Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1>C(Cl)Cl>[O:1]=[C:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.4 %

Procedure:
To a solution of (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (40 g, 157 mmol) in DCM (500 mL) was added DMP (80 g, 189 mmol) at 0° C. and the reaction mixture was stirred at RT for 4 h, quenched with NaHSO3, extracted with DCM and washed with NaHCO3. The organic phase was concentrated to provide the title intermediate (33 g, 89% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ(ppm) 1.51 (s, 9H), 2.550-2.597 (d, 1H, J=18.8 Hz), 2.876-2.944 (t, 1H, J=13.6 Hz), 3.895 (s, 3H), 3.766-3.895 (m, 1H), 4.696-4.814 (m, 1H).
Reaction SMILES: [OH-].[CH2:2]([N+:6]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH3:5].CO.[C:21]([OH:26])(=[O:25])[CH:22]([CH3:24])[CH3:23]>>[C:21]([O-:26])(=[O:25])[CH:22]([CH3:24])[CH3:23].[CH2:15]([N+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18]
Reactant: CC(C)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Product: CC(C)C(=O)[O-]

Procedure:
Alternatively, a 1M solution of tetrabutylammonium hydroxide in methanol (1 L, 1 mol) and isobutyric acid (88.5 g, 1 mol) was stirred at ambient temperature for 30 min. The solvent was removed in vacuo to afford the title compound (5) as a waxy solid, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[CH:8][C:9]=1[CH3:10])=[O:4].[H-].[Na+].[N+:13](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:13])[CH:7]=[CH:8][C:9]=1[CH3:10])=[O:4]
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: COC(=O)c1[nH]ccc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)ccn1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 249.9 %

