Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:10][C:9]=1[N+:25]([O-:27])=[O:26].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O.CN(C)C=O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][S:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:22][CH:23]=2)(=[O:16])=[O:17])=[CH:10][C:9]=1[N+:25]([O-:27])=[O:26]
Reactant: BrCc1ccccc1
Reactant: Nc1ccc(OS(=O)(=O)c2ccc(O)cc2)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(OS(=O)(=O)c2ccc(OCc3ccccc3)cc2)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A solution of cesium carbonate (156 mg) in water (0.3 ml) was added to a solution of 4-hydroxy-benzenesulfonic acid 4-amino-3-nitro-phenyl ester (150 mg) and benzyl bromide (58 μl) in dimethylformamide (3 ml). The reaction mixture was heated at 80° C. for 3 hours then allowed to cool to ambient temperature, poured into water (25 ml) and extracted three times with ethyl acetate (30 ml). The combined extracts were dried over magnesium sulfate then evaporated to give 189 mg of crude 4-benzyloxy-benzenesulfonic acid 4-amino-3-nitrophenyl ester.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:38]=[CH:37][C:6]([O:7][C:8]2[N:12]([CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[N:11]=[C:10]([C:19]3[CH:20]=[C:21]([C:25]4([NH:29]C(=O)OC(C)(C)C)[CH2:28][O:27][CH2:26]4)[CH:22]=[CH:23][CH:24]=3)[CH:9]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:29][C:25]1([C:21]2[CH:20]=[C:19]([C:10]3[CH:9]=[C:8]([O:7][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:39])[F:40])=[CH:38][CH:37]=4)[N:12]([CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[N:11]=3)[CH:24]=[CH:23][CH:22]=2)[CH2:28][O:27][CH2:26]1
Reactant: CN(C)C(=O)Cn1nc(-c2cccc(C3(NC(=O)OC(C)(C)C)COC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)Cn1nc(-c2cccc(C3(N)COC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
A stirred solution of tert-butyl [3-(3-{5-(4-trifluoromethylphenoxy)-1-[2-(dimethylamino)-2-oxoethyl]-1H-pyrazol-3-yl}phenyl)oxetan-3-yl]carbamate (70 mg, 0.13 mmol) in 2 mL of CH2Cl2 was cooled in an ice bath. To the solution was added 1 mL of TFA and the mixture was stirred for 1 h. The cooling bath was removed and the mixture was stirred at ambient temperature for 1 h. 10% Aqueous Na2CO3 solution was added and the mixture was extracted with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give 2-{3-[3-(3-aminooxetan-3-yl)phenyl]-5-(4-trifluoromethylphenoxy)-1H-pyrazol-1-yl}-N,N-dimethylacetamide as an oil. Calcd (M+1)+: 461.4. Found: 461.5
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH2:12]C)[CH2:6][CH2:5]1.Br[C:38]1[CH:43]=[C:42]([CH3:44])[N:41]([CH3:45])[C:40](=[O:46])[CH:39]=1>>[CH3:45][N:41]1[C:42]([CH3:44])=[CH:43][C:38]([C:17]2[CH:16]=[CH:15][C:14]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:36])([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:19][CH:18]=2)=[CH:39][C:40]1=[O:46]
Reactant: Cc1cc(Br)cc(=O)n1C
Reactant: CC[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc(=O)n1C

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan -2-one and 4-bromo-1,6-dimethylpyridin-2(1H)-one following a procedure analogous to that described in Example 6 Step 1. LC-MS Method 2 tR=1.173 min, m/z=475.2; 1H NMR (CDCl3) 1.10 (s, 3H), 1.16 (s, 3H), 1.51 (d, 3H), 2.18 (m, 3H), 2.21 (m, 1H), 2.42 (m, 4H), 2.86 (m, 1H), 3.54 (s, 3H), 5.66 (m, 1H), 6.21 (s, 1H), 6.60 (s, 1H), 6.97 (m, 2H), 7.23-7.34 (m, 7H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:24]#[N:25])[C:17]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:18][C:13]=2[NH:12][C:11](=S)[CH2:10][N:9]=1.CO[C:29](OC)([N:31](C)C)[CH3:30].[NH2:36]N>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:24]#[N:25])[C:17]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:18][C:13]=2[N:12]=[C:11]2[NH:36][NH:31][C:29]([CH3:30])=[C:10]2[N:9]=1
