred at this temperature overnight. After cooling to room temperature, the precipitate formed was filtered and the filtrate was concentrated under vacuum and the residue treated with 5N HCl (4.5mL) then concentrated HCl (2.5 mL); the mixture was heated at 55° C. for 2.5 h then 60° C. for 15 min. The reaction was cooled to room temperature extracted into benzene (15 mL), the aqueous layer was basified with NH4OH the extracted into EtOAc (2×25 mL), the combined organic layers were dried over Na2SO4 filtered, concentrated and the residue was purified by flash chromatography eluting with Hex:EtOAc 7:3 to yield 1.8 g of 6-(2-fluoro-phenoxy)-1H-indazole: MS: 229 (M+H).
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:2]1=[O:3].[OH-:12].[K+].[CH2:14](Br)[CH:15]=[CH2:16]>CS(C)=O>[CH2:14]([O:1][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:5]=[CH:4]\[C:2]([OH:3])=[O:12])[CH:15]=[CH2:16]
Reactant: C=CCBr
Reactant: [OH-]
Reactant: O=c1ccc2ccccc2o1
Agent: [K+]
Solvent: CS(C)=O
Product: C=CCOc1ccccc1/C=C\C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A slurry of coumarin (14.6 g, 0.10 mol) and potassium hydroxide (83 g, 1.48 mol) in 300 mL dimethyl sulfoxide was stirred at ambient temperature for 4 hours. Allyl bromide (8.66 mL, 0.10 mol) was added over 5 minutes and the reaction stirred at ambient temperature for 30 minutes. The mixture was poured into ice water, the solution filtered and then acidified (pH<3.0) with hydrochloric acid. The solid was filtered, air dried, then recrystallized from methlcyclohexane to yield cream needles (12.04 g, 59.0%), mp 80°-82° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1CCCC1.[CH3:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[O:19].[C:27]([O:34][CH2:35][CH3:36])(=[O:33])[C:28]([O:30]CC)=O>C(OCC)C>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([C:18](=[O:19])[CH:17]([CH3:16])[C:28](=[O:30])[C:27]([O:34][CH2:35][CH3:36])=[O:33])=[CH:25][CH:24]=1
Reactant: CCC(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(C)C(=O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 33.7 %

Procedure:
A 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (30 mL, 30 mmol) in anhydrous diethyl ether (120 mL) under argon was cooled to −78° C. in a dry ice/acetone bath. A solution of 4-chloropropiophenone (5.0 g, 29.7 mmol) in anhydrous ether (24 mL) was added dropwise and the mixture was stirred an additional 45 minutes at −78° C. Diethyl oxalate (4.6 mL, 33.9 mmol) was added in one portion; the reaction was warmed to room temperature, and stirred overnight. The light yellow precipitate that formed was collected, washed with ether and dried under vacuum to obtain the lithium enolate of ethyl 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutanoate (2.75 g, 10.0 mmol).
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[CH2:15]([NH2:18])[CH2:16][CH3:17]>CCCCCC>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[NH:18][CH2:15][CH2:16][CH3:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCCN
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Solvent: CCCCCC
Product: CCCN[SiH]1N(C(C)(C)C)C=CN1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
In an argon atmosphere, 5.90 g (25.4 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 40 mL of hexane and after adding 3.03 g (51.3 mmol) of propylamine, the mixture was stirred at room temperature for 3 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 92° C./3.5×102 Pa) to obtain 1,3-di-tert-butyl-2-propylamino-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NHPr) as a pale yellow liquid (yielded amount: 5.99 g, yield: 92%).
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC([O-])(C)C.[K+].Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:34][CH3:35])=[CH:31][CH:32]=2)[N:27]=[C:26]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[CH:25]=1>CS(C)=O.O>[C:4]([O:3][C:1]([N:8]1[CH2:15][CH:14]([O:16][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:34][CH3:35])=[CH:31][CH:32]=3)[N:27]=[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[CH:25]=2)[CH2:13][CH:9]1[C:10]([OH:12])=[O:11])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: COc1ccc2c(Cl)cc(-c3ccccn3)nc2c1
Reactant: CC(C)(C)OC(=O)N1CC(O)C[C@H]1C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2c(OC3CC(C(=O)O)N(C(=O)OC(C)(C)C)C3)cc(-c3ccccn3)nc2c1
Reaction time: 1.5 h
Yield: 51.3 %