Procedure:
A suspension of 5-methyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid (18.1 gm, 93.7 mmole) in 85% aq. H3PO4 (250 mL) was heated at 110° C. for 3.5 h. After cooling to RT, ice water (500 mL) was added and the precipitate was collected, washed with water, and dried. This afforded 5.8 gm of the product as a brown solid. An additional 4.1 gm (total of 9.9 gm, 71%) of product was obtain by extraction of the filtrate with DCM (4×500 mL), drying (Na2SO4), and removal of the solvent. 1H NMR (CDCl3) δ 2.54 (s, 3H), 6.35 (d, 1H, J=3 Hz), 7.31 (d, 1H, J=3 Hz), 7.42 (s, 1H), 9.52 (br s, 1H); HPLC Ret Time: 1.17 min (YMC C18 S5, 4.6×50 mm column, 3 min gradient, 4 mL/min). Procedure II: A suspension of 5-methyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester (5.81 gm, 0.028 mol) in 85% aq. H3PO4 (60 mL) was heated at 110° C. for 6 h. After cooling to RT, ice (120 gm) was added and the precipitate was collected, washed with water and dried to afforded the product (3.47 gm, 83%). Procedure III: A solution of 3-methyl-1H-pyrrole-2-carboxylic acid methyl ester (4.59 gm, 33 mmole) in dry DMF (100 mL) was added slowly to an ice cooled suspension of NaH (1.72 gm, 60% dispersion in oil, 1.3 equiv) in dry DMF (300 mL). After 30 min, O-(2,4-dinitro-phenyl)-hydroxylamine (1.53 gm, 1.1 equiv) was added in one portion and the reaction was left stirring in the ice bath for 1 hr. After 0.5 hr it was removed from the bath and diluted with brine. This was extracted with EtOAc (3 times) and the combined extracts were dried (Na2SO4) and the solvents were removed. The residue was chromatographed on a silica gel column (gradient elution with hexane containing 5 to 20% EtOAc) to give 1-amino-3-methyl-1H-pyrrole-2-carboxylic acid methyl ester (2.96 gm, 58%) as a yellow solid. 1H NMR (MeOH-D4) δ 2.25 (s, 3H), 3.81 (s, 3H), 5.83 (d, 1H, J=2 Hz), 6.82 (d, 1H, J=2 Hz); MS: 155 (M+H)+; HPLC Ret Time: 0.97 min (YMC Exterra ODS S7 3.0×50 mm, 2 min gradient, 5 mL/min). A mixture of this 1-amino-pyrrole (2.96 gm, 19.2 mmole) in formamide (30 mL) was heated at 165° C. for 10 hr. After cooling to RT, this was diluted with cold water and the precipitate was collected, washed with cold water followed by a mixture of Et2O and hexane (6:4). This gave 5-methyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (1.83 gm, 64%) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[C:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[C:4]#[N:5]>CCOC(C)=O.CCO.[Pd]>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[C:4]#[N:5]
Reactant: CC(C)(C)C#Cc1cccc(N)c1C#N
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)CCc1cccc(N)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
A suspension of 2-amino-6-(3,3-dimethylbut-1-ynyl)benzonitrile (Example 21c, 690 mg, 3.48 mmol) and 10% Pd/C (100 mg) in EtOAc/EtOH (1:1, 20 mL) was stirred under an atmosphere of H2 with a balloon at room temperature overnight. The Pd/C was removed by filtration, the filtrate was concentrated, and purified by chromatography on silica gel eluting with 20% EtOAc in hexanes to give the title compound as a light yellow oil (620 mg, 88%). 1H NR (400 MHz, DMSO-d6) δ 0.92 (s, 9H), 1.36-1.40 (m, 2H), 2.52-2.56 (m, 2H), 5.88 (s, 2H), 6.45 (d, J=7.6 Hz, 1H), 6.57 (d, J=7.6 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H). MS 203 (MH+).
Reaction SMILES: [CH:1]1([CH:7]([NH:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)[C:8]2[CH:12]=[C:11]([CH:13]=[O:14])[S:10][C:9]=2[CH2:15][CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:28]1([Mg]Br)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.O1CCCC1.[Cl-].[NH4+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.C(Cl)Cl>[CH:1]1([CH:7]([NH:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)[C:8]2[CH:12]=[C:11]([C:13]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:14])[S:10][C:9]=2[CH2:15][CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1sc(C=O)cc1C(Nc1ccc(C(=O)OC)cc1)C1CCCCC1
Reactant: Br[Mg]C1CCCCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1sc(C(=O)C2CCCCC2)cc1C(Nc1ccc(C(=O)OC)cc1)C1CCCCC1
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of methyl 4-{[cyclohexyl(2-ethyl-5-formylthiophen-3-yl)methyl]amino}benzoate (500 mg) synthesized in Example 287 (6) in tetrahydrofuran (10 mL) was added dropwise 1.0M cyclohexylmagnesium bromide-tetrahydrofuran solution (3.25 mL) at −45° C., and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a yellow oil. To a solution of the obtained oil in methylene chloride (10 mL) was added Dess-Martin reagent (827 mg) at 0° C., and the mixture was stirred for 1 hr. Saturated aqueous sodium sulfite solution was added to quench the reaction, methylene chloride was evaporated using evaporator, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the title compound (347 mg, 57%) as a pale-brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH:12]([N:17]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]([O:32]C)=[O:31])[CH2:25][CH2:24][N:23]([CH2:34][C:35]([O:37]C)=[O:36])[CH2:22][CH2:21][N:20]([CH2:39][C:40]([O:42]C)=[O:41])[CH2:19][CH2:18]1)[C:13]([O:15]C)=[O:14]>Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH:12]([N:17]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]([OH:32])=[O:31])[CH2:25][CH2:24][N:23]([CH2:34][C:35]([OH:37])=[O:36])[CH2:22][CH2:21][N:20]([CH2:39][C:40]([OH:42])=[O:41])[CH2:19][CH2:18]1)[C:13]([OH:15])=[O:14]
Reactant: COC(=O)CN1CCN(CC(=O)OC)CCN(C(C(=O)OC)c2cc([N+](=O)[O-])ccc2OC)CCN(CC(=O)OC)CC1
Agent: Cl
Product: COc1ccc([N+](=O)[O-])cc1C(C(=O)O)N1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1