Reactant: NN
Reactant: COC(C)(OC)N(C)C
Reactant: COCCOc1cc2c(cc1C#N)C(c1ccccc1Cl)=NCC(=S)N2
Product: COCCOc1cc2c(cc1C#N)C(c1ccccc1Cl)=NC1=C(C)NNC1=N2

Procedure:
5-(2-chlorophenyl)-7-cyano-1,2-dihydro-8-methoxyethoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVm) was prepared by reacting 0.00048 moles of 5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-methoxyethoxy-2H-1,4-benzodiazepin-2-thione (IIm) with 1,1-dimethoxy-N,N-dimethyl-ethanamine and then hydrazine in a manner analogous to Example 55.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH2:31]([NH2:33])[CH3:32]>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[C:15]2[O:14][CH:13]([CH2:12][NH:33][CH2:31][CH3:32])[CH2:17][C:16]=2[CH:18]=1
Reactant: CCN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4c(C)cccc4C)c3O2)cc1
Product: CCNCC1Cc2cc(Cl)cc(-c3c(C)cccc3C)c2O1

Procedure:
The title compound was prepared (0.079 g, 66%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and ethylamine (0.14 g, 3.38 mmol). mp 230-232° C.
Reaction SMILES: [CH:1]1[C:14]2[C:5]([S:6][C:7]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][C:3](=[O:15])[CH:2]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Cl:25]Cl.O>C(O)(=O)C>[Cl:25][C:4]1[C:3](=[O:15])[CH:2]=[CH:1][C:14]2[C:5]=1[S:6][C:7]1[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=1)[N:13]=2
Reactant: ClCl
Reactant: O=c1ccc2nc3ccccc3sc-2c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1ccc2nc3ccccc3sc-2c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 500 g (2.34 mol) of 3H-phenothiaz-3-one in 12.5 L of glacia acetic acid was added 1.25 kg of ptassium dichromate. The mixture was stirred at room temperature for 1/2 hour. To this resulting mixture was then added 2.34 mol of a 1M solution of chlorine in glacial acetic acid dropwise over a period of 4 hours. The progress of the reaction was monitored by tlc to ensure no excess chlorine was added. After addition of chlorine was completed the mixture was stirred at room temperature for another 1/2 hour and was then poured into 120 L of H2O with vigorous stirring. The 4-chlorophenothiazin-3-one precipitated was allowed to settle overnight. The majority of the aqueous solution was siphoned and discarded and the rest was filtered. The filtered precipitate was washed thoroughly with water and then rinsed with methanol and was allowed to dry to give 504 g crude 4-chlorophenothiazin-3-one which was recrystallized from toluene.
Reaction SMILES: [CH2:1]([C:3]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH3:19])[CH:13]=1)([C:6]1[S:7][CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH2:4][CH3:5])[CH3:2].Br[CH2:21][C:22]([O:24][CH3:25])=[O:23].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:25][O:24][C:22](=[O:23])[CH2:21][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:3]([CH2:4][CH3:5])([C:6]2[S:7][CH:8]=[C:9]([CH3:11])[CH:10]=2)[CH2:1][CH3:2])=[CH:13][C:14]=1[CH3:19]
Reactant: COC(=O)CBr
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1cc(C)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(CC)(c1ccc(OCC(=O)OC)c(C)c1)c1cc(C)cs1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
4-[1-Ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenol (10.66 g, 38.9 mmol) is reacted with methyl bromoacetate (4.4 ml, 46.7 mmol) and K2CO3 (10.70 g, 77.81 mmol) in acetone (100 m) at refluxing temperature overnight. The reaction is cooled to RT, filtered and washed with Et2O and concentrated. The crude product is purified by chromatography to give the titled compound (12.15 g, 35.1 mmol, 90%). 1H NMR (CD3Cl3), δ 0.70 (t, J=7.2 Hz, 6H), 2.04-2.12 (m, 4H), 2.21 (s, 3H), 2.26 (s, 3H), 3.81 (s, 3H), 4.63 (s, 2H), 6.57-6.61 (m, 2H), 6.69-6.71 (m, 1H), 7.02-7.06 (m, 2H). LC/MS (m/z): calcd for C20H27O3S (M+H)+:347.5; found: 347.1.