Procedure:
To a solution of N—Boc-4-hydroxyproline (1.6 g, 6.7 mmol) in DMSO (20 mL) was added t-BuOK (1.9 g, 16.8 mmol). The generated mixture was stirred for 1.5 h and 4-Chloro-7-methoxy-2-pyridin-2-yl-quinoline (2.0 g, 7.4 mmol) and DMSO (10 mL) were added. The reaction mixture was stirred for 38 h, diluted with cold water and extracted with EtOAc/ether (1/4, 2×). the aqueous layer was acidified to pH 4 and extracted with EtOAc/THF (5×). the combined extract was dried (Na2SO4/MgSO4), removed the solvent in vacuo and the residue was purified by preparative HPLC (0-80% solvent B) to provide the product (1.6 g, 50%): LC-MS (retention time: 1.23, Method I), MS m/z 466 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([OH:14])=O)[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C:36]1=[O:41].C(N(CC)CC)C>CN(C)C=O.O>[O:41]=[C:36]1[CH2:37][CH2:38][CH2:39][CH2:40][CH:35]1[NH:34][C:12]([C:10]1[S:11][C:7]2[C:6]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:14]
Reactant: NC1CCCCC1=O
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)O)nc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCOCC2)c2sc(C(=O)NC3CCCCC3=O)nc12
Yield: 2 %

Procedure:
6.00 g 4-Methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 3.75 g 1,1′-carbonyl-diimidazole in 360 ml dimethylformamide were stirred at room temperature for 16 hours. 3.36 g 2-amino-cyclohexanone hydrochloride and 3.14 ml triethylamine were added and stirring was continued over night at room temperature. Water was added and the mixture was extracted with ethylacetate. Chromatography on silicagel with ethylacetate/hexane 1:1 to yielded 0.16 g (2%) 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid (2-oxo-cyclohexyl)-amide as a yellow solid; M.p.: 195–197° C.; MS (ISP): m/e=390 (M+H+).
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH2:22][CH3:23])[N:13]=2)=[O:11])[CH2:4][CH2:3]1.CO>ClC(OC(Cl)C)=O>[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH2:22][CH3:23])[N:13]=2)=[O:11])[CH2:4][CH2:3]1
Reactant: CCCn1nc(C(=O)NCC2CCN(C)CC2)c2ccccc21
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Product: CCCn1nc(C(=O)NCC2CCNCC2)c2ccccc21
Yield: 20.9 %

Procedure:
A solution of N-(1-methyl-4-piperidyl)methyl-1-n-propylindazole-3-carboxamide (2.00 g) obtained in Example 7 in α-chloroethyl chloroformate (8 ml) was stirred at 70° C. for 6 hours, then methanol (20 ml) was added, and the mixture was heated under reflux for 2 hours. The reaction solution was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol:aqueous ammonia=90:10:1) to give the title compound (0.40g) as a yellow oily substance. Yield=21%.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[CH2:6][C:5]1=[O:14])(=[O:3])[CH3:2].[CH3:15][N:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25](O)=[O:26])=[CH:24][C:19]=2[N:18]=[CH:17]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6](=[C:25]([OH:26])[C:23]2[CH:22]=[CH:21][C:20]3[N:16]([CH3:15])[CH:17]=[N:18][C:19]=3[CH:24]=2)[C:5]1=[O:14])(=[O:3])[CH3:2]
Reactant: Cn1cnc2cc(C(=O)O)ccc21
Reactant: CC(=O)N1C(=O)Cc2ccc(Cl)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1C(=O)C(=C(O)c2ccc3c(c2)ncn3C)c2ccc(Cl)cc21

Procedure:
3.5 g of 1-acetyl-6-chloro-2-indolinone, 3.4 g of 1-methylbenzimidazole-5-carboxylic acid, 6.1 g of TBTU, 2.9 g of HOBT-hydrate and 8.7 ml ethyldiisopropylamine are stirred in 100 ml DMF for 15 hours at ambient temperature. The mixture is combined with water and extracted with ethyl acetate, while the crude product is partially precipitated. The residue obtained by distilling off the solvent is taken up in dichloromethane and a little methanol and extracted with water. The organic phase is evaporated down, the residue stirred successively with ethyl acetate and diethyl ether, suction filtered and dried.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:25][CH:26]1[C:44](=[O:45])[N:28]2[C:29]([C:41]([OH:43])=[O:42])=[C:30]([CH2:33][S:34][C:35]3[N:39]([CH3:40])[N:38]=[N:37][N:36]=3)[CH2:31][S:32][C@H:27]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:10]([NH:25][CH:26]2[C:44](=[O:45])[N:28]3[C:29]([C:41]([OH:43])=[O:42])=[C:30]([CH2:33][S:34][C:35]4[N:39]([CH3:40])[N:38]=[N:37][N:36]=4)[CH2:31][S:32][C@H:27]23)=[O:12])[N:8]=1)=[O:2]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=CNc1nc(C(=NOCC(F)(F)F)C(=O)O)cs1
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(F)(F)F)c3csc(NC=O)n3)[C@H]2SC1
Yield: 28.9 %