Procedure:
A solution of α-(2-methoxy-5-nitrophenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, tetramethyl ester (prepared by the procedure of Example 10) in concentrated HCl (5 ml, J. T. Baker ULTREX) was refluxed under a nitrogen atmosphere for 5 hours. The solution was then concentrated to dryness in vacuo to leave a solid residue. This was purified by chromatography (silica gel, Solvent System 6) to yield the title product as an off-white solid (209 mg). This material was converted to the tetrahydrochloride salt and was characterized by:
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[C:8]1([S:14][CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCC(Cl)(Cl)Cl>[CH3:15][S:14][C:8]1[CH:13]=[CH:12][C:11]([C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[CH:10][CH:9]=1
Reactant: CSc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: ClCC(Cl)(Cl)Cl
Agent: [Al+3]
Product: CSc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 60 °C

Procedure:
In a 500 ml flask with a ground neck, 0.17 mol of succinic anhydride is added to a solution of 0.17 mol of thioanisole in 140 ml of tetrachloroethane. The mixture is cooled with the aid of an ice bath, and 0.34 mol of aluminium chloride is added in small portions. The mixture is then heated at 60° C. for 3 hours. The reaction mixture is then cooled, poured into ice-cold water and acidified with 3M HCl solution. The precipitate formed is filtered off under suction, washed with cyclohexane and recrystallised.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][C:12](=[O:16])[NH:13]2)=[CH:8][CH:7]=1.[Na+].[I-].Cl.[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:34][CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([CH2:10][CH2:11][C:12](=[O:16])[NH:13]3)=[CH:8][CH:7]=2)[CH2:30][CH2:29]1
Reactant: O=C1CCc2ccc(OCCCBr)cc2N1
Reactant: Clc1cccc(N2CCCNCC2)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: O=C1CCc2ccc(OCCCN3CCCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
A mixture of intermediate 3 (142 mg, 0.5 mmol) and NaI (150 mg, 1.0 mmol) in CH3CN was heated to reflux for 30 min and then cooled to rt. Intermediate 2 (196 mg, 0.7 mmol) and anhydrous K2CO3 (173 mg, 1.25 mmol) were added to the mixture. The resulting mixture was heated to reflux for 4 h. Precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=30:1) to give 7-(3-(4-(2,3-dichlorophenyl)-1,4-diazepan-1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one (compound 1) (140 mg, 63%). 1H NMR (300 MHz, CDCl3): δ 8.16 (s, 1H), 7.10-6.98 (m, 4H), 6.53 (dd, J=8.1 Hz, 2.4 Hz, 1H), 6.34 (d, J=2.1 Hz, 1H), 4.01 (t, J=6.6 Hz, 2H), 3.32-3.28 (m, 4H), 2.92-2.87 (m, 6H), 2.76 (t, J=6.6 Hz, 2H), 2.62 (t, J=6.6 Hz, 2H), 2.04-1.97 (m, 4H). HPLC: 99%, RT 2.421 min. MS (ESI) m/z 448.1 [M+H]+. mp: 130-131° C.
Reaction SMILES: [H-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](O)=[CH:5][N:4]=1.NCC(C1C=CC=CC=1)=O.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.[C:45]([N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46]>CN(C=O)C>[C:48]([O:47][C:45]([N:52]1[CH2:57][CH2:56][N:55]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:3]=[N:4][CH:5]=2)[CH2:54][CH2:53]1)=[O:46])([CH3:51])([CH3:49])[CH3:50]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Oc1cnnc2ccccc12
Agent: NCC(=O)c1ccccc1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [H-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cnnc3ccccc23)CC1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a suspension of NaH (60% in mineral oil, 0.099 g, 2.46 mmol) in DMF (5 mL) was added cinnolin-4-ol (prepared from 2-aminoacetophenone according to the procedures described in U.S. Pat. No. 4,620,000), 0.300 g, 2.05 mmol) in DMF (2 mL) dropwise. The reaction mixture was warmed at 40° C. and stirred for 30 minutes. After cooling, N-phenyltrifluoromethanesulfonimide (0.880 g, 2.46 mmol) in DMF (2 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. 1-Boc piperazine (0.765 g, 4.11 mmol) was added to the mixture. The reaction was stirred at 80° C. for 4 hours. After cooling, the mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with water, brine, dried and concentrated. The residue was purified by column chromatography (1:1 to 1:3 hexanes/EtOAc) to give 4-Cinnolin-4-yl-piperazine-1-carboxylic acid tert-butyl ester (0.246 g, 38%) as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.91 (s, 1H), 8.47 (d, J=8.4 Hz, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.80 (t, J=7.2 Hz, 1H), 7.69 (t, J=7.2 Hz, 1H), 3.74 (m, 4H), 3.34 (m, 4H), 1.51 (s, 9H). LCMS (APCI+) m/z 315 [M+H]+; Rt=2.14 minutes.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.C[O:20][C:21](=[O:29])[CH2:22][CH2:23][C:24](=O)[CH2:25][S:26][CH3:27]>C(O)(C)(C)C>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:25]([S:26][CH3:27])=[C:24]2[CH2:23][CH2:22][C:21]([OH:29])=[O:20])=[CH:5][CH:4]=1
Reactant: COC(=O)CCC(=O)CSC
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(F)cc1
Agent: Cl
Solvent: CC(C)(C)O
Product: CSc1c(CCC(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(F)cc12