Reaction SMILES: [H-].[Na+].O([C:10]1[CH:11]=[C:12]([CH2:17][CH2:18][CH2:19][C:20]([C:23]2[CH:28]=[CH:27]C(OCC)=CC=2)([CH3:22])C)[CH:13]=[CH:14][C:15]=1F)C1C=CC=CC=1.[Br:32][C:33]1[CH:34]=[C:35]([C:42]([CH3:47])([CH3:46])[CH2:43][CH:44]=O)[CH:36]=[CH:37][C:38]=1[O:39][CH2:40][CH3:41].[OH2:48]>COCCOC>[C:17]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:44][CH2:43][C:42]([C:35]2[CH:36]=[CH:37][C:38]([O:39][CH2:40][CH3:41])=[C:33]([Br:32])[CH:34]=2)([CH3:47])[CH3:46])[CH:23]=[CH:28][CH:27]=1)(=[O:48])[C:12]1[CH:11]=[CH:10][CH:15]=[CH:14][CH:13]=1
Reactant: O
Reactant: CCOc1ccc(C(C)(C)CCCc2ccc(F)c(Oc3ccccc3)c2)cc1
Reactant: CCOc1ccc(C(C)(C)CC=O)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOc1ccc(C(C)(C)CC=Cc2cccc(C(=O)c3ccccc3)c2)cc1Br
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To 5 ml of anhydrous dimethyl cellosolve was added 0.1 g of 60% sodium hydride, and thereinto 0.9 g of diethyl 3-benzoylbenzylphosphonate (prepared according to (1) of Synthetic Example 11) was added dropwise, and the mixture was stirred at 50° C. for 30 minutes. Then, a solution of 0.6 g of 3-(3-bromo-4-ethoxyphenyl)-3-methylbutanal in 2 ml of dimethyl cellosolve was added dropwise into the mixture, and stirred at 80° C. for one hour. After cooling, the reaction mixture was poured into water and extracted with benzene, and the benzene extract was washed with water and dried, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: benzene) to give 0.7 g of the desired product.
Reaction SMILES: CSC.S([O:9][CH3:10])(OC)(=O)=O.C[O-].[Na+].[Cl:14][C:15]1[CH:28]=[CH:27][C:18]([O:19][CH2:20][C:21](=O)[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=1>C(#N)C>[Cl:14][C:15]1[CH:28]=[CH:27][C:18]([O:19][CH2:20][C:21]2([C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:10][O:9]2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)C(=O)COc1ccc(Cl)cc1
Reactant: COS(=O)(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CSC
Solvent: CC#N
Product: CC(C)(C)C1(COc2ccc(Cl)cc2)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
A solution of 162 ml (2.2 moles of dimethyl sulphide in 400 ml of absolute acetonitrile was added to a solution of 189 ml (2.0 moles) of dimethyl sulphate in 1,200 ml of absolute acetonitrile at room temperature. The reaction mixture was stirred overnight at room temperature. 118.8 g (2.2 moles) of sodium methylate were then added. The mixture was stirred for 30 minutes and a solution of 272 g (1.2 moles) of 1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one in 600 ml of absolute acetonitrile was then added dropwise in the course of 30 minutes. The reaction mixture was subsequently stirred overnight. It was then concentrated, the residue was partitioned between water and ethyl acetate, the organic phase was separated off, washed twice with water and once with saturated sodium chloride solution, dried over sodium sulphate and concentrated and the residue was distilled in vacuo. 242.4 g (84% of theory) of 2-(4-chlorophenoxymethyl)-2-tert.-butyl-oxirane of boiling point 115°-22° C./0.003 mm Hg column and of melting point 50°-52° C. were obtained.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]([O:12]CC)=[O:11])[NH:7][C:8]=1[CH3:9]>CO>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]([OH:12])=[O:11])[NH:7][C:8]=1[CH3:9]
Reactant: CCOC(=O)c1cc(Cl)c(C)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1[nH]c(C(=O)O)cc1Cl
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Lithium hydroxide (2 M, 4 ml) was warmed to 50° C. and a solution of ethyl 4-chloro-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 9, 0.30 g, 1.60 mmol) in MeOH was added to it. The reaction was heated to 80° C. and stirred for two hours. The MeOH was removed and the aqueous solution was cooled to 0° C. and acidified with 30% HCl. The precipitated product (0.23 g, 92%) was filtered and dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].[H-].[Na+].[CH2:13]([O:15][CH2:16]Cl)[CH3:14]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:16][O:15][CH2:13][CH3:14])[C:5]#[N:6]
