Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[C:2]1=O.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:2]1[N:3]2[C:12]3[C:7]([CH2:6][CH2:5][CH2:4]2)=[CH:8][CH:9]=[CH:10][C:11]=3[N:1]=1
Reactant: O=c1[nH]c2cccc3c2n1CCC3
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc2cccc3c2n1CCC3

Procedure:
7.6 g (0.0436 mol) of 5,6-dihydro-4H-imidazo[4,5,1-ij]quino1-2(1H)-one are heated in the presence of 70 ml of phosphoryl chloride at the reflux 20 temperature for 3 hours. The solvent is evaporated to dryness and the residue is taken up in ice. The pH of the reaction mixture is adjusted to 8 with a concentrated sodium hydroxide solution and extraction is carried out with dichloromethane. The organic phase is dried over sodium sulphate and the solvent evaporated to dryness. The residue is purified by chromatography on a column of silica gel, the eluent being an ethyl acetate/hexane (30/70) mixture. There are obtained 5.8 g of product which is used as is in the following stage.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.N1C=CC=CC=1.[C:14]([C:16]1[NH:17][CH2:18][CH2:19][NH:20][CH:21]=1)#[N:15]>>[C:5]([N:17]1[CH2:18][CH2:19][NH:20][CH:21]=[C:16]1[C:14]#[N:15])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: N#CC1=CNCCN1
Solvent: c1ccncc1
Product: CC(=O)N1CCNC=C1C#N
Temperature: 20 °C
Reaction time: 18 h

Procedure:
10.0 ml (106 mmol) of acetic anhydride and 8.0 ml (99 mmol) of pyridine were added to 5.10 g (47 mmol) of 2-cyano-1,4,5,6-tetrahydropyrazine, and the mixture was stirred at 20° C. for 18 h. After aqueous work-up, the reaction product was extracted three times with 100-200 ml of ethyl acetate each. The combined organic extracts were dried over magnesium sulphate and concentrated. The crude product was then purified by flash chromatography (silica gel 40×3 cm, ethyl acetate:hexane=4:1, Rf =0.25). the fraction having Rf =0.25 (5.82 g) was taken up in 40 ml of diethyl ether and the precipitated solid was filtered off and dried.
Reaction SMILES: C1(C([N:6]2[C:14]3[CH:13]=[C:12]([N:15]([C:21]([CH3:28])([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:22])[C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:11]=[CH:10][C:9]=3[CH:8]=[CH:7]2)=O)CC1.C(=O)([O-])[O-].[K+].[K+].CO>O>[NH:6]1[C:14]2[CH:13]=[C:12]([N:15]([C:21]([CH3:28])([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:22])[C:16]([CH:18]3[CH2:19][CH2:20]3)=[O:17])[N:11]=[CH:10][C:9]=2[CH:8]=[CH:7]1
Reactant: CC(C)(C)CC(C)(C)N(C(=O)C1CC1)c1cc2c(ccn2C(=O)C2CC2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)CC(C)(C)N(C(=O)C1CC1)c1cc2[nH]ccc2cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of N-[1-(cyclopropylcarbonyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-N-(2,4,4-trimethylpentan-2-yl)cyclopropanecarboxamide (65 mg, 0.16 mmol), potassium carbonate, methanol and water was stirred at room temperature for 20 minutes. Methanol was removed under vacuum. The residue was stirred in water for 30 minutes. The precipitated solid was filtered and dried to 47 mg (90%) N-(1H-pyrrolo[3,2-c]pyridin-6-yl)-N-(2,4,4-trimethylpentan-2-yl)cyclopropane carboxamide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([C:16]([N:18]=[S@:19]([CH2:27][C:28]([O:30]CC)=O)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:20])=[O:17])[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:33][NH2:34]>>[OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[N:14][CH:13]=[C:12]([CH:11]=2)[C:16]([N:18]=[S:19]([CH2:27][C:28]([NH:34][CH3:33])=[O:30])(=[O:20])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:17])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Reactant: CN
Product: CNC(=O)CS(=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Yield: 90.2 %