Procedure:
Following the procedure of Example 10, but using 1-(p-chlorobenzyl)-1-(4-fluorophenyl)hydrazine hydrochloride and methyl-5-methylthio-4-oxopentanoate as starting materials and t-butanol as the solvent, the title compound was prepared. 1H NMR (250 MHz, CDCl3) δ 2.29 (s, 3H), 2.58 (broad t, 2H, J-7.8 Hz), 3.23 (broad t, 2H, J =7.8 Hz), 5.37 (s, 2H), 6.87 (d, 2H, J =8.5 Hz), 6.89-6.95 (m, 1H), 7.08 (dd, 1H, J =4.3 and 8.9 Hz), 7.25 (d, 2H, J =8.5 Hz), 7.40 (d,d, 1H, J =2.6 and 9.4 Hz).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)([O:23][CH3:24])[CH2:21][CH3:22])=[CH:16][C:15]=1[O:30][CH3:31]>>[CH3:24][O:23][C:20]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:2][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)=[C:15]([O:30][CH3:31])[CH:16]=1)[CH2:21][CH3:22]
Reactant: BrCc1ccc2ccccc2n1
Reactant: CCC(OC)(c1ccc(O)c(OC)c1)c1nccs1
Product: CCC(OC)(c1ccc(OCc2ccc3ccccc3n2)c(OC)c1)c1nccs1
Yield: 52 %

Procedure:
Using a similar procedure to that described in Example 1, 2-bromomethylquinoline was reacted with 2-[1 -(4-hydroxy-3-methoxyphenyl)-1-methoxypropyl]thiazole to give 2-[1-methoxy-1-[3-methoxy-4-(quinol-2-ylmethoxy)phenyl]propyl]thiazole in 52% yield, m.p. 100°-102° C. (recrystallised from a mixture of petroleum ether (b.p. 60°-80° C.) and methylene chloride).
Reaction SMILES: [N+](C1C=CC(COC([N:12]=[C:13]([N:15]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([C@@H:24]3[CH2:28][C@H:27]([S:29][C:30]4[C@H:31]([CH3:54])[C@@H:32]5[C@@H:49]([C@H:50]([OH:52])[CH3:51])[C:48](=[O:53])[N:33]5[C:34]=4[C:35]([O:37]CC4C=CC([N+]([O-])=O)=CC=4)=[O:36])[CH2:26][N:25]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:23])[CH2:17][CH2:16]2)[CH3:14])=O)=CC=1)([O-])=O>O1CCCC1.O>[C:13]([N:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([C@@H:24]2[CH2:28][C@H:27]([S:29][C:30]3[C@H:31]([CH3:54])[C@@H:32]4[C@@H:49]([C@H:50]([OH:52])[CH3:51])[C:48](=[O:53])[N:33]4[C:34]=3[C:35]([OH:37])=[O:36])[CH2:26][NH:25]2)=[O:23])[CH2:17][CH2:16]1)(=[NH:12])[CH3:14]
Reactant: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCCN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Solvent: C1CCOC1
Solvent: O
Product: CC(=N)N1CCCN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2)CC1
Yield: 33.8 %