Reactant: CCOCCl
Reactant: N#Cc1ccc(O)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCOc1ccc(C#N)cc1Br
Temperature: 60 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
A solution of 3-bromo-4-hydroxybenzonitrile (25 g, 125 mmol) in THF (375 mL) at room temperature was treated with 95% NaH (4.3 g, 170 mmol) in a few portions. The resulting slurry was heated to 60° C. for 30 minutes, treated with chloromethyl ethyl ether (25 g, 260 mmol), and the mixture was stirred at 60° C. for another 2 hours. The reaction was cooled to room temperature, concentrated to a slush, treated with water (200 mL), and filtered. The solid was dried for about 16 hours under vacuum in the presence of P2O5 to provide 30 g (95%) of the desired product. MS (DCI/NH3) m/z 273, 275 (M+H+NH3)+; 1H NMR (CDCl3) δ 7.84 (d, 1H), 7.56 (dd, 1H), 7.25 (d, 1H), 5.35 (s, 2H), 3.76 (q, 2H), 1.23 (t, 3H).
Reaction SMILES: [NH2:1][C:2](=[N:22][OH:23])[C:3]1[CH:4]=[CH:5][C:6]([F:21])=[C:7]([CH:20]=1)[CH2:8][N:9]([CH3:19])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[CH3:24][O:25][CH2:26][C:27]1[CH:32]=[C:31]([C:33](O)=O)[CH:30]=[CH:29][C:28]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH3:42]>>[F:21][C:6]1[CH:5]=[CH:4][C:3]([C:2]2[N:1]=[C:33]([C:31]3[CH:30]=[CH:29][C:28]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[CH3:42])=[C:27]([CH2:26][O:25][CH3:24])[CH:32]=3)[O:23][N:22]=2)=[CH:20][C:7]=1[CH2:8][N:9]([CH3:19])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: CN(CCC(=O)OC(C)(C)C)Cc1cc(C(N)=NO)ccc1F
Product: COCc1cc(-c2nc(-c3ccc(F)c(CN(C)CCC(=O)OC(C)(C)C)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 63 (268.44 mg; 0.83 mmol) and Intermediate 28 (192.22 mg; 0.75 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1), affording the title compound as a colorless oil. 1H NMR (CDCl3) δ 8.42 (d, J=1.4 Hz, 1H), 8.25-8.22 (m, 1H), 8.17 (dd, J=7.8, 1.9 Hz, 1H), 8.12-8.07 (m, 1H), 7.36-7.23 (m, 4H), 7.20-7.12 (m, 2H), 4.23 (s, 2H), 3.65 (s, 2H), 3.33 (s, 3H), 2.80 (t, J=7.3 Hz, 2H), 2.49 (t, J=7.2 Hz, 2H), 2.27 (s, 3H), 2.08 (s, 3H), 1.45 (s, 9H). 19F NMR (CDCl3) δ-113.6 ppm. LC/MS (Method B): 546.4 (M+H)+. HPLC (Method A) Rt 5 min (Purity: 97.8%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH:18]([N:21]=[C:22]=[O:23])([CH3:20])[CH3:19]>>[CH:18]([NH:21][C:22]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:23])([CH3:20])[CH3:19]
Reactant: CC(C)N=C=O
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CC(C)NC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 71.2 %

Procedure:
Beginning with 0.15 gm (0.65 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.077 mL (0.78 mMol) isopropyl isocyanate, 0.146 gm (71%) of the title compound were recovered essentially by the procedure of Example 122. An analytical sample was crystallized from aqueous ethanol. m.p.=217-219° C. (dec.) MS(m/e): 315(M+) Calculated for C17H25N5O: Theory: C, 64.74; H, 7.99; N, 22.20; Found: C, 64.84; H, 8.06; N, 22.44.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:5]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[C:20](=[N:25][OH:26])[C:21](=[O:24])[CH2:22][Br:23])[C@H:4]2[S:3]1.[N+](=[CH2:31])=[N-]>C(O)C.C(OCC)C>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][C:12]([Cl:13])([Cl:14])[Cl:15])=[O:9])[N:5]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[C:20](=[N:25][O:26][CH3:31])[C:21](=[O:24])[CH2:22][Br:23])[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)C(=NO)C(=O)CBr)[C@H]2S1
Reactant: C=[N+]=[N-]
Solvent: CCO
Solvent: CCOCC
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CC(C)S[C@H]12