Procedure:
In a manner similar to that described for Example 471, (S)-Ethyl [N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate (50 mg, 0.11 mmol) and methylamine (2.0 M solution in MeOH, 0.5 mL, 1.0 mmol) were reacted to give the title compound as colorless oil (43 mg, 90%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5]1.[H-].[Na+].[CH3:17]I>CN(C)C=O>[OH:1][CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[N:8]([CH3:17])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5]1
Reactant: CI
Reactant: O=C1Nc2ccccc2SC1CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)C(CCO)Sc2ccccc21
Yield: 87.4 %

Procedure:
To a solution of 4.18 g of 2-(2-hydroxyethyl)-2H-1,4-benzothiazin-3(4H)-one in 50 ml of dimethylformamide, was added portionwise 0.8 g of 60% sodium hydride in oil with stirring under ice-cooling. After the mixture was stirred for 10 minutes, 1.24 ml of methyl iodide was added thereto. The temperature of the reaction system was then reverted to room temperature and the mixture was stirred for one hour. After dilution with water, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to a column chromatography on silica-gel (50 g). From the eluate with hexane-using silica-gel (50 g). From the eluate with hexane-ethyl acetate (2:1, v/v) was obtained 3.90 g (87.4%) of 2-(2-hydroxyethyl)-4-methyl-2H-1,4-benzothiazin-3(4H)-one as an oily substance.
Reaction SMILES: FC1C=C([C:8]2[C:17](N(C(C)C)C)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([O:25]C)=[O:24])[CH:14]=3)[N:9]=2)C=CC=1.CO.[OH-].[Na+]>O>[N:9]1[C:10]2[C:15](=[CH:14][C:13]([C:23]([OH:25])=[O:24])=[CH:12][CH:11]=2)[N:16]=[CH:17][CH:8]=1
Reactant: COC(=O)c1ccc2nc(-c3cccc(F)c3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nccnc2c1
Temperature: 50 °C
Reaction time: 0.13 h

Procedure:
Into a 50-mL round-bottom flask, was placed methyl 2-(3-fluorophenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (75 mg, 0.21 mmol, 1.00 equiv), methanol (15 mL), sodium hydroxide (42 mg, 1.05 mmol, 4.94 equiv), water (2 mL). The resulting solution was stirred for 2 hs at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 20 mL of H2O. The pH value of the aqueous solution was adjusted to 4-5 with aqueous hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-2): Column, SunFire Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (50% CH3CN up to 80% in 8 min, up to 100% in 1.5 min); Detector, uv 220 & 254 nm. This resulted in 20 mg (27%) of 2-(3-fluorophenyl)-3-(isopropylmethyl)amino)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[N:3]1[CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=1.[CH3:20][C:21]1[C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>>[CH3:20][C:21]1[C:22]([N:28]2[CH2:29][CH2:30][N:31]([C:14]([C:13]3[CH:12]=[CH:11][C:10]([CH2:9][N:3]4[C@H:2]([CH3:1])[CH2:6][CH2:5][S:4]4(=[O:7])=[O:8])=[CH:19][CH:18]=3)=[O:16])[CH2:32][CH2:33]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: COC(=O)c1ccc(CN2[C@H](C)CCS2(=O)=O)cc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(CN4[C@H](C)CCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 78.3 %

Procedure:
Using methyl (R)-4-(3-methyl-1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)benzoate (79 mg) described in Preparation Example 42 and 1-(3,5-dimethylpyridin-2-yl)piperazine (53 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (96 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[C:5]([NH2:21])=[C:4]([SH:22])[N:3]=1.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=O)=[CH:25][CH:24]=1>>[N:8]1([C:6]2[C:5]3[N:21]=[C:32]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)[S:22][C:4]=3[N:3]=[C:2]([NH2:1])[N:7]=2)[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N)nc(S)c2N)CC1
Product: Cc1ccc(-c2nc3c(N4CCNCC4)nc(N)nc3s2)cc1
Yield: 80 %