Procedure:
A solution of 2-(2-formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetic acid (syn isomer, 1.78 g.), N,N-dimethylformamide (0.48 g.) and phosphoryl chloride (1.01 g.) in ethyl acetate (18 ml.), and a solution of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.97 g.) and trimethylsilylacetamide (4.72 g.) in ethyl acetate (28 ml.). were treated in a similar manner to that of Example 17 (1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.05 g.).
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[C:18]([CH2:21][N:22]([CH3:24])[CH3:23])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].N1C[CH2:36][O:35][CH2:34]C1>>[C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[C:18]([CH2:21][N:22]2[CH2:24][CH2:36][O:35][CH2:34][CH2:23]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1COCCN1
Reactant: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1CN(C)C
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1CN1CCOCC1

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-(morpholinomethyl)naphthalen-2-yl)acetic acid (134) was prepared in a manner similar to 2-tert-butoxy-2-(1-(4-chlorophenyl)-4-((dimethylamino)methyl)-3-methylnaphthalen-2-yl)acetic acid of Example 131, except using morpholine in the reductive amination step. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H33ClNO4: 482.2; Found: 482.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:31](Cl)(=[O:33])[CH3:32]>C(O)(=O)C>[C:31]([NH:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][N:10]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:11]=23)=[CH:22][CH:23]=1)(=[O:29])=[O:28])(=[O:33])[CH3:32]
Reactant: NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Reactant: CC(=O)Cl
Solvent: CC(=O)O
Product: CC(=O)NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Yield: 77 %

Procedure:
A mixture of 4-[2-(3-fluoro-phenyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridin-3-yl]benzenesulfonamide (0.2 g, 0.46 mmol) and acetyl chloride (Aldrich) (1 ml) in acetic acid (1 ml) was heated at 95° for 1 hr. The solvent was removed and the resulting oil was dissolved in ethyl acetate (30 ml), washed with M Na2CO3 (10 ml) and brine (10 ml). Drying (MgSO4) and removal of solvent gave a white solid which was triturated with 40-60 petroleum ether, filtered and dried to give the title compound (0.17 g 77%). MH− 476
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[O:14]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38]([N:40]2[CH2:45][CH2:44][CH:43]([O:46][C:47]([O:49]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:42][CH2:41]2)=[O:39])=[O:29])=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[O:14]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38]([N:40]2[CH2:41][CH2:42][CH:43]([O:46][C:47]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:49])[CH2:44][CH2:45]2)=[O:39])=[O:29])=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(NCCCCCCOC(=O)N1CCC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1)Oc1ccc(Oc2ccccc2)cc1
Reactant: C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCCCCOC(=O)N1CCC(OC(=O)N2CCCCC2)CC1)Oc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
A solution of piperidine (382 μl, 3.86 mmol) and triethylamine (2.24 mL, 16.1 mmol) in 30 mL of methylene chloride was added under nitrogen dropwise to a solution of the carbonate prepared in Example 5 (2.0 g, 3.22 mmol) in 30 mL of methylene chloride at ice bath temperature. After the addition the cooling bath was removed and the reaction stirred at room temperature overnight. The reaction was extracted one time with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 1.85 g of an oil. Purification of the oil on silica gel (230-400 mesh) using 5%-20% ethyl acetate-methylene chloride as the eluent gave 1.23 g (68%) of the title compound as a white crystalline solid, mp 56°-61° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23](O)=O)=[O:17])([CH3:14])([CH3:13])[CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[N:9]=[C:23]([C@@H:19]3[CH2:20][CH2:21][CH2:22][N:18]3[C:16]([O:15][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:17])[NH:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(F)c(Br)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(F)c(Br)cc2[nH]1
Reaction time: 16 h
Yield: 76.2 %

Procedure:
To a solution of 4-bromo-5-fluorobenzene-1,2-diamine (1.7 g, 8.4 mmol) in DMSO (42 mL) was added (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.8 g, 8.4 mmol) followed by HATU (3.5 g, 9.3 mmol) and N,N-diisopropyl-N-ethylamine (3.7 mL, 21.1 mmol), and the solution was stirred for 16 hours. The reaction mixture was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4), filtered and concentrated. Acetic acid (40 mL) was added, and the mixture was stirred at 60° C. for 4 hours. Then, the reaction mixture was cooled and concentrated. The residue was azeotroped 2 times with toluene to give crude product which was purified by flash chromatography (0-50% EtOAc/hexane) to give the title compound (2.5 g, 6.4 mmol, 77%).