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-7-(2-hydroxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylate (a mixture of syn and anti isomers) (1.2 g.) in ethanol (20 ml.) was added dropwise a solution of diazomethane (0.1 mole) in diethyl ether under stirring and ice-cooling to complete the reaction. After the reaction mixture was concentrated under reduced pressure, the residue was pulverized in diisopropyl ether, collected by filtration and then dried to give brown powder of 2,2,2-trichloroethyl 2-methyl-7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylate (a mixture of syn and anti isomers) (1.1 g.), mp 80° to 83° C. (dec.).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH2:17])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:24]1CCC[CH2:25]1>>[NH2:17][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]([CH2:10][CH2:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:25][OH:24]
Reactant: C1CCOC1
Reactant: NC(=O)CCCCCCCOC1CCCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCCCCC(CO)CCCOC1CCCCO1
Reaction time: 0.25 h

Procedure:
A solution of 1.0 g (3.17 mmol) of 5-[3-(tetrahydropyranyloxy)propyl]valeramide in 5 ml tetrahydrofuran is added dropwise to a suspension of 0.481 g (12.68 mmol) lithium aluminium hydride in 20 ml dry tetrahydrofuran. The reaction mixture is refluxed for 2.5 h, cooled in an ice-bath and quenched by the addition of 0.5 ml water, 0.5 ml 15% aqueous sodium hydroxide followed by 1.5 ml water. The mixture is stirred for 15 min and filtered, washed and then subjected to evaporation to give 6-amino-2-[3-(tetrahydropyranyloxy)propyl]-hexan-1-ol.
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43]([OH:45])=O)[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:46][CH:47]2[CH2:51][CH2:50][CH:49]([OH:52])[CH2:48]2)[CH:27]=1.CCN(C(C)C)C(C)C.N>CN(C=O)C.CO>[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43]([NH2:2])=[O:45])[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:46][CH:47]2[CH2:51][CH2:50][CH:49]([OH:52])[CH2:48]2)[CH:27]=1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CCC(O)C3)c12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC3CCC(O)C3)c12
Temperature: 25 °C

Procedure:
HATU (147 mg) was added at 0° C. to a mixture of 4-(4-fluoro-2-(3-hydroxycyclopentyloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxilic acid (130 mg) and DIPEA (67 μl) in DMF (2.0 ml). After 30 min 7 M NH3 in MeOH (1.0 ml) was added and the mixture was allowed to warm to room temperature over weekend. The reaction mixture was concentrated in vacuo. The residue was treated with hot MeOH. The mixture was allowed to cool, then it was filtered to yield the desired product.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][CH2:14][C:13]=34)[N:5]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[C:31](Cl)(Cl)=[O:32].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>C1COCC1>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([C:31]([N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[O:32])[CH2:14][C:13]=34)[N:5]=2)[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=C(Cl)Cl
Reactant: c1ccc2c(c1)NCc1c(-c3noc(C4CC4)n3)ncn1-2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(N1CCOCC1)N1Cc2c(-c3noc(C4CC4)n3)ncn2-c2ccccc21
Reaction time: 0.17 h

Procedure:
To a slurry consisting of 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)4,5-dihydroimidazo[1,5-a]quinoxaline (XXXIII, EXAMPLE 88, 0.499 g), diisopropylethylamine (0.81 ml) and THF (15 ml) is added phosgene (1.93 M in toluene, 1.20 ml). A slight exotherm ensues and the slurry becomes homogeneous. After 10 min, morpholine (0.20 ml) is added. The mixture is stirred for 2 hr and then partitioned between ethyl acetate, water, and saline. The phases are separated and the organic phase is dried over magnesium sulfate and concentrated. The crude product is chromatographed on silica gel (150 ml) eluting with methanol/dichloromethane (2/98). The appropriate fractions are pooled and concentrated to give the product. Recrystallization from dichloromethane and hexane gives the title compound, mp 198.0°-198.5°; MS (m/z) at 392; IR 1662, 1506, 1409, 1277, and 1579 cm-1 ; NMR (CDCl3) 1.24, 1.36, 2.27, 3.33, 3.64, 5.02, 7.21, 7.27, 7.55 and 8.11 δ.