Procedure:
This compound was synthesized from tert-butyl 4-(2,5-diamino-6-mercaptopyrimidin-4-yl)piperazine-1-carboxylate using p-toluoyl chloride, yielding the title compound in 80% yield.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][N:3]=1.[CH3:10][Mg]Br>O1CCCC1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:9])[CH3:10])=[CH:4][N:3]=1
Reactant: C[Mg]Br
Reactant: Cc1ncc(C=O)cn1
Solvent: C1CCOC1
Product: Cc1ncc(C(C)O)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-methylpyrimidine-5-carbaldehyde (5.00 g, 38.9 mmol) in tetrahydrofuran (85 mL) was slowly added 33 μL of 1.4 M methylmagnesium bromide solution in tetrahydrofuran at 0° C. The mixture was stirred at room temperature for 1 hour and then quenched with water (50 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc/hexane) to afford a colorless oil.
Reaction SMILES: [BH3-]C#N.[Na+].Cl.[NH2:6][C:7]1[NH:11][CH:10]=[N:9][C:8]=1[C:12]([NH2:14])=[O:13].[CH2:15]([O:17][C:18]1[C:19]([CH:30]=O)=[N:20][CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][O:27][CH2:28][CH3:29])[CH3:16]>CO>[CH2:15]([O:17][C:18]1[C:19]([CH2:30][NH:6][C:7]2[N:11]=[CH:10][NH:9][C:8]=2[C:12]([NH2:14])=[O:13])=[N:20][CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][O:27][CH2:28][CH3:29])[CH3:16]
Reactant: CCOCCOc1ccnc(C=O)c1OCC
Reactant: NC(=O)c1nc[nH]c1N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOCCOc1ccnc(CNc2nc[nH]c2C(N)=O)c1OCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
NaCNBH3 (0.046 g, 0.73 mmol) was added in portions to a stirred solution of 5-amino-4-imidazolecarboxamide hydrochloride (0.150 g, 0.92 mmol) and 3-ethoxy-4-(2-ethoxyethoxy)pyridine-2-carbaldehyde (0.220 g, 0.92 mmol, obtained from Example 4(d)) in MeOH (1.5 mL) at r.t. over 10 minutes. The reaction mixture was stirred at r.t. for 2 days. The mixture was filtrated and the filtrate was evaporated in vacuo to give a crude of the title compound in quantitative yield. MS (ESI) m/z 364 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1([C:14]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=O)[CH2:13][CH2:12]1)=O.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].C(OCC)C>C1COCC1>[N:16]1([CH2:14][C:11]2([CH2:9][OH:8])[CH2:13][CH2:12]2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)C1(C(=O)N2CCCC2)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: OCC1(CN2CCCC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
Lithium aluminium hydride solution (20 mL, 1M) in THF was added slowly to a solution of 1-(pyrrolidine-1-carbonyl)-cyclopropanecarboxylic acid methyl ester (2.2 g, 11 mmol) in THF at 0° C. (ice/water), under a nitrogen atmosphere, and the resulting solution stirred for ˜3 hrs at room temperature. The solution was cooled, 0° C. (ice/water), and sodium sulphate decahydrate (4.9 g, 15 mmol) was added portion-wise to give a white suspension. Diethyl ether (25 mL) was added and the suspension stirred for ˜18 hrs. at room temperature. The resulting suspension was filtered, through celite, and the solids washed with diethyl ether (2×50 mL). The combined filtrates were concentrated to give (1-pyrrolidin-1-ylmethyl-cyclopropyl)-methanol as a pale yellow oil 1.45 g, 84%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].[C:11](OC=C)(=O)[CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Ir].[Ir].C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10][CH:11]=[CH2:12]
Reactant: OCCc1ccccc1F
Reactant: C=COC(C)=O
Agent: [Ir]
Agent: C1=C\CC/C=C\CC/1
Agent: O=C([O-])[O-]
Solvent: C1=CCCC=CCC1
Solvent: Cc1ccccc1
Product: C=COCCc1ccccc1F
Temperature: 95 °C
Yield: 72.2 %