Procedure:
144 mg of 4-nitrobenzyl (1R,5S,6S)-2-[(2S,4S)-2-(4-(N-4-nitrobenzyloxycarbonylacetimidoyl)homopiperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 7.5 ml of a 2:1 by volume mixture of tetrahydrofuran and water, and were hydrogenated by bubbling hydrogen through the solution at room temperature for 1.5 hours in the presence of 375 mg of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 1(b), to give 24 mg of the title compound as a powder.
Reaction SMILES: [N+](=[CH:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[O:8][N:7]=1)=[O:5])=[N-].FC(F)(F)C(O)=[O:15].O>C(OCC)C>[OH:15][CH2:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[O:8][N:7]=1)=[O:5]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(C(=O)C=[N+]=[N-])no1
Solvent: CCOCC
Solvent: O
Product: Cc1cc(C(=O)CO)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
2-Diazo-1-(5-methylisoxazol-3-yl)ethanone (7.0 g, 46 mmol) was dissolved in diethyl ether (100 ml) and trifluoroacetic acid (25 ml) and water (100 ml) were added. The solution was stirred at room temperature for 2 hours, then the diethyl ether was removed in vacuo and the aqueous solution was stirred at room temperature for 18 hours. Further water (100 ml) was added and the aqueous solution was extracted twice with ethyl acetate. The organic extracts were washed successively with water, 10% aqueous potassium carbonate solution and brine, and dried (Na2SO4). Evaporation of the solvent yielded the title-compound as a pale solid (4.0 g, 61%), 1H NMR (360 MHz, CDCl3) 2.52 (3H, s), 4.90 (2H, s), 6.44 (1H, s).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:3]1=2.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:18]([Cl:33])=[CH:17][N:16]=1>CO.C(Cl)Cl>[Cl:33][C:18]1[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[N:20][C:15]([NH:13][C:10]2[CH:11]=[CH:12][C:3]3[N:2]([CH3:1])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[CH:9]=2)=[N:16][CH:17]=1
Reactant: CS(=O)(=O)Nc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1CCCCc2cc(N)ccc21
Solvent: ClCCl
Solvent: CO
Product: CN1CCCCc2cc(Nc3ncc(Cl)c(Nc4ccccc4NS(C)(=O)=O)n3)ccc21