Reaction SMILES: [OH-].[K+].N(N(C)[C:6](N)=O)=O.[N+](=C)=[N-].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)=[CH:16][C:15]=1[NH:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:30][CH:29]=1)=[O:27]>O.C(OCC)C.C(Cl)Cl>[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)=[CH:16][C:15]=1[NH:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38][CH3:6])=[O:37])=[CH:30][CH:29]=1)=[O:27]
Reactant: Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CCC(=O)O)cc1
Reactant: CN(N=O)C(N)=O
Agent: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1
Temperature: 0 °C
Yield: 94.1 %

Procedure:
A mixture of 50% potassium hydroxide in H2O (30 mL) and diethyl ether (100 mL), stirred at 0° C., was treated portion wise with solid N-nitroso-N-methyl urea (3.0 g, 29.1 mmol). The reaction mixture was stirred for 30 min then transferred into a separatory funnel, the aqueous layer was discarded and the yellow ethereal phase (diazomethane solution) was cooled to −78° C. in an Erlenmeyer flask. A suspension of the acid 230 (20 mg, 0.055 mmol) in DCM (2 mL) was treated with the diazomethane solution in diethyl ether (3 mL) and the yellow solution was stirred at room temperature for 3 h, concentrated and the residue was purified by flash chromatography (eluent: 2% isopropanol in DCM) to provide title compound 231 (19.7 mg, 94% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:22]([C:23](=O)/[CH:24]=[CH:25]/N(C)C)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.S(O)(O)(=O)=O.[NH2:35][C:36]([NH2:38])=[NH:37]>>[NH2:37][C:36]1[N:38]=[C:23]([C:22]2[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)=[N:9][N:10]3[C:15]([NH:16][CH:17]4[CH2:18][CH2:19][CH2:20][CH2:21]4)=[CH:14][CH:13]=[CH:12][C:11]=23)[CH:24]=[CH:25][N:35]=1
Reactant: N=C(N)N
Reactant: CN(C)/C=C/C(=O)c1c(-c2cccc(Br)c2)nn2c(NC3CCCC3)cccc12
Agent: O=S(=O)(O)O
Product: Nc1nccc(-c2c(-c3cccc(Br)c3)nn3c(NC4CCCC4)cccc23)n1
Yield: 76.9 %

Procedure:
In a similar manner as described in Example 1 from (2E)-1-[2-(3-bromophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (500 mg, 1.1 mmol) and guanidine sulfate (358 mg, 1.65 mmol), N-[3-(2-amino-4-pyrimidinyl)-2-(3-bromophenyl)pyrazolo[1,5-a]pyridin-7-yl]-N-cyclopentylamine (380 mg, 77%) was obtained as a yellow solid. 1H NMR (CDCl3): δ 8.01 (d, 1H), 7.84 (s, 1H), 7.64 (d, 1H), 7.54–7.49 (m, 2H), 7.30–7.22 (m, 2H), 6.36 (d, 1H), 6.01 (d, 1H), 5.97 (d, 1H), 4.95 (broad s, 2H), 3.97 (m, 1H), 2.12 (m, 2H), 1.79–1.57 (m, 6H); MS m/z 448 (M+1); Anal. Calcd. for C22H21N6Br: C, 58.80; H, 4.71; N,18.70. Found: C, 58.61; H, 4.75; N, 18.58.