Procedure:
Combine 2-(2-fluorophenyl)-ethanol (3.08 g, 22.0 mmol), vinyl acetate (4 mL, 43.3 mmol), anhydrous toluene (22 mL), chloro(1,5-cyclooctadiene)iridium(I) dimer (155 mg, 0.231 mmol), and anhydrous sodium carbonate (1.5 g, 14.2 mmol) in a dry round-bottom flask fitted with a reflux condensor under a nitrogen atmosphere. Heat the resulting mixture to 95° C. for 5 hours. Cool the reaction mixture to room temperature. Vacuum filter the resultant slurry to remove inorganic precipitates, washing the collected solid with hexanes. Concentrate and purify (silica gel chromatography, eluting with hexanes) to give the title compound as a yellow oil (2.64 g, 72%).
Reaction SMILES: C([CH:8]1[NH:14][CH2:13][CH2:12][S:11][C:10]2[C:15](=[O:20])[N:16]([CH3:19])[N:17]=[CH:18][C:9]1=2)C1C=CC=CC=1.P(=O)(O)(O)O.C1(O)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:19][N:16]1[C:15](=[O:20])[C:10]2[S:11][CH2:12][CH2:13][NH:14][CH2:8][C:9]=2[CH:18]=[N:17]1
Reactant: Cn1ncc2c(c1=O)SCCNC2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: Oc1ccccc1
Product: Cn1ncc2c(c1=O)SCCNC2
Temperature: 150 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
To a solution of 13.10 g (45.5 mmol) 5-benzyl-8-methyl-2,3,4,5-tetrahydro-9(8H)-pyridazino[4,5-b][1,5]thiazepinone in 116 ml of 85% phosphoric acid 5.00 g (53.0 mmol) of phenol are added and the solution is stirred for 3 hours at 150° C. After cooling the solution is poured onto 100 g of ice-water and the pH of the mixture is adjusted to neutral with 138 g of solid sodium carbonate. The precipitate is filtered and the wet filter-cake is boiled with 12×40 ml of isopropanol. The combined isopropanol solutions are evaporated. The residue is triturated with diethyl ether, filtered and washed. In this way 6.50 g (72%) of the title compound are obtained with a melting point of 254-256° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH2:9])=[CH:4][C:3]=1[Cl:20].C(=O)([O-])[OH:22].[Na+]>C1(C)C=CC=CC=1>[Cl:20][C:3]1[CH:4]=[C:5]([C:8]2([CH2:10][O:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[CH2:9][O:22]2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=C([O-])O
Reactant: C=C(COc1ccc(OC)cc1)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(OCC2(c3ccc(Cl)c(Cl)c3)CO2)cc1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
To a solution of 1,2-dichloro-4-{1-[(4-methoxyphenoxy)methyl]ethenyl}benzene (15.1 g) in toluene (161 ml) was added methachloroperbenzoic acid (21.6 g), and the mixture was stirred at 60° C. for 14 hr. The reaction mixture was cooled to 0° C., and diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The obtained extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.08 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@H:11]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:9]2([CH3:10])[C@@H:8]([OH:26])[CH2:7]1)[C:20]1[CH:19]=[CH:18][C:17]([O:24][CH3:25])=[CH:16][C:15]=1[CH2:14][CH2:13]3)=[O:5])[CH3:2].[CH2:27](Cl)[O:28][CH3:29].O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C@@H:6]1[C@H:11]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:9]2([CH3:10])[C@@H:8]([O:26][CH2:27][O:28][CH3:29])[CH2:7]1)[C:20]1[CH:19]=[CH:18][C:17]([O:24][CH3:25])=[CH:16][C:15]=1[CH2:14][CH2:13]3)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1C[C@H](O)[C@@]2(C)CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@H]12
Reactant: COCCl
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H]1C[C@H](OCOC)[C@@]2(C)CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@H]12
Yield: 86.1 %