Procedure:
Following the procedure of Example 101b, 1-Methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamine (48 mgs, 0.27 mmol) and N-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenyl]-methanesulfonamide (0.9 eq) were reacted except that the ISCO chromatography gradient was 0% to 10% MeOH/CH2Cl2 and the final product was triturated from 4 mL of EtOAc with hexane to give N-{2-[5-Chloro-2-(1-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (30.6 mgs) as an off-white/grey solid. MP=170-172° C. 1H-NMR (CDCl3) δ δ 7.88 (s, 1H), 7.50-7.48 (m, 1H), 7.36-7.33 (m, 1H), 7.23 (s, 1H), 7.17-7.13 (m, 2H), 6.95-6.89 (m, 3H), 6.68 (s, 1H), 6.63 (br s, 1H), 2.71-2.68 (m, 8H), 2.50-2.47 (m, 2H), 1.63-1.55 (m, 2H), 1.42-1.38 (m, 2H); LC/MS (ESI+): 273 (M+H).
Reaction SMILES: [NH3:1].C([O:5][CH2:6][C:7]1[O:8][CH:9]=[C:10]([C:12]([O:14]C)=O)[N:11]=1)(=O)C>>[C:12]([C:10]1[N:11]=[C:7]([CH2:6][OH:5])[O:8][CH:9]=1)(=[O:14])[NH2:1]
Reactant: N
Reactant: COC(=O)c1coc(COC(C)=O)n1
Product: NC(=O)c1coc(CO)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
20 mL (352 mmol) of 28% aqueous ammonia are added to a round-bottomed flask containing 0.60 g (3.01 mmol) of methyl 2-acetoxymethyloxazole-4-carboxylate, prepared in step 5.1., and the reaction medium is then stirred at room temperature for 24 hours.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[OH-].[K+].[CH3:13][O:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[C:20]([CH3:24])[NH:21]2)=[CH:17][CH:16]=1>CS(C)=O>[CH3:13][O:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[C:20]([CH3:24])[N:21]2[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)=[CH:17][CH:16]=1
Reactant: COc1ccc2cc(C)[nH]c2c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc2cc(C)n(CCN3CCOCC3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-chloroethylmorpholine HCl (138 mg, 0.74 mmol) in 0.3 mL DMSO was added pulverized KOH (104 mg, 1.86 mmol), then after 10 min, a solution of 6-methoxy-2-methylindole (138 mg, 0.74 mmol) in 0.2 mL DMSO was added and the reaction stirred at room temperature overnight. The reaction mixture was partitioned between H2O and toluene, and the organic extract washed two times with H2O, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 10% MeOH in CH2Cl2 to give a final yield of 17 mg (0.062 mmol). 1H NMR (500 MHz, CDCl3, δ): 2.45 (s, 3H), 2.50-2.63 (m, 4H), 2.67 (t, J=7.4 Hz, 2H), 3.71-3.83 (m, 4H), 3.90 (s, 3H), 4.18 (t, J=7.4 Hz, 2H), 6.19 (s, 1H), 6.78 (dd, J=8.5 Hz, 2.2 Hz, 1H), 6.81 (s, 1H), 7.42 (d, J=8.5 Hz, 1H). 13C NMR (500 MHz, CDCl3, δ): 12.77, 40.98, 54.13, 55.92, 57.74, 66.94, 93.50, 99.82, 108.35, 120.26, 122.51, 135.31, 137.25, 155.53. MS m/z 275.3 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][O:13][C:9]=2[C:8]=1[Cl:23])C.[OH-].[Na+].Cl>C(O)C.O>[Cl:23][C:8]1[C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[C:10]=2[CH:21]=[CH:22][C:7]=1[O:6][CH2:5][C:4]([OH:24])=[O:3]
Reactant: CCOC(=O)COc1ccc2c(-c3ccc(Cl)cc3)noc2c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)COc1ccc2c(-c3ccc(Cl)cc3)noc2c1Cl
Reaction time: 0.5 h

Procedure:
A mixture of 25 g of ethyl{[7-chloro-3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate, Example 14, and 20 ml of 50% sodium hydroxide in 400 ml of ethyl alcohol is refluxed for 1 hour The hot mixture is diluted with 300 ml of water and then acidified with concentrated hydrochloric acid. The acidified mixture is stirred for 30 minutes and then filtered and the filter cake is recrystallized from a dimethylformamide-ethylacetate mixture to yield the product {[7-chloro-3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid having a melting point of 254° to 257° C.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][C:7](=[O:16])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[Si]([I:28])(C)(C)C>C(Cl)Cl>[I:28][N:6]1[C:7](=[O:16])[CH2:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: C[Si](C)(C)I
Reactant: O=C1Cc2ccccc2-c2ccccc2N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1Cc2ccccc2-c2ccccc2N1I
Temperature: 7.5 °C

Procedure:
A solution of 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.0 g, 4.77 mmol) (Example 7-A) and Et3N (2.66 ml, 19.12 mmol) were stirred for 5.0 minutes at −15° C. in CH2Cl2 and treated with TMSI (1.36 ml, 9.54 mmol). After stirring for 15 minutes 12 (1.81 g, 7.16 mmol) was added in a single portion and the reaction allowed to warm to 5-10° C. over 3 h. The reaction was quenched with sat. Na2SO3, diluted with CH2Cl2 and separated. The organics were washed with Na2SO3 and NaHSO3 and dried over MgSO4. After filtration, the organics were concentrated to approximately 20 ml and diluted with an additional 20 ml of hexanes. The title compound was isolated as a tan precipitate by filtration.