Procedure:
A solution of 59.9 mg (0.155 mmol) of 55, 269 μL (1.55 mmol) of iPrEt2N, 118 μL (1.55 mmol) of MOMCl in anhydrous toluene (2 mL) was stirred at rt for 22 h. The reaction mixture was poured into H2O (70 mL) and extracted with CH2Cl2 (3×, 50 mL). Combined organic extracts were dried over Na2SO4 and concentrated in vacuo giving a yellow oil. Purification by flash chromatography on a 2×17 cm column of silica gel using 3:1 hexanes/EtOAc as eluent gave 53.7 mg (80%) of 56. Data for 56: TLC, T-2, Rf 0.8; 1H NMR (500 MHz, CDCl3) δ 0.85 (s, 3H, H-18), 1.29 (t, 3H, J=7.2 Hz, CH2CH3), 3.37 (s, 3H, —CH2OCH3), 3.77 (t, 1H, J=8.7 Hz, H-17α), 3.78 (s, 3H, ArOCH3), 4.20–4.14 (m, 2H, —CH2CH3), 4.66 (s, 2H, OCH2O), 6.61 (d, 1H, J=2.8 Hz, H-4), 6.71 (dd, 1H, J=8.8, 2.8 Hz, H-2), 7.21 (d, 1H, J=8.8 Hz, H-1).
Reaction SMILES: [C:1]([NH:8][C:9]1[C:14]([N+:15]([O-:17])=O)=[CH:13][C:12]([C:18]([F:21])([F:20])[F:19])=[C:11]([N:22]2[CH:26]=[CH:25][N:24]=[C:23]2[CH3:27])[CH:10]=1)([C:3]([O:5]CC)=O)=[O:2]>C(O)C.[Pd]>[OH:17][N:15]1[C:14]2[C:9](=[CH:10][C:11]([N:22]3[CH:26]=[CH:25][N:24]=[C:23]3[CH3:27])=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[NH:8][C:1](=[O:2])[C:3]1=[O:5]
Reactant: CCOC(=O)C(=O)Nc1cc(-n2ccnc2C)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1nccn1-c1cc2[nH]c(=O)c(=O)n(O)c2cc1C(F)(F)F
Yield: 59.2 %

Procedure:
A solution of 19 g crude 4-ethoxalylamino-2-(2-methyl-1H-imidazol-1-yl)-5-nitrobenzotrifluoride in 500 ml 96% ethanol was hydrogenated in a Parr hydrogenation apparatus at 28.12 kPa (40 psi) by using 2 g 5% Pd-C as a catalyst. The catalyst plus precipitated product was filtered off and washed with ethanol. The filter cake was washed several times with 1N aqueous potassium hydroxide. The combined aqueous filtrates were added 4N hydrochloric acid to pH=4 to give the title compound (9.5 g; 58%). M.p.>300° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([N:21]3[CH2:24][CH:23]([NH:25][C:26](=[O:63])[C:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH:39]([C:60]([OH:62])=[O:61])[NH:40]C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)=[CH:32][CH:31]=4)=[N:28][OH:29])[C:22]3=[O:64])[C:18]([OH:20])=[O:19])=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(O)(=O)C.C(=O)(O)[O-].[Na+]>[NH2:40][CH:39]([C:60]([OH:62])=[O:61])[CH2:38][CH2:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([C:27](=[N:28][OH:29])[C:26]([NH:25][CH:23]2[CH2:24][N:21]([CH:17]([C:14]3[CH:15]=[CH:16][C:11]([O:10][C:8](=[O:9])[CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:12][CH:13]=3)[C:18]([OH:20])=[O:19])[C:22]2=[O:64])=[O:63])=[CH:35][CH:34]=1
Reactant: O=C(Cc1ccccc1)Oc1ccc(C(C(=O)O)N2CC(NC(=O)C(=NO)c3ccc(OCCC(NC(c4ccccc4)(c4ccccc4)c4ccccc4)C(=O)O)cc3)C2=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: NC(CCOc1ccc(C(=NO)C(=O)NC2CN(C(C(=O)O)c3ccc(OC(=O)Cc4ccccc4)cc3)C2=O)cc1)C(=O)O
Reaction time: 0.75 h
Yield: 39 %

Procedure:
2-[4-(2-Phenylacetoxy)phenyl]-2-[3-[2-{4-(3-carboxy-3-tritylaminopropoxy)phenyl}-2-hydroxyiminoacetamido]-2-oxo-1-azetidinyl]acetic acid (0.5 g.) was dissolved in 80% acetic acid (10 ml.) and the mixture was stirred for 45 minutes. Insoluble materials were filtered off from the reaction mixture and the filtrate was evaporated to dryness under reduced pressure. The residue obtained was triturated with ethyl acetate to give a powder (0.27 g.). This powder (0.2 g.) was dissolved in an aqueous sodium bicarbonate and the solution was adjusted to pH 3 with 10% hydrochloric acid to give crystals of 2-[3-[2-{4-(3-amino-3-carboxypropoxy)phenyl}-2-hydroxyiminoacetamido]-2-oxo-1-azetidinyl]-2-[4-(2-phenylacetoxy)phenyl]acetic acid (0.14 g.).
Reaction SMILES: NN.[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH3:14])=[CH:8][C:7]=1[C:15]([F:18])([F:17])[F:16])([O-])=O>[Pd].C(O)C>[CH2:13]([S:12][C:9]1[CH:10]=[CH:11][C:6]([NH2:3])=[C:7]([C:15]([F:17])([F:16])[F:18])[CH:8]=1)[CH3:14]
Reactant: CCSc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: CCSc1ccc(N)c(C(F)(F)F)c1
Temperature: 50 °C

Procedure:
A solution of 64 percent aqueous hydrazine (75.6 g., 1.5 moles) is added dropwise to a warm (50° C.) stirred mixture of 2-nitro-5-ethylthiobenzotrifluoride (168.3 g, 0.67 mole) and 5 percent palladium on carbon catalyst (14.5 g) in 95 percent ethanol (1200 ml). After all of the hydrazine has been added, the reaction mixture is heated under reflux overnight. Thin layer chromatography indicates all of the nitro compound is reduced. The reaction mixture is then filtered and concentrated under reduced pressure. The residual golden colored liquid is taken up in methylene chloride and washed with water. The methylene chloride is removed by evaporation leaving the product,
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][C:9]=2[CH3:20])=[O:7])=[CH:4][CH:3]=1.[CH3:23]S(C)=O.[H-].[Na+].CI>O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH:14]([CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][C:9]=2[CH3:20])=[O:7])=[CH:4][CH:3]=1
Reactant: CS(C)=O
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCOC(=O)C(C)c1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Reaction time: 0.5 h

Procedure:
6.4 grams (0.02 mole) of ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate is dissolved in 100 ml. of dimethyl sulfoxide (DMSO) and added to a slurry of 0.48 g. (0.02 mole) of sodium hydride in approximately 30 ml. of DMSO. The mixture is stirred for 30 minutes before 2.84 g. (0.02 mole) of methyl iodide is added. Stirring is continued for 15 minutes. The reaction mixture is then poured into water, and the precipitate filtered off and recrystallized from 2-propanol to yield ethyl 5-(p-chlorobenzoyl)-1,4,α-trimethylpyrrole-2-acetate, m.p. 88-90° C.
Reaction SMILES: C1COCC1.[NH:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:7]([C:12]([OH:14])=O)[CH2:8][CH:9]([CH3:11])[CH3:10].O.[NH:23]1[CH2:37][CH2:36][CH2:35][C@H:24]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>CN(C=O)C>[NH:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:7]([C:12]([N:23]1[CH2:37][CH2:36][CH2:35][C@H:24]1[C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])=[O:14])[CH2:8][CH:9]([CH3:10])[CH3:11]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
THF (300 ml) was added to BOC-Leu-OH.H2O (149.59 g, 0.6 M). THF (150 ml) and DMF (100 ml) were added thereto to prepare a solution. Then H-Pro-OBzl (152.28 g, 0.63 M) was added thereto, and WSCI (120.8 ml, 0.66 M) was added dropwise at -10° C., and further DMF (100 ml) was added; then the mixture was stirred at room temperature overnight. After distilling off the solvent in vacuo, ethyl acetate (600 ml) was added to the residue, which was then washed three times with 5% aqueous sodium bicarbonate, twice with 1 N HCl and twice with water. The ethyl acetate layer was dried with anhydrous sodium sulfate and concentrated in vacuo. The resultant oily material was dissolved in benzene (1 l.) and concentrated in vacuo to obtain an oily substance